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Top 10 Scientific Articles in the field of anaphylaxis published in 2017.

Anaphylactic Reactions After Discontinuation of Hymenoptera Venom Immunotherapy: A Clonal Mast Cell Disorder Should Be Suspected.
Bonadonna P, Zanotti R, Pagani M, Bonifacio M, Scaffidi L, Olivieri E, Franchini M, Reccardini F, Costantino MT, Roncallo C, Mauro M, Boni E, Rizzini FL, Bilò MB, Marcarelli AR, Passalacqua G.
J Allergy Clin Immunol Pract. 2018; 6:2. doi: 10.1016/j.jaip.2017.11.025. [Epub ahead of print]
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Reviewer’s Comments: The association between venom allergy and clonal mast cell disorders has consistently been described. This paper shows the importance of assessing the presence of a clonal mast cell disorder in case of elevated basal serum tryptase or a REMA score ≥ 2.

Background: Up to 75% of patients with severe anaphylactic reactions after Hymenoptera sting are at risk of further severe reactions if re-stung. Venom immunotherapy (VIT) is highly effective in protecting individuals with ascertained Hymenoptera venom allergy (HVA) and previous severe reactions. After a 3- to 5-year VIT course, most patients remain protected after VIT discontinuation. Otherwise, a lifelong treatment should be considered in high-risk patients (eg, in mastocytosis). Several case reports evidenced that patients with mastocytosis and HVA, although protected during VIT, can re-experience severe and sometimes fatal reactions after VIT discontinuation.
Objective: To evaluate whether patients who lost protection after VIT discontinuation may suffer from clonal mast cell disorders.
Methods:The survey describes the characteristics of patients who received a full course of VIT for previous severe reactions and who experienced another severe reaction at re-sting after VIT discontinuation. Those with a Red Española de Mastocitosis score of 2 or more or a serum basal tryptase level of more than 25 ng/mL underwent a hematological workup (bone marrow biopsy, KIT mutation, expression of aberrant CD25) and/or skin biopsy.
Results: Nineteen patients (mean age, 56.3 years; 89.5% males) were evaluated. All of them had received at least 4 years of VIT and were protected. After VIT discontinuation they were re-stung and developed, in all but 1 case, severe anaphylactic reactions (12 with loss of consciousness, in the absence of urticaria/angioedema). Eighteen patients (94.7%) had a clonal mast cell disorder, 8 of them with normal tryptase.
Conclusions Looking at this selected population, we suggest that mastocytosis should be considered in patients developing severe reactions at re-sting after VIT discontinuation and, as a speculation, patients with mastocytosis and HVA should be VIT-treated lifelong.


Risk factors for severe anaphylaxis in the United States.
Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL.
Ann Allergy Asthma Immunol. 2017; 119:4. doi: 10.1016/j.anai.2017.07.014.
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Reviewer’s Comments: There is an urgent need to better stratify the risk of patients with anaphylaxis. This large cohort study shows that age of 65 years or older, medication as a trigger, and presence of comorbid conditions (specifically cardiac and lung disease) were associated with significantly higher odds of severe anaphylaxis.

Background: Anaphylaxis is an acute systemic allergic reaction and may be life-threatening.
Objective: To assess risk factors associated with severe and near-fatal anaphylaxis in a large observational cohort study.
Methods: We analyzed administrative claims data from Medicare Advantage and privately insured enrollees in the United States from 2005 to 2014. Severe anaphylaxis was defined as anaphylaxis resulting in hospital or intensive care unit (ICU) admission, requiring endotracheal intubation, or meeting criteria for near-fatal anaphylaxis.
Results: Of 38,695 patients seen in the emergency department for anaphylaxis during the study period, 4,431 (11.5%) required hospitalization, 2,057 (5.3%) were admitted to the ICU, 567 (1.5%) required endotracheal intubation, and 174 (0.45%) were classified as having a near-fatal episode. Multivariable analysis revealed that medication-related anaphylaxis (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.38-1.63; P < .001), age of 65 years or older (OR, 3.15; 95% CI, 2.88-3.44; P < .001), and the presence of cardiac disease (OR, 1.56; 95% CI, 1.50-1.63; P < .001) or lung disease (OR, 1.23; 95% CI, 1.16-1.30; P < .001) were associated with increased odds of severeanaphylaxis requiring any hospital admission, ICU admission, or intubation or being a near-fatal reaction.
Conclusion: In this large contemporary cohort study, 11.6% of patients had severe anaphylaxis. Age of 65 years or older, medication as a trigger, and presence of comorbid conditions (specifically cardiac and lung disease) were associated with significantly higher odds of severe anaphylaxis. Additional studies examining risk factors for severe anaphylaxis are needed to define risk assessment strategies and establish a framework for management.


Outcomes of Emergency Department Anaphylaxis Visits from 2005 to 2014.
Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Li JT, Campbell RL.
J Allergy Clin Immunol Pract. 2017. pii: S2213-2198(17)30605-0. doi: 10.1016/j.jaip.2017.07.041. [Epub ahead of print]
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Reviewer’s Comments: This is a comprehensive epidemiologic study of anaphylaxis trends in the USA during 10 years, showing an increase in anaphylaxis-related ED visits and also in their severity.

Background: Although the incidence of anaphylaxis appears to be increasing, trends in anaphylaxis-related health care utilization are not well understood.
Objective: To better understand the potential increasing health care burden, we analyzed the changes in anaphylaxis-related health care utilization, including emergency department (ED) discharges, observation stays, inpatient admissions, intensive care unit admissions, and endotracheal intubations.
Methods: We conducted an observational study examining outcomes of anaphylaxis-related ED visits between January 1, 2005, and December 31, 2014. We analyzed administrative claims data from OptumLabs Data Warehouse, which includes more than 100 million Medicare Advantage and privately insured enrollees in the United States. We studied trends in the proportions of ED-related anaphylaxis visits based on demographic characteristics, triggers, and ED disposition for our study population.
Among 56,212 anaphylaxis-related ED visits during a 10-year period, the proportion of patient observation/inpatient admissions increased by 37.6% (P = .02), from 13.2% of anaphylaxis-related ED visits in 2005 to 18.2% in 2014. The proportion of patients admitted to the intensive care unit increased by 27.4% (P = .001), from 4.5% in 2005 to 5.8% in 2014. Proportions of endotracheal intubation increased by 145.2% (P < .001).
Conclusions: The increasing proportions of observation/inpatient admissions, intensive care unit admissions, and endotracheal intubations suggest an increase in anaphylaxis severity. Enhanced awareness of these trends among patients, practitioners, and the community is necessary to create effective strategies to prevent anaphylaxis and decrease associated adverse consequences.


Further Evaluation of Factors That May Predict Biphasic Reactions in Emergency Department Anaphylaxis Patients.
Lee S, Peterson A, Lohse CM, Hess EP, Campbell RL.
J Allergy Clin Immunol Pract. 2017; 5:5. doi: 10.1016/j.jaip.2017.07.020.
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Reviewer’s Comments: Biphasic anaphylactic reactions have been described with different prevalence in multiple studies. This study describes a frequency of 4.1% of biphasic reactions and identifies prior anaphylaxis, unknown inciting trigger, and delayed epinephrine injection as risk factors. This may render in specific management strategies in such patients, such as prolongued abservation time.

Background: Anaphylaxis is a systemic allergic reaction that is commonly treated in the emergency department (ED). The risk of a biphasic reaction is the rationale for observation.
Objective: To derive a prediction rule to stratify ED anaphylaxis patients at risk of a biphasic reaction.
Methods: We conducted an observational study of a cohort of patients presenting to an academic ED with signs and symptoms of anaphylaxis. We collected clinical data on biphasic reactions meeting National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network diagnostic criteria. Logistic regression analyses were conducted to identify predictors of biphasic reactions, and odds ratios (ORs) with 95% CIs are reported. The predictive ability of the model features is summarized using the area under a receiver operating characteristics curve, or AUC. Internally validated AUCs were obtained using bootstrap resampling.
Results: We identified 872 anaphylaxis-related visits. Thirty-six (4.1%) visits resulted in biphasic reactions. Multivariable analysis showed that prior anaphylaxis (OR, 2.74; 95% CI, 1.33-5.63), unknown inciting trigger (OR, 2.40; 95% CI, 1.14-4.99), and first epinephrine administration more than 60 minutes after symptom onset (OR, 2.29; 95% CI, 1.09-4.79) were statistically significantly associated with biphasic reactions. The AUC of this model was 0.70 (95% CI, 0.61-0.79), with an internally validated AUC of 0.67 (95% CI, 0.59-0.76). The P value from the goodness-of-fit test was .91.
Conclusions: Our study demonstrated a 4.1% rate of biphasic reactions and found that prior anaphylaxis, unknown inciting trigger, and delayed epinephrine use were risk factors for biphasic reactions.


Safety of Adrenaline Use in Anaphylaxis: A Multicentre Register.
Cardona V, Ferré-Ybarz L, Guilarte M, Moreno-Pérez N, Gómez-Galán C, Alcoceba-Borràs E, Delavalle MB, Garriga-Baraut T; AdreSCAIC Research Group.
Int Arch Allergy Immunol. 2017; 173:3. doi: 10.1159/000477566. Epub 2017 Aug 9.
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Reviewer’s Comments: The objective of this study was to assess the risk associated with the use of epinephrine in anaphylaxis and debunk the gereneralized perception of frequent and severe side effects which may preclude the optimal use of this first line treatment.

Background: The use of intramuscular adrenaline to treat anaphylaxis is suboptimal, despite being the first-line treatment recommended by national and international anaphylaxis guidelines. Fear of potentially severe side effects may be one of the underlying factors. The aim of this study was to assess the incidence and severity of adverse side effects after the use of adrenaline in anaphylaxis, as well as potential risk factors.
Methods: Observational study based on a multicenter online registry of cases of adrenaline administration for suspected anaphylaxis.
Results: 277 registered valid cases were included: 138 (51.49%) female, median age 29 years (12-47), and 6 children under 2 years with a median age of 9 months (1-21). Side effects occurred in 58 cases (21.64%), with tremors, palpitations, and anxiety being the most frequent. There was a significant association of developing side effects with older age, higher dose of adrenaline, or use of the intravenous route. Potentially severe adverse effects (high blood pressure, chest discomfort, or ECG alterations) occurred only in 8 cases (2.99%); in these cases, no differences were found according to age or adrenaline dose, but again, intravenous administration was associated with more severe adverse events.
Conclusion: This study shows that side effects affect less than 1 in 5 patients who receive adrenaline for an anaphylactic reaction, and are usually mild and transient. Therefore, in an emergency situation such as anaphylaxis, restricting adrenaline administration due to potential adverse effects would, in general, not be justified.


Patterns of anaphylaxis after diagnostic workup: A follow-up study of 226 patients with suspected anaphylaxis.
Oropeza AR, Bindslev-Jensen C, Broesby-Olsen S, Kristensen T, Møller MB, Vestergaard H, Kjaer HF, Halken S, Lassen A, Mortz CG.
Allergy. 2017; 72:12. doi: 10.1111/all.13207. Epub 2017 Jun 20.
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Reviewer’s Comments: This interesting study highlights the importance of considering the assessment of a potential mast cell disorder and the role of cofactors in all anaphylactic reactions.

Background: Most published studies on anaphylaxis are retrospective or register based. Data on subsequent diagnostic workup are sparse. We aimed to characterize patients seen with suspected anaphylaxis at the emergency care setting (ECS), after subsequent diagnostic workup at our Allergy Center (AC).
Methods: Prospective study including patients from the ECS, Odense University Hospital, during May 2013-April 2014. Possible anaphylaxis cases were daily identified based on a broad search profile including history and symptoms in patient records, diagnostic codes and pharmacological treatments. At the AC, all patients were evaluated according to international guidelines.
Results: Among 226 patients with suspected anaphylaxis, the diagnosis was confirmed in 124 (54.9%) after diagnostic workup; 118 of the 124 fulfilled WAO/EAACI criteria of anaphylaxis at the ECS, while six were found among 46 patients with clinical suspicion but not fulfilling the WAO/EAACI criteria at the ECS. The estimated incidence rate of anaphylaxis was 26 cases per 100 000 person-years and the one-year period prevalence was 0.04%. The most common elicitor was drugs (41.1%) followed by venom (27.4%) and food (20.6%). In 13 patients(10.5%), no elicitor could be identified. Mastocytosis was diagnosed in 7.7% of adult patients and was significantly associated with severe anaphylaxis. Atopic diseases were significantly associated only with food-induced anaphylaxis. Cofactors were present in 58.1% and were significantly associated with severe anaphylaxis.
Conclusion: A broad search profile in the ECS and subsequent diagnostic workup is important for identification and classification of patients with anaphylaxis. Evaluation of comorbidities and cofactors is important.


In-flight allergic emergencies.
Sánchez-Borges M, Cardona V, Worm M, Lockey RF, Sheikh A, Greenberger PA, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fineman S, Geller M, Gonzalez-Estrada A, Tanno L, Thong BY; WAO Anaphylaxis Committee.
World Allergy Organ J. 2017; 10(1):15. doi: 10.1186/s40413-017-0148-1. eCollection 2017.
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Reviewer’s Comments: At a time when air-travel is continuingly increasing, together with the high prevalence of allergies and asthma, reactions during flihghts are expected to rise. Therefore there is a need to address this topic in order to ensure an optimal prevention and management, as reviewed in this paper.

Abstract: Allergic and hypersensitivity reactions such as anaphylaxis and asthma exacerbations may occur during air travel. Although the exact incidence of in-flight asthma and allergic emergencies is not known, we have concerns that this subject has not received the attention it warrants. There is a need to provide passengers at risk and airlines with the necessary measures to prevent and manage these emergencies. A review of the epidemiology, management and approaches to prevention of allergic and asthma emergencies during air travel is presented with the goal of increasing awareness about these important, potentially preventable medical events.


Serum levels of 9α,11β-PGF2 and apolipoprotein A1 achieve high predictive power as biomarkers of anaphylaxis.
Wittenberg M, Nassiri M, Francuzik W, Lehmann K, Babina M, Worm M.
Allergy. 2017; 72:11. doi: 10.1111/all.13176. Epub 2017 May 10.
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Reviewer’s Comments: There is an urgent need to find optimal biomarkers of anaphylaxis, both for research and for diagnosis. This paper describes ApoA1 combined with 9α,11ß-PGF2 as a candidate which merits further investigation.

Abstract: Anaphylaxis is a life-threatening hypersensitivity reaction. To identify biomarkers for the condition, we assessed serum levels of apolipoprotein (Apo)A and ApoE. We found a reduction of both lipoproteins in anaphylactic mice as well as in orally challenged food allergic patients. We then compared patients after acute anaphylaxis with several control groups (nonallergic, history of allergen-triggered anaphylaxis, acute cardiovascular/febrile reactions). In this unpaired setting, ApoE levels were unaltered, while ApoA1 was reduced in the anaphylactic group. Although unable to discriminate between anaphylaxis and cardiovascular/febrile reactions, ROC curve analysis revealed a reasonably high area under the curve (AUC) of 0.91 for ApoA1. Serum 9α,11ß-PGF2 , recently identified as a suitable biomarker for anaphylaxis, outperformed ApoA1 with AUC=0.95. Intriguingly however its power further increased upon combination of both mediators reaching AUC=1. Our data suggest that ApoA1 combined with 9α,11ß-PGF2 represents a useful composite biomarker of anaphylaxis, achieving superior diagnostic power over either factor alone.


Impact of school peanut-free policies on epinephrine administration.
Bartnikas LM, Huffaker MF, Sheehan WJ, Kanchongkittiphon W, Petty CR, Leibowitz R, Hauptman M, Young MC, Phipatanakul W.
J Allergy Clin Immunol. 2017; 140:2. doi: 10.1016/j.jaci.2017.01.040. Epub 2017 Mar 25.
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Reviewer’s Comments: The application of prevention policies of food allergy in public spaces should be based in solid evidence, in order to maximize cost-effectiveness. This paper describes different outcomes in shools restricting peanuts from home, served in schools, or having peanut-free classrooms to those with peanut-free tables.

Background: Children with food allergies spend a large proportion of time in school but characteristics of allergic reactions in schools are not well studied. Some schools self-designate as peanut-free or have peanut-free areas, but the impact of policies on clinical outcomes has not been evaluated.
Objective: We sought to determine the effect of peanut-free policies on rates of epinephrine administration for allergic reactions in Massachusetts public schools.
Methods: In this retrospective study, we analyzed (1) rates of epinephrine administration in all Massachusetts public schools and (2) Massachusetts public school nurse survey reports of school peanut-free policies from 2006 to 2011 and whether schools self-designated as "peanut-free" based on policies. Rates of epinephrine administration were compared for schools with or without peanut-restrictive policies.
Results: The percentage of schools with peanut-restrictive policies did not change significantly in the study time frame. There was variability in policies used by schools self-designated as peanut-free. No policy was associated with complete absence of allergic reactions. Both self-designated peanut-free schools and schools banning peanuts from being served in school or brought from home reported allergic reactions to nuts. Policies restricting peanuts from home, served in schools, or having peanut-free classrooms did not affect epinephrine administration rates. Schools with peanut-free tables, compared to without, had lower rates of epinephrine administration (incidence rate per 10,000 students 0.2 and 0.6, respectively, P = .009).
Conclusions: These data provide a basis for evidence-based school policies for children with food allergies. Further studies are required before decisions can be made regarding peanut-free policies in schools.


Trends, characteristics, and incidence of anaphylaxis in 2001-2010: A population-based study.
Lee S, Hess EP, Lohse C, Gilani W, Chamberlain AM, Campbell RL.
J Allergy Clin Immunol. 2017; 139:1. doi: 10.1016/j.jaci.2016.04.029. Epub 2016 Jun 4.
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Reviewer’s Comments: This is a population based epidemiological study on the prevalence of anaphylaxis in Olmsted County, Minnesota, describing an overall age- and sex-adjusted incidence rate was 42 (95% CI, 38.7-45.3) per 100,000 person-years. Also, it shows a progressive increase in incidence rates through the 10 year study period.

Background: Anaphylaxis is a potentially life-threatening systemic allergic reaction.
Objective: We aimed to determine the incidence rate and causes of anaphylaxis during a 10-year period in Olmsted County, Minnesota.
Methods: Using the resources of the Rochester Epidemiology Project, a comprehensive records linkage system, we performed a population-based incidence study in Olmsted County, Minnesota, from 2001 through 2010. All cases with a diagnosis of anaphylactic shock and 20% of cases with related diagnoses were manually reviewed. The relationships of age group, sex, and year of anaphylaxis with incidence rates were assessed by fitting Poisson regression models.
Results: Six hundred thirty-one cases of anaphylaxis were identified. The median age was 31 years (interquartile range, 19-44 years). The overall age- and sex-adjusted incidence rate was 42 (95% CI, 38.7-45.3) per 100,000 person-years. There was a significant increase in the overall incidence of anaphylaxis during the study period, with an average increase of 4.3% per year (P < .001). In addition, there was a 9.8% increase per year in the incidence rate of food-related anaphylaxis. Food-related anaphylaxis was most common in children aged 0 to 9 years, venom-related anaphylaxis was most common in those 20 to 39 years of age, and medication-related anaphylaxis was most common in those 30 to 39 years of age.
Conclusion: The overall incidence rate of anaphylaxis was 42 per 100,000 person-years from 2001-2010 in Olmsted County, Minnesota. The incidence of anaphylaxis increased over time, and several inciting triggers were uniquely associated with different age groups.

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