今日の臨床サポート

アナフィラキシー

著者: 永井秀哉 福井県立病院 救命救急センター

監修: 林寛之 福井大学医学部附属病院

著者校正/監修レビュー済:2022/03/16
参考ガイドライン:
  1. 日本アレルギー学会アナフィラキシーガイドライン第1版(2014)
  1. 世界アレルギー機構(WAO):World Allergy Organization guidelines for the assessment and management of anaphylaxis(2011)
  1. Cardona V. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J.2020 Oct 30;13(10):100472. PMID: 33204386
患者向け説明資料

概要・推奨   

  1. アナフィラキシーは「急速に発症した重度の全身性アレルギー反応で、死に至る危険があるもの」と定義される。
  1. 皮膚粘膜症状に加えて呼吸・循環・消化器症状がある場合、原因不明のショックや呼吸困難をみた場合には、必ずアナフィラキシーを鑑別に入れる。
  1. アナフィラキシーの初期診療では、早期治療に寄与する有用な検査はなく、経過と症状から臨床診断することが重要である(推奨度1)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. H1受容体拮抗薬は、呼吸・循環の安定化を図るための初期治療としては勧められない(推奨度3)
  1. H2受容体拮抗薬は、呼吸・循環の安定化を図るための初期治療としては勧められない。アドレナリンの投与でも喘鳴、皮膚症状が改善しない場合に、投与してもよい。H1受容体拮抗薬と併用することが望ましい(推奨度3)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
永井秀哉 : 特に申告事項無し[2022年]
監修:林寛之 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 世界アレルギー機構(WAO)が2011年に採用した診断基準が、2020年のガイダンスで改訂された。
  1. 遅発型アナフィラキシー(α-Gal症候群、PGA)について、食物アレルギーの項に記載を追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
アナフィラキシー全般:
  1. アナフィラキシーは「急速に発症した重度の全身性アレルギー反応で、死に至る危険があるもの」と定義される[1][2]。そのうち、血圧低下等の循環障害を伴うものをアナフィラキシーショックと呼ぶ。
  1. 刺激された肥満細胞と好塩基球から放出されたメディエーターが全身に作用する。
  1. 全人口の0.05~2%がアナフィラキシーを発症する。
  1. 全年齢で発症の可能性がある。平均発症年齢20~30歳代で、19歳未満で最も発症率が高い。アナフィラキシーの発症は増加傾向にあり、特に若年者での増加が目立つ[3]
  1. 日本ではアナフィラキシーの既往を有する児童・生徒の割合は、小学生0.6%、中学生0.4%、高校生0.3%である(平成25年度文部科学省:学校生活における健康管理に関する調査)。
 
時間経過: 
  1. 急性期症状:
  1. アレルゲンへの曝露後、数秒~2時間(通常は5~30分)で発症する。まれには数時間後に発症することもある。
  1. 無治療でも数時間かけて自然軽快することが多い(が、それを期待して治療を控えてはならない)。
  1. 二相性反応:
  1. 急性期症状が治まった後、発症から1~72時間(多くは8~10時間)後に起こる症状の再燃を指す。
  1. 初期治療薬剤の効果切れ、不十分な治療、アレルゲンの再吸収、遅発型のIgE反応など、複数の機序が関与すると考えられている。
  1. アナフィラキシー全体の1~23%にみられるとされるが、2010年以降は0~6%の報告が多い。多くはアナフィラキシーに至らない軽症で、蕁麻疹がみられる程度であるが、まれに重症である場合もある[4]
  1. 二相性反応のリスク因子:初回反応が重症(オッズ比 2.11; 95%CI 1.23-3.61)、2回以上のアドレナリン投与(オッズ比 4.82; 95%CI 2.70-8.58)、脈圧上昇(オッズ比 2.11; 95%CI 1.32-3.37)、アレルゲン未特定(オッズ比 1.63; 95%CI 1.14-2.33)、皮膚症状(オッズ比 2.54; 95%CI 1.25-5.15)、小児で薬剤性(オッズ比 2.35; 95%CI 1.16-4.76)で、呼吸困難はリスクを下げる(オッズ比 0.6; 95%CI 0.38-0.96-3.61)[5]
  1. 遷延性反応:
  1. 急性期症状が32時間まで持続する例も報告されており、遷延性反応と呼ばれる[3]が、その定義は曖昧である。
 
問診・診察のポイント  
診察:
  1. 気道、呼吸、循環の評価を優先し、意識状態、皮膚粘膜所見、腹部所見を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Joshua A Boyce, Amal Assa'ad, A Wesley Burks, Stacie M Jones, Hugh A Sampson, Robert A Wood, Marshall Plaut, Susan F Cooper, Matthew J Fenton, S Hasan Arshad, Sami L Bahna, Lisa A Beck, Carol Byrd-Bredbenner, Carlos A Camargo, Lawrence Eichenfield, Glenn T Furuta, Jon M Hanifin, Carol Jones, Monica Kraft, Bruce D Levy, Phil Lieberman, Stefano Luccioli, Kathleen M McCall, Lynda C Schneider, Ronald A Simon, F Estelle R Simons, Stephen J Teach, Barbara P Yawn, Julie M Schwaninger, NIAID-Sponsored Expert Panel
Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report.
J Allergy Clin Immunol. 2010 Dec;126(6):1105-18. doi: 10.1016/j.jaci.2010.10.008.
Abstract/Text
PMID 21134568
Jasmeet Soar, Richard Pumphrey, Andrew Cant, Sue Clarke, Allison Corbett, Peter Dawson, Pamela Ewan, Bernard Foëx, David Gabbott, Matt Griffiths, Judith Hall, Nigel Harper, Fiona Jewkes, Ian Maconochie, Sarah Mitchell, Shuaib Nasser, Jerry Nolan, George Rylance, Aziz Sheikh, David Joseph Unsworth, David Warrell, Working Group of the Resuscitation Council (UK)
Emergency treatment of anaphylactic reactions--guidelines for healthcare providers.
Resuscitation. 2008 May;77(2):157-69. doi: 10.1016/j.resuscitation.2008.02.001. Epub 2008 Mar 20.
Abstract/Text *The UK incidence of anaphylactic reactions is increasing. *Patients who have an anaphylactic reaction have life-threatening airway and, or breathing and, or circulation problems usually associated with skin or mucosal changes. *Patients having an anaphylactic reaction should be treated using the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach. *Anaphylactic reactions are not easy to study with randomised controlled trials. There are, however, systematic reviews of the available evidence and a wealth of clinical experience to help formulate guidelines. *The exact treatment will depend on the patient's location, the equipment and drugs available, and the skills of those treating the anaphylactic reaction. *Early treatment with intramuscular adrenaline is the treatment of choice for patients having an anaphylactic reaction. *Despite previous guidelines, there is still confusion about the indications, dose and route of adrenaline. *Intravenous adrenaline must only be used in certain specialist settings and only by those skilled and experienced in its use. *All those who are suspected of having had an anaphylactic reaction should be referred to a specialist in allergy. *Individuals who are at high risk of an anaphylactic reaction should carry an adrenaline auto-injector and receive training and support in its use. *There is a need for further research about the diagnosis, treatment and prevention of anaphylactic reactions.

PMID 18358585
Phillip Lieberman, Richard A Nicklas, John Oppenheimer, Stephen F Kemp, David M Lang, David I Bernstein, Jonathan A Bernstein, A Wesley Burks, Anna M Feldweg, Jordan N Fink, Paul A Greenberger, David B K Golden, John M James, Stephen F Kemp, Dennis K Ledford, Phillip Lieberman, Albert L Sheffer, David I Bernstein, Joann Blessing-Moore, Linda Cox, David A Khan, David Lang, Richard A Nicklas, John Oppenheimer, Jay M Portnoy, Christopher Randolph, Diane E Schuller, Sheldon L Spector, Stephen Tilles, Dana Wallace
The diagnosis and management of anaphylaxis practice parameter: 2010 update.
J Allergy Clin Immunol. 2010 Sep;126(3):477-80.e1-42. doi: 10.1016/j.jaci.2010.06.022. Epub 2010 Aug 7.
Abstract/Text These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, or the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
PMID 20692689
Brian E Grunau, Jennifer Li, Tae Won Yi, Robert Stenstrom, Eric Grafstein, Matthew O Wiens, R Robert Schellenberg, Frank Xavier Scheuermeyer
Incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis.
Ann Emerg Med. 2014 Jun;63(6):736-44.e2. doi: 10.1016/j.annemergmed.2013.10.017. Epub 2013 Nov 13.
Abstract/Text STUDY OBJECTIVE: Allergic reactions are common presentations to the emergency department (ED). An unknown proportion of patients will develop biphasic reactions, and patients are often monitored for prolonged periods to manage potential reactions. We seek to determine the incidence of clinically important biphasic reactions.
METHODS: Consecutive adult patients presenting to 2 urban EDs with allergic reactions during a 5-year period were identified. Encounters were dichotomized as "anaphylaxis" or "allergic reaction" with an explicit algorithm. A comprehensive chart review was conducted on each index and all subsequent visits to detail patient presentations, comorbidities, ED management, and predefined clinically important biphasic reactions. Regional and provincial databases were linked to identify subsequent ED visits and deaths within a 7-day period. The primary outcome was the proportion of patients with a clinically important biphasic reaction, and the secondary outcome was mortality.
RESULTS: Of 428,634 ED visits, 2,819 (0.66%) encounters were reviewed (496 anaphylactic and 2,323 allergic reactions). Overall, 185 patients had at least 1 subsequent visit for allergic symptoms. Five clinically important biphasic reactions were identified (0.18%; 95% confidence interval [CI] 0.07% to 0.44%), with 2 occurring during the ED visit and 3 postdischarge. There were no fatalities (95% CI 0% to 0.17%). In the anaphylaxis and allergic reaction groups, clinically important biphasic reactions occurred in 2 patients (0.40%; 95% CI 0.07% to 1.6%) and 3 patients (0.13%; 95% CI 0.03% to 0.41%), respectively.
CONCLUSION: Among ED patients with allergic reactions or anaphylaxis, clinically important biphasic reactions and fatalities are rare. Our data suggest that prolonged routine monitoring of patients whose symptoms have resolved is likely unnecessary for patient safety.

Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.
PMID 24239340
Marcus S Shaker, Dana V Wallace, David B K Golden, John Oppenheimer, Jonathan A Bernstein, Ronna L Campbell, Chitra Dinakar, Anne Ellis, Matthew Greenhawt, David A Khan, David M Lang, Eddy S Lang, Jay A Lieberman, Jay Portnoy, Matthew A Rank, David R Stukus, Julie Wang, Collaborators, Natalie Riblet, Aiyana M P Bobrownicki, Teresa Bontrager, Jarrod Dusin, Jennifer Foley, Becky Frederick, Eyitemi Fregene, Sage Hellerstedt, Ferdaus Hassan, Kori Hess, Caroline Horner, Kelly Huntington, Poojita Kasireddy, David Keeler, Bertha Kim, Phil Lieberman, Erin Lindhorst, Fiona McEnany, Jennifer Milbank, Helen Murphy, Oriana Pando, Ami K Patel, Nicole Ratliff, Robert Rhodes, Kim Robertson, Hope Scott, Audrey Snell, Rhonda Sullivan, Varahi Trivedi, Azadeh Wickham, Chief Editors, Marcus S Shaker, Dana V Wallace, Workgroup Contributors, Marcus S Shaker, Dana V Wallace, Jonathan A Bernstein, Ronna L Campbell, Chitra Dinakar, Anne Ellis, David B K Golden, Matthew Greenhawt, Jay A Lieberman, Matthew A Rank, David R Stukus, Julie Wang, Joint Task Force on Practice Parameters Reviewers, Marcus S Shaker, Dana V Wallace, David B K Golden, Jonathan A Bernstein, Chitra Dinakar, Anne Ellis, Matthew Greenhawt, Caroline Horner, David A Khan, Jay A Lieberman, John Oppenheimer, Matthew A Rank, Marcus S Shaker, David R Stukus, Julie Wang
Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.
J Allergy Clin Immunol. 2020 Apr;145(4):1082-1123. doi: 10.1016/j.jaci.2020.01.017. Epub 2020 Jan 28.
Abstract/Text Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
PMID 32001253
F Estelle R Simons, Ledit R F Ardusso, M Beatrice Bilò, Yehia M El-Gamal, Dennis K Ledford, Johannes Ring, Mario Sanchez-Borges, Gian Enrico Senna, Aziz Sheikh, Bernard Y Thong, World Allergy Organization
World Allergy Organization anaphylaxis guidelines: summary.
J Allergy Clin Immunol. 2011 Mar;127(3):587-93.e1-22. doi: 10.1016/j.jaci.2011.01.038.
Abstract/Text
PMID 21377030
Victoria Cardona, Ignacio J Ansotegui, Motohiro Ebisawa, Yehia El-Gamal, Montserrat Fernandez Rivas, Stanley Fineman, Mario Geller, Alexei Gonzalez-Estrada, Paul A Greenberger, Mario Sanchez Borges, Gianenrico Senna, Aziz Sheikh, Luciana Kase Tanno, Bernard Y Thong, Paul J Turner, Margitta Worm
World allergy organization anaphylaxis guidance 2020.
World Allergy Organ J. 2020 Oct;13(10):100472. doi: 10.1016/j.waojou.2020.100472. Epub 2020 Oct 30.
Abstract/Text Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions. The occurrence of anaphylaxis has increased in recent years, and subsequently, there is a need to continue disseminating knowledge on the diagnosis and management, so every healthcare professional is prepared to deal with such emergencies. The rationale of this updated position document is the need to keep guidance aligned with the current state of the art of knowledge in anaphylaxis management. The World Allergy Organization (WAO) anaphylaxis guidelines were published in 2011, and the current guidance adopts their major indications, incorporating some novel changes. Intramuscular epinephrine (adrenaline) continues to be the first-line treatment for anaphylaxis. Nevertheless, its use remains suboptimal. After an anaphylaxis occurrence, patients should be referred to a specialist to assess the potential cause and to be educated on prevention of recurrences and self-management. The limited availability of epinephrine auto-injectors remains a major problem in many countries, as well as their affordability for some patients.

© 2020 The Author(s).
PMID 33204386
Hugh A Sampson, Anne Muñoz-Furlong, Ronna L Campbell, N Franklin Adkinson, S Allan Bock, Amy Branum, Simon G A Brown, Carlos A Camargo, Rita Cydulka, Stephen J Galli, Jane Gidudu, Rebecca S Gruchalla, Allen D Harlor, David L Hepner, Lawrence M Lewis, Phillip L Lieberman, Dean D Metcalfe, Robert O'Connor, Antonella Muraro, Amanda Rudman, Cara Schmitt, Debra Scherrer, F Estelle R Simons, Stephen Thomas, Joseph P Wood, Wyatt W Decker
Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
J Allergy Clin Immunol. 2006 Feb;117(2):391-7. doi: 10.1016/j.jaci.2005.12.1303.
Abstract/Text There is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis. In July 2005, the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network convened a second meeting on anaphylaxis, which included representatives from 16 different organizations or government bodies, including representatives from North America, Europe, and Australia, to continue working toward a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, further review the evidence on the most appropriate management of anaphylaxis, and outline the research needs in this area.

PMID 16461139
Ronna L Campbell, John B Hagan, Veena Manivannan, Wyatt W Decker, Abhijit R Kanthala, Maria Fernanda Bellolio, Vernon D Smith, James T C Li
Evaluation of national institute of allergy and infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients.
J Allergy Clin Immunol. 2012 Mar;129(3):748-52. doi: 10.1016/j.jaci.2011.09.030. Epub 2011 Nov 1.
Abstract/Text BACKGROUND: Diagnostic criteria were proposed at the Second Symposium on the Definition and Management of Anaphylaxis convened by the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN). Validation is needed before these criteria can be widely adapted into clinical practice.
OBJECTIVE: Our aim was to retrospectively assess the diagnostic accuracy of the NIAID/FAAN criteria for the diagnosis of anaphylaxis in emergency department (ED) patients.
METHODS: A retrospective cohort study of ED patients presenting from April to October 2008 was conducted. Patients given a diagnosis of an allergic reaction or anaphylaxis and a subset of patients with related diagnoses were included. Electronic medical records were reviewed and data were abstracted to determine whether the NIAID/FAAN criteria were met. Records were also independently reviewed in a blinded fashion by 2 experienced attending allergists. Final diagnosis by allergists was considered the reference standard.
RESULTS: Of 214 patients, 86 (40.2%) met the NIAID/FAAN criteria for anaphylaxis. Allergists gave 61 (28.5%) patients diagnoses of anaphylaxis, 59 (96.7%) of whom satisfied the NIAID/FAAN criteria. The interrater agreement between allergists was substantial (κ = 0.77). The test characteristics of the NIAID/FAAN criteria were as follows: sensitivity, 96.7% (95% CI, 88.8% to 99.1%); specificity, 82.4% (95% CI, 75.5% to 87.6%); positive predictive value, 68.6% (95% CI, 58.2% to 77.4%); negative predictive value, 98.4% (95% CI, 94.5% to 99.6%); positive likelihood ratio, 5.48; and negative likelihood ratio, 0.04.
CONCLUSIONS: These results suggest that the NIAID/FAAN criteria are highly sensitive but less specific and are likely to be useful in the ED for the diagnosis of anaphylaxis.

Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
PMID 22051698
Nicholas G Kounis, George D Soufras, George Hahalis
Anaphylactic Shock: Kounis Hypersensitivity-Associated Syndrome Seems to be the Primary Cause.
N Am J Med Sci. 2013 Nov;5(11):631-6. doi: 10.4103/1947-2714.122304.
Abstract/Text Experiments have shown that anaphylaxis decreases cardiac output; increases left ventricular end diastolic pressure; induces severe early acute increase in respiratory resistance with pulmonary interstitial edema; and decreases splanchnic, cerebral, and myocardial blood flow more than what would be expected from severe arterial dilation and hypotension. This is attributed to the constrictive action of inflammatory mediators released during anaphylactic shock. Inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet-activating factor (PAF), and a variety of cytokines and chemokines constitute the pathophysiologic basis of Kounis hypersensitivity-associated acute coronary syndrome. Although the mechanisms of anaphylactic shock still remain to be elucidated, myocardial involvement due to vasospasm-induced coronary blood flow reduction manifesting as Kounis syndrome should be always considered. Searching current experimental and clinical literature on anaphylactic shock pathophysiology, causality, clinical appearance, and treatment via PubMed showed that differentiating global hypoperfusion from primary tissue suppression due to mast cell mediator constrictive action on systemic arterial vasculature is a challenging procedure. Combined tissue suppression from arterial involvement and peripheral vasodilatation, perhaps, occur simultaneously. In cases of anaphylactic shock treatment targeting the primary cause of anaphylaxis together with protection of coronary vasculature and subsequently the cardiac tissue seems to be of paramount importance.

PMID 24404540
Filippo Fassio, Laura Losappio, Dario Antolin-Amerigo, Silvia Peveri, Gianni Pala, Donatella Preziosi, Ilaria Massaro, Gabriele Giuliani, Chiara Gasperini, Marco Caminati, Enrico Heffler
Kounis syndrome: A concise review with focus on management.
Eur J Intern Med. 2016 May;30:7-10. doi: 10.1016/j.ejim.2015.12.004. Epub 2016 Jan 12.
Abstract/Text Kounis syndrome is defined as the co-incidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergenic event and was first described by Kounis and Zavras in 1991 as an allergic angina syndrome. Multiple causes have been described and most of the data in the literature are derived from the description of clinical cases - mostly in adult patients - and the pathophysiology remains only partly explained. Three different variants of Kounis syndrome have been defined: type I (without coronary disease) is defined as chest pain during an acute allergic reaction in patients without risk factors or coronary lesions in which the allergic event induces coronary spasm that electrocardiographic changes secondary to ischemia; type II (with coronary disease) includes patients with pre-existing atheromatous disease, either previously quiescent or symptomatic, in whom acute hypersensitive reactions cause plaque erosion or rupture, culminating in acute myocardial infarction; more recently a type-III variant of Kounis syndrome has been defined in patients with preexisting coronary disease and drug eluting coronary stent thrombosis. The pathogenesis of the syndrome is discussed, and a therapeutic algorithm is proposed.

Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
PMID 26795552
Sangil Lee, Erik P Hess, David M Nestler, Venkatesh R Bellamkonda Athmaram, M Fernanda Bellolio, Wyatt W Decker, James T C Li, John B Hagan, Veena Manivannan, Samuel C Vukov, Ronna L Campbell
Antihypertensive medication use is associated with increased organ system involvement and hospitalization in emergency department patients with anaphylaxis.
J Allergy Clin Immunol. 2013 Apr;131(4):1103-8. doi: 10.1016/j.jaci.2013.01.011. Epub 2013 Feb 27.
Abstract/Text BACKGROUND: Risk factors for increased anaphylaxis severity are poorly understood. Angiotensin-converting enzyme (ACE) inhibitors have been associated with severe anaphylactic reactions in patients with hymenoptera venom allergy. Studies evaluating the association between beta-blockers and severe anaphylaxis have been conflicting.
OBJECTIVE: To evaluate the association between antihypertensive medication use and increased anaphylaxis severity.
METHODS: We included emergency department anaphylaxis patients aged 18 years and older. Markers of severe anaphylaxis were defined as (1) syncope, hypotension, or hypoxia; (2) signs and symptoms involving 3 or more organ systems; and (3) hospitalization. Antihypertensive medications evaluated included beta-blockers, ACE inhibitors, calcium channel blockers, angiotensin receptor blockers, and diuretics. Simple and multiple logistic regression analyses were conducted to estimate the association between antihypertensive medication use and markers of increased anaphylaxis severity.
RESULTS: Among 302 patients with anaphylaxis, 55 (18%) had syncope, hypoxia, or hypotension, 57 (19%) required hospitalization, and 139 (46%) had 3 or more organ system involvement. After adjusting for age, gender, suspected trigger, and preexisting lung disease, beta-blocker, ACE-inhibitor, diuretic, or antihypertensive medication use in aggregate remained associated with both 3 or more organ system involvement and need for hospital admission. The adjusted associations between antihypertensive medication use in aggregate and 3 or more organ system involvement yielded an odds ratio of 2.8 (95% CI, 1.5-5.2; P=.0008) and with hospitalization an odds ratio of 4.0 (95% CI, 1.9-8.4; P=.0001).
CONCLUSIONS: In emergency department anaphylaxis patients, antihypertensive medication use is associated with increased organ system involvement and increased odds of hospital admission, independent of age, gender, suspected trigger, or preexisting lung disease.

Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
PMID 23453138
D A Moneret-Vautrin, M Morisset, J Flabbee, E Beaudouin, G Kanny
Epidemiology of life-threatening and lethal anaphylaxis: a review.
Allergy. 2005 Apr;60(4):443-51. doi: 10.1111/j.1398-9995.2005.00785.x.
Abstract/Text Severe anaphylaxis is a systemic reaction affecting two or more organs or systems and is due to the release of active mediators from mast cells and basophils. A four-grade classification routinely places 'severe' anaphylaxis in grades 3 and 4 (death could be graded as grade 5). Studies are underway to determine the prevalence of severe and lethal anaphylaxis in different populations and the relative frequencies of food, drug, latex and Hymenoptera anaphylaxis. These studies will also analyse the risk arising from the lack of preventive measures applied in schools (personalized management protocols) and from the insufficient use of self-injected adrenalin. Allergy-related conditions may account for 0.2-1% of emergency consultations. Severe anaphylaxis affects 1-3 per 10 000 people, but for the United States and Australia figures are even higher. It is estimated to cause death in 0.65-2% of patients, i.e. 1-3 per million people. An increased prevalence has been revealed by monitoring hospitalized populations by reference to the international classification of disease (ICD) codes. The relative frequency of aetiological factors of allergy (food, drugs, insects and latex) varies in different studies. Food, drug and Hymenoptera allergies are potentially lethal. The risk of food-mediated anaphylaxis can be assessed from the number of personalized management protocols in French schools: 0.065%. Another means of assessment may be the rate of adrenalin prescriptions. However, an overestimation of the anaphylaxis risk may result from this method (0.95% of Canadian children). Data from the literature leads to several possibilities. First, a definition of severe anaphylaxis should be agreed. Secondly, prospective, multicentre enquiries, using ICD codes, should be implemented. Moreover, the high number of anaphylaxis cases for which the aetiology is not identified, and the variation in aetiology in the published series, indicate that a closer cooperation between emergency specialists and allergists is essential.

PMID 15727574
A F Brown, D McKinnon, K Chu
Emergency department anaphylaxis: A review of 142 patients in a single year.
J Allergy Clin Immunol. 2001 Nov;108(5):861-6. doi: 10.1067/mai.2001.119028.
Abstract/Text BACKGROUND: There are few data on the incidence, clinical features, and management of patients with acute anaphylaxis presenting to the emergency department. We investigated all presentations to one department during the course of a year to improve current awareness of this medical emergency.
OBJECTIVE: The purpose of the study was to describe the clinical features, management, and outcome of anaphylaxis presentations to a single Australian adult emergency department in a single year, 1998-1999.
METHODS: This was a retrospective, case-based study of adult patients (>or=13 years of age) attending a single emergency department in Brisbane, Australia, during the year 1998-1999. The medical records of 304 patients satisfying the relevant discharge diagnostic codes were studied. We determined incidence, sex ratio, age, clinical features, management, disposal, asthma prevalence, and causes in patients presenting with acute allergic reactions and anaphylaxis.
RESULTS: In all, 162 emergency department patients with acute allergic reactions and 142 emergency department patients with anaphylaxis, including 60 whose anaphylaxis was severe, were seen during the year, for an anaphylaxis presentation incidence of 1 in 439. One patient died; this gave a case fatality rate of 0.70%. Cutaneous features were present in 94% of the patients with anaphylaxis. Of those with severe anaphylaxis, 35% had dizziness/syncope before hospital presentation, 25% laryngeal edema, and 21.7% systolic hypotension on hospital presentation. A cause was recognized in 73% of the anaphylaxis cases; most commonly, the causative agent was a drug, insect venom, or food. Adrenaline was used in 57% of the severe cases before hospital presentation or in the hospital. The emergency department alone definitively cared for 94% of all patients, though only 43% severe anaphylaxis cases were referred for follow-up.
CONCLUSION: The emergency department anaphylaxis presentation incidence of 1 in 439 cases is greater than previously recognized, though death remains rare. In three fourths of cases, a precipitant was identified, a fact that emphasizes the need for a detailed initial history. Definitive management in the emergency department alone is possible in most cases, provided that the appropriate use of adrenaline and the need for allergy clinic follow-up are appreciated.

PMID 11692116
Hugh A Sampson, Anne Muñoz-Furlong, S Allan Bock, Cara Schmitt, Robert Bass, Badrul A Chowdhury, Wyatt W Decker, Terence J Furlong, Stephen J Galli, David B Golden, Rebecca S Gruchalla, Allen D Harlor, David L Hepner, Marilyn Howarth, Allen P Kaplan, Jerrold H Levy, Lawrence M Lewis, Phillip L Lieberman, Dean D Metcalfe, Ramon Murphy, Susan M Pollart, Richard S Pumphrey, Lanny J Rosenwasser, F Estelle Simons, Joseph P Wood, Carlos A Camargo
Symposium on the definition and management of anaphylaxis: summary report.
J Allergy Clin Immunol. 2005 Mar;115(3):584-91. doi: 10.1016/j.jaci.2005.01.009.
Abstract/Text
PMID 15753908
Simon G A Brown
Anaphylaxis: clinical concepts and research priorities.
Emerg Med Australas. 2006 Apr;18(2):155-69. doi: 10.1111/j.1742-6723.2006.00831.x.
Abstract/Text Anaphylaxis is a severe immediate-type hypersensitivity reaction characterized by life-threatening upper airway obstruction bronchospasm and hypotension. Although many episodes are easy to diagnose by the combination of characteristic skin features with other organ effects, this is not always the case and a workable clinical definition of anaphylaxis and useful biomarkers of the condition have been elusive. A recently proposed consensus definition is ready for prospective validation. The cornerstones of management are the supine position, adrenaline and volume resuscitation. An intramuscular dose of adrenaline is generally recommended to initiate treatment. If additional adrenaline is required, then a controlled intravenous infusion might be more efficacious and safer than intravenous bolus administration. Additional bronchodilator treatment with continuous salbutamol and corticosteroids are used for severe and/or refractory bronchospasm. Aggressive volume resuscitation, selective vasopressors, atropine (for bradycardia), inotropes that bypass the beta-adrenoreceptor and bedside echocardiographic assessment should be considered for hypotension that is refractory to treatment. Management guidelines continue to be opinion- and consensus-based, with retrospective studies accounting for the vast majority of clinical research papers on the topic. The clinical spectrum of anaphylaxis including major disease subgroups requires clarification, and validated scoring systems and outcome measures are needed to enable good-quality prospective observational studies and randomized controlled trials. A systematic approach with multicentre collaboration is required to improve our understanding and management of this disease.

PMID 16669942
R S Pumphrey, I S Roberts
Postmortem findings after fatal anaphylactic reactions.
J Clin Pathol. 2000 Apr;53(4):273-6.
Abstract/Text AIMS: To determine the frequency at which classic manifestations of anaphylaxis are present at necropsy after fatal anaphylactic reactions.
METHODS: A register has been established of fatal anaphylactic reactions in the UK since 1992, traced from the certified cause of death and other sources. Details of the previous medical history and the reaction suggest anaphylaxis as the cause of death for 130 cases; a postmortem report was available for 56.
RESULTS: The 56 deaths studied included 19 reactions to bee or wasp venom, 16 to foods, and 21 to drugs or contrast media. Death occurred within one hour of anaphylaxis in 39 cases. Macroscopic findings included signs of asthma (mucous plugging and/or hyper-inflated lungs) (15 of 56), petechial haemorrhages (10 of 56), pharyngeal/laryngeal oedema (23 of 56), but for 23 of 56 there was nothing indicative of an allergic death. Mast cell tryptase was raised in 14 of 16 cases tested; three of three tested had detectable IgE specific for the suspected allergen.
CONCLUSIONS: In many cases of fatal anaphylaxis no specific macroscopic findings are present at postmortem examination. This reflects the rapidity and mode of death, which is often the result of shock rather than asphyxia. Investigations that might help determine whether anaphylaxis was the cause of death had rarely been performed. In the presence of a typical clinical history, absence of postmortem findings does not exclude the diagnosis of anaphylaxis.

PMID 10823122
R S Pumphrey
Lessons for management of anaphylaxis from a study of fatal reactions.
Clin Exp Allergy. 2000 Aug;30(8):1144-50.
Abstract/Text BACKGROUND: The unpredictability of anaphylactic reactions and the need for immediate, often improvised treatment will make controlled trials impracticable; other means must therefore be used to determine optimal management.
OBJECTIVES: This study aimed to investigate the circumstances leading to fatal anaphylaxis.
METHODS: A register was established including all fatal anaphylactic reactions in the UK since 1992 that could be traced from the certified cause of death. Data obtained from other sources suggested that deaths certified as due to anaphylaxis underestimate the true incidence. Details of the previous medical history, the reaction and necropsy were sought for all cases.
RESULTS: Approximately half the 20 fatal reactions recorded each year in the UK were iatrogenic, and a quarter each due to food or insect venom. All fatal reactions thought to have been due to food caused difficulty breathing that in 86% led to respiratory arrest; shock was more common in iatrogenic and venom reactions. The median time to respiratory or cardiac arrest was 30 min for foods, 15 min for venom and 5 min for iatrogenic reactions. Twenty-eight per cent of fatal cases were resuscitated but died 3 h-30 days later, mostly from hypoxic brain damage. Adrenaline (epinephrine) was used in treatment of 62% of fatal reactions but before arrest in only 14%.
CONCLUSIONS: Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. Predictable cross-reactivity between the cause of the fatal reaction and that of previous reactions had been overlooked. Adrenaline overdose caused at least three deaths and must be avoided. Kit for self-treatment had proved unhelpful for a variety of reasons; its success depends on selection of appropriate medication, ease of use and good training.

PMID 10931122
F Estelle R Simons, Michael Schatz
Anaphylaxis during pregnancy.
J Allergy Clin Immunol. 2012 Sep;130(3):597-606. doi: 10.1016/j.jaci.2012.06.035. Epub 2012 Aug 4.
Abstract/Text Anaphylaxis during pregnancy, labor, and delivery can be catastrophic for the mother and, especially, the infant. Symptoms and signs can include intense vulvar and vaginal itching, low back pain, uterine cramps, fetal distress, and preterm labor. During the first 3 trimesters, etiologies are similar to those in nonpregnant women. During labor and delivery, common etiologies are β-lactam antibiotics, natural rubber latex, and other agents used in medical and perioperative settings. Important caveats in management include injecting epinephrine (adrenaline) promptly, providing high-flow supplemental oxygen, positioning the mother on her left side to improve venous return to the heart, maintaining a minimum maternal systolic blood pressure of 90 mm Hg to ensure adequate placental perfusion, and continuous electronic monitoring. Cardiopulmonary resuscitation and emergency cesarean delivery should be performed when indicated. In all women of child-bearing age, allergy/immunology specialists can help to prevent anaphylaxis in pregnancy through prepregnancy risk assessment and risk reduction strategies, such as confirming the etiology of systemic allergic reactions, providing written instructions for allergen avoidance, and initiating relevant immune modulation. In pregnant women the benefits versus risks of skin tests, challenge tests, desensitization, and initiation of immunotherapy with allergens should be carefully weighed; if possible, these procedures should be deferred until after parturition. Prospective interdisciplinary studies of anaphylaxis during pregnancy are needed.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
PMID 22871389
Motohiro Ebisawa, Komei Ito, Takao Fujisawa, Committee for Japanese Pediatric Guideline for Food Allergy, The Japanese Society of Pediatric Allergy and Clinical Immunology, The Japanese Society of Allergology
Japanese guidelines for food allergy 2017.
Allergol Int. 2017 Apr;66(2):248-264. doi: 10.1016/j.alit.2017.02.001. Epub 2017 Mar 10.
Abstract/Text Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
PMID 28285847
F E Simons, X Gu, K J Simons
Epinephrine absorption in adults: intramuscular versus subcutaneous injection.
J Allergy Clin Immunol. 2001 Nov;108(5):871-3. doi: 10.1067/mai.2001.119409.
Abstract/Text We report a prospective, randomized, blinded, placebo-controlled, 6-way crossover study of intramuscular versus subcutaneous injection of epinephrine in young men. Peak plasma epinephrine concentrations were significantly higher (P < .01) after epinephrine was injected intramuscularly into the thigh than after epinephrine was injected intramuscularly or subcutaneously into the upper arm. We recommend intramuscular injection of epinephrine into the thigh as the preferred route and site of injection of this life-saving medication in the initial treatment of anaphylaxis.

PMID 11692118
Stephen F Kemp, Richard F Lockey, F Estelle R Simons, World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
Epinephrine: the drug of choice for anaphylaxis-a statement of the world allergy organization.
World Allergy Organ J. 2008 Jul;1(7 Suppl):S18-26. doi: 10.1097/WOX.0b013e31817c9338.
Abstract/Text Anaphylaxis is an acute and potentially lethal multisystem allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The committee strongly believes that epinephrine is currently underused and often dosed suboptimally to treat anaphylaxis, is underprescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate intramuscular doses.

PMID 23282530
Terry L Vanden Hoek, Laurie J Morrison, Michael Shuster, Michael Donnino, Elizabeth Sinz, Eric J Lavonas, Farida M Jeejeebhoy, Andrea Gabrielli
Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Circulation. 2010 Nov 2;122(18 Suppl 3):S829-61. doi: 10.1161/CIRCULATIONAHA.110.971069.
Abstract/Text
PMID 20956228
A Sheikh, V Ten Broek, S G A Brown, F E R Simons
H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review.
Allergy. 2007 Aug;62(8):830-7. doi: 10.1111/j.1398-9995.2007.01435.x.
Abstract/Text BACKGROUND: Anaphylaxis is an acute systemic allergic reaction, which can be life-threatening. H(1)-antihistamines are commonly used as an adjuvant therapy in the treatment of anaphylaxis. We sought to assess the benefits and harm of H(1)-antihistamines in the treatment of anaphylaxis.
METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); MEDLINE (1966 to June 2006); EMBASE (1966 to June 2006); CINAHL (1982 to June 2006) and ISI Web of Science (1945 to July 2006). We also contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized-controlled trials comparing H(1)-antihistamines with placebo or no intervention were eligible for inclusion. Two authors independently assessed articles for inclusion.
RESULTS: We found no studies that satisfied the inclusion criteria.
CONCLUSIONS: Based on this review, we are unable to make any recommendations for clinical practice. Randomized-controlled trials are needed, although these are likely to prove challenging to design and execute.

PMID 17620060
Ulugbek B Nurmatov, Edmund Rhatigan, F Estelle R Simons, Aziz Sheikh
H2-antihistamines for the treatment of anaphylaxis with and without shock: a systematic review.
Ann Allergy Asthma Immunol. 2014 Feb;112(2):126-31. doi: 10.1016/j.anai.2013.11.010. Epub 2013 Dec 5.
Abstract/Text BACKGROUND: Anaphylaxis is a serious allergic or hypersensitivity reaction, which is rapid in onset and sometimes can prove fatal. Although H2-antihistamines are often administered for emergency treatment in anaphylaxis, there is uncertainty about their effectiveness in this disease.
OBJECTIVE: To assess the benefits and harms of H2-antihistamines in the treatment of anaphylaxis.
METHODS: A systematic review was performed of randomized controlled trials and quasi-randomized controlled trials comparing H2-antihistamines with placebo or no intervention in patients with anaphylaxis.
RESULTS: The authors failed to identify any eligible studies for inclusion in this systematic review.
CONCLUSION: When H2-antihistamines are recommended for anaphylaxis treatment, the status of the evidence base supporting their use should be described. Well-designed randomized controlled trials investigating the role of H2-antihistamines in anaphylaxis treatment are urgently needed.

Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
PMID 24468252
R Y Lin, A Curry, G R Pesola, R J Knight, H S Lee, L Bakalchuk, C Tenenbaum, R E Westfal
Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists.
Ann Emerg Med. 2000 Nov;36(5):462-8. doi: 10.1067/mem.2000.109445.
Abstract/Text STUDY OBJECTIVE: Although the addition of H(2) blockers to H(1) antagonists has been promoted for use in anaphylaxis, there have been no large studies establishing the advantage of this approach in treating acute allergic syndromes. In this study we tested the hypothesis that combined H(1) and H(2) blockage results in improved outcomes in patients treated for acute allergic syndromes compared with treatment with H(1) blockade alone.
METHODS: In a randomized, double-blind, placebo-controlled trial, 91 adult patients with acute allergic syndromes were treated with either 50 mg of diphenhydramine and saline solution (control group) or with 50 mg of diphenhydramine and 50 mg of ranitidine (active group). These patients were treated with parenteral administration. Patients were recruited from an emergency department at an urban academic medical center. The primary endpoints were resolution of urticaria, angioedema, or erythema at 2 hours after protocol treatment. Areas of cutaneous involvement, heart rates, blood pressures, respiratory findings, and symptom scores were also assessed at baseline, 1 hour, and 2 hours.
RESULTS: There were significantly more patients without urticaria at 2 hours among the patients in the active group compared with those in the control group. Both groups had similar proportions of urticaria at baseline. Logistic regression models to predict resolution of urticaria, which accounted for baseline urticarial involvement, showed odds ratios in favor of the active group treatment. Similar findings were observed when the absence of both urticaria and angioedema was considered as the dependent variable. There was not a significant difference between the 2 groups with regard to the absence of erythema or angioedema (irrespective of the presence of urticaria) at 2 hours. Blood pressure and symptoms did not show differences between the 2 groups over time. Lower heart rates were observed 1 hour after treatment in the active treatment group (mean reduction 10 beats/min) compared with those found in the placebo group (mean reduction 6 beats/min).
CONCLUSION: These data show that adding H(2) blockers to H(1) antagonists results in additional improvement of certain cutaneous outcomes for patients presenting with acute allergic syndromes. These findings favor the recommendation for using combined H(1) and H(2) antihistamines in acute allergic syndromes.

PMID 11054200
K J L Choo, E Simons, Aziz Sheikh
Glucocorticoids for the treatment of anaphylaxis: Cochrane systematic review.
Allergy. 2010 Oct;65(10):1205-11. doi: 10.1111/j.1398-9995.2010.02424.x. Epub 2010 Jun 18.
Abstract/Text BACKGROUND: Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. A number of guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis.
OBJECTIVES: We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis.
METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (Ovid) (1966 to September 2009), EMBASE (Ovid) (1988 to September 2009), CINAHL (EBSCOhost) (to September 2009) and The Science Citation Index Expanded (SCI-EXPANDED) (1945 to September 2009). We also searched the UK National Research Register and websites listing ongoing trials and contacted international experts in anaphylaxis in an attempt to locate unpublished material. We sought to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). Two authors independently assessed articles for inclusion.
RESULTS: None of the 2496 reports identified satisfied the inclusion criteria.
CONCLUSIONS: We conclude that there is no evidence from high-quality studies for the use of steroids in the emergency management of anaphylaxis. Therefore, we can neither support nor refute the use of these drugs for this purpose.

PMID 20584003
Karen Jui Lin Choo, F Estelle R Simons, Aziz Sheikh
Glucocorticoids for the treatment of anaphylaxis.
Cochrane Database Syst Rev. 2012 Apr 18;(4):CD007596. doi: 10.1002/14651858.CD007596.pub3. Epub 2012 Apr 18.
Abstract/Text BACKGROUND: Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. Anaphylaxis guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis.
OBJECTIVES: We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis.
SEARCH METHODS: In our previous version we searched the literature until September 2009. In this version we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (Ovid) (1956 to September 2011), EMBASE (Ovid) (1982 to September 2011), CINAHL (EBSCOhost) (to September 2011). We also searched the UK National Research Register and websites listing ongoing trials, and contacted international experts in anaphylaxis in an attempt to locate unpublished material.
SELECTION CRITERIA: We planned to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these).
DATA COLLECTION AND ANALYSIS: Two authors independently assessed articles for inclusion.
MAIN RESULTS: We found no studies that satisfied the inclusion criteria.
AUTHORS' CONCLUSIONS: We are, based on this review, unable to make any recommendations for the use of glucocorticoids in the treatment of anaphylaxis.

PMID 22513951
Phillip Lieberman, Richard A Nicklas, Christopher Randolph, John Oppenheimer, David Bernstein, Jonathan Bernstein, Anne Ellis, David B K Golden, Paul Greenberger, Steven Kemp, David Khan, Dennis Ledford, Jay Lieberman, Dean Metcalfe, Anna Nowak-Wegrzyn, Scott Sicherer, Dana Wallace, Joann Blessing-Moore, David Lang, Jay M Portnoy, Diane Schuller, Sheldon Spector, Stephen A Tilles
Anaphylaxis--a practice parameter update 2015.
Ann Allergy Asthma Immunol. 2015 Nov;115(5):341-84. doi: 10.1016/j.anai.2015.07.019.
Abstract/Text
PMID 26505932
Waleed Alqurashi, Anne K Ellis
Do Corticosteroids Prevent Biphasic Anaphylaxis?
J Allergy Clin Immunol Pract. 2017 Sep - Oct;5(5):1194-1205. doi: 10.1016/j.jaip.2017.05.022.
Abstract/Text Anaphylaxis is a severe hypersensitivity reaction that is rapid in onset and can result in death. The pattern of an anaphylactic reaction can be uniphasic (or monophasic), biphasic (also called delayed or late phase), or refractory in nature. The most widely cited definition of biphasic anaphylaxis is a recurrence of anaphylactic symptoms after initial resolution despite no further exposure to the trigger. Corticosteroids are thought by some to prevent the development of biphasic symptoms and, therefore, commonly used in the emergency treatment of anaphylaxis but this has not been systemtically analyzed. In this review, Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus were searched for articles using "anaphylaxis" combined with the key terms "biphasic" and/or "corticosteroids" and/or "epinephrine." A total of 31 appropriate studies were identified. Biphasic anaphylactic reactions are more likely to occur in moderate to severe anaphylaxis or when anaphylaxis is not treated with timely epinephrine. Because of the potential detrimental adverse effects of corticosteroids and lack of compelling evidence demonstrating an effective role in reducing anaphylaxis severity or preventing biphasic anaphylaxis, we do not advocate for their routine use in anaphylaxis.

Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
PMID 28888249
A Muraro, G Roberts, M Worm, M B Bilò, K Brockow, M Fernández Rivas, A F Santos, Z Q Zolkipli, A Bellou, K Beyer, C Bindslev-Jensen, V Cardona, A T Clark, P Demoly, A E J Dubois, A DunnGalvin, P Eigenmann, S Halken, L Harada, G Lack, M Jutel, B Niggemann, F Ruëff, F Timmermans, B J Vlieg-Boerstra, T Werfel, S Dhami, S Panesar, C A Akdis, A Sheikh, EAACI Food Allergy and Anaphylaxis Guidelines Group
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014 Aug;69(8):1026-45. doi: 10.1111/all.12437. Epub 2014 Jun 9.
Abstract/Text Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence-based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life-threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First-line treatment for anaphylaxis is intramuscular adrenaline. Useful second-line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto-injector. If an adrenaline auto-injector is prescribed, education on when and how to use the device should be provided. Specialist follow-up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PMID 24909803
Martin Thomas, Ian Crawford
Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers.
Emerg Med J. 2005 Apr;22(4):272-3. doi: 10.1136/emj.2005.023507.
Abstract/Text A short cut review was carried out to establish whether a glucagon infusion is of benefit in patients with refractory anaphylaxis. 62 papers were found using the reported search, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.

PMID 15788828
Jean C Y Lo, Michael A Darracq, Richard F Clark
A review of methylene blue treatment for cardiovascular collapse.
J Emerg Med. 2014 May;46(5):670-9. doi: 10.1016/j.jemermed.2013.08.102. Epub 2014 Feb 6.
Abstract/Text BACKGROUND: Historically, methylene blue (MB) has been used for multiple purposes, including as an antidote for toxin-induced and hereditary methemoglobinemia, ifosfamide-induced encephalopathy, and ackee fruit and cyanide poisoning; as an aniline dye derivative, antimalarial agent, and antidepressant.
DISCUSSION: Most recently, the use of MB has been advocated as a potential adjunct in the treatment of shock states. Our article reviews the role of MB in septic shock, anaphylactic shock, and toxin-induced shock. MB is proposed to increase blood pressure in these shock states by interfering with guanylate cyclase activity, and preventing cyclic guanosine monophosphate production and vasodilatation.
SUMMARY: MB may be an adjunct in the treatment of septic shock, anaphylactic shock, and toxin-induced shock.

Copyright © 2014 Elsevier Inc. All rights reserved.
PMID 24508113
Paulo Roberto B Evora
Methylene blue for the treatment of refractory anaphylaxis without hypotension.
Am J Emerg Med. 2013 Apr;31(4):753. doi: 10.1016/j.ajem.2013.01.033. Epub 2013 Feb 27.
Abstract/Text
PMID 23453364
Matthew S Davenport, Richard H Cohan
The Evidence for and Against Corticosteroid Prophylaxis in At-Risk Patients.
Radiol Clin North Am. 2017 Mar;55(2):413-421. doi: 10.1016/j.rcl.2016.10.012.
Abstract/Text Corticosteroid prophylaxis is commonly used for the prevention of allergiclike reactions to iodinated and gadolinium-based contrast material in patients at highest risk of an allergiclike reaction. However, it has only a weak mitigating effect on allergiclike reactions, probably does not affect the severity of subsequent reactions, and does not prevent all reactions. Breakthrough reactions occur, are usually the same severity as the index reaction, and can occasionally be life threatening. Premedication of inpatients is likely associated with substantial cost and harm because of hospital length-of-stay prolongation; these indirect effects may exceed the benefits of premedication in this population.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 28126223
David I Bernstein, Mark Wanner, Larry Borish, Gary M Liss, Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology
Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
J Allergy Clin Immunol. 2004 Jun;113(6):1129-36. doi: 10.1016/j.jaci.2004.02.006.
Abstract/Text BACKGROUND: Fatal reactions associated with skin testing and injection immunotherapy have not been surveyed in North America since 1989.
OBJECTIVE: A survey of fatal reactions related to skin testing and immunotherapy and of near-fatal immunotherapy reactions that transpired from 1990 through 2001 was conducted among member practices of the American Academy of Allergy, Asthma and Immunology.
METHODS: A short survey of fatal reactions was sent to all American Academy of Allergy, Asthma and Immunology physicians, and an 87-item follow-up detailed questionnaire was sent to those reporting fatal reactions.
RESULTS: Of 2404 members, 646 (25%) responded to the short survey. There were 20 fatal immunotherapy reactions that were directly reported and 21 indirectly reported cases by local physicians. There were 273 (42% of the responding sample) reports of near-fatal reactions. It was estimated that fatal reactions occurred every 1 per 2.5 million injections, with an average of 3.4 deaths per year. One fatality was confirmed after skin prick testing with multiple food allergens. Of 17 fatal deaths described in long questionnaires, 15 were in asthmatic patients, the majority of whose symptoms were not optimally controlled. Three reactions occurred in a medically unsupervised setting. None were receiving beta-blockers, and one was taking an angiotensin-converting enzyme inhibitor. Most fatal reactions (59%) occurred with maintenance allergen doses. The onset of 3 reactions began more than 30 minutes after injections, with a significant delay in starting epinephrine. Epinephrine was not administered in 3 other fatal reactors.
CONCLUSIONS: Fatal reactions to immunotherapy injections occurred at similar rates reported in previous surveys. Certain clinical practices have improved (ie, exclusion of beta-blockers), and dosing errors were infrequent. Fatal reactions to immunotherapy often occur in settings inappropriate for optimal treatment of anaphylaxis. Strict adherence to practice guidelines might prevent or minimize future fatal reactions.

PMID 15208595
Sarah K Wise, Rodney J Schlosser
Evidence-based practice: sublingual immunotherapy for allergic rhinitis.
Otolaryngol Clin North Am. 2012 Oct;45(5):1045-54. doi: 10.1016/j.otc.2012.06.008. Epub 2012 Jul 24.
Abstract/Text In this article, the authors review the current evidence regarding the public health and economic impact of allergic rhinitis. Diagnostic methods for allergic disease are discussed as well as certain nuances of allergy skin testing protocols. In addition, the evidence supporting sublingual immunotherapy (SLIT) for allergic rhinitis is reviewed, with subsequent attention to certain subgroups, such as adults and children, seasonal versus perennial allergens, and SLIT efficacy for individual antigens. The authors consider the evidence supporting appropriate SLIT dosing as well as the existing data on SLIT safety.

Published by Elsevier Inc.
PMID 22980684
Kunio Dobashi, Kazuo Akiyama, Atsushi Usami, Hiroo Yokozeki, Zenro Ikezawa, Naomi Tsurikisawa, Yoichi Nakamura, Kazuhiro Sato, Jiro Okumura, Kaoru Takayama, Committee for Japanese Guideline for Diagnosis and Management of Occupational Allergic Disease, The Japanese Society of Allergology
Japanese guidelines for occupational allergic diseases 2017.
Allergol Int. 2017 Apr;66(2):265-280. doi: 10.1016/j.alit.2016.12.010. Epub 2017 Feb 15.
Abstract/Text In 2013, a guideline for occupational allergic diseases was published for the first time in Japan. Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative antigens, and are socioeconomically important diseases with which the patients might sometimes lose jobs due to work interruptions. Guidelines for occupational allergic diseases have been published in many countries. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis and occupational anaphylaxis shock, and legal aspects of these diseases. The guideline is characterized with the following basic structure: Clinical Questions (CQs) are set with reference to Minds (Medical Information Network Distribution Service), statements by the committee are correspondingly listed, recommended grades and evidence levels are defined, and then descriptions and references are indicated.

Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
PMID 28214136
David B K Golden, Jeffrey Demain, Theodore Freeman, David Graft, Michael Tankersley, James Tracy, Joann Blessing-Moore, David Bernstein, Chitra Dinakar, Matthew Greenhawt, David Khan, David Lang, Richard Nicklas, John Oppenheimer, Jay Portnoy, Christopher Randolph, Diane Schuller, Dana Wallace
Stinging insect hypersensitivity: A practice parameter update 2016.
Ann Allergy Asthma Immunol. 2017 Jan;118(1):28-54. doi: 10.1016/j.anai.2016.10.031.
Abstract/Text
PMID 28007086
Charles Feng, Suzanne Teuber, M Eric Gershwin
Histamine (Scombroid) Fish Poisoning: a Comprehensive Review.
Clin Rev Allergy Immunol. 2016 Feb;50(1):64-9. doi: 10.1007/s12016-015-8467-x.
Abstract/Text Histamine fish poisoning, also known as scombroid poisoning, is the most common cause of ichythyotoxicosis worldwide and results from the ingestion of histamine-contaminated fish in the Scombroidae and Scomberesocidae families, including mackerel, bonito, albacore, and skipjack. This disease was first described in 1799 in Britain and re-emerged in the medical literature in the 1950s when outbreaks were reported in Japan. The symptoms associated with histamine fish poisoning are similar to that of an allergic reaction. In fact, such histamine-induced reactions are often misdiagnosed as IgE-mediated fish allergy. Indeed, histamine fish poisoning is still an underrecognized disease. In this review, we discuss the epidemiology, pathophysiology, evaluation, and treatment of scombroid disease. Because more than 80% of fish consumed in the USA is now imported from other countries, the disease is intimately linked with the global fish trade (National Marine Fisheries Service, 2012). Preventing future scombroid outbreaks will require that fishermen, public health officials, restaurant workers, and medical professionals work together to devise international safety standards and increase awareness of the disease. The implications of scombroid poisoning go far beyond that of fish and have broader implications for the important issues of food safety.

PMID 25876709
Nana Fenny, Leslie C Grammer
Idiopathic anaphylaxis.
Immunol Allergy Clin North Am. 2015 May;35(2):349-62. doi: 10.1016/j.iac.2015.01.004. Epub 2015 Mar 6.
Abstract/Text Idiopathic anaphylaxis is a diagnosis of exclusion after other causes have been thoroughly evaluated and excluded. The pathogenesis of idiopathic anaphylaxis remains uncertain, although increased numbers of activated lymphocytes and circulating histamine-releasing factors have been implicated. Signs and symptoms of patients diagnosed with idiopathic anaphylaxis are indistinguishable from the manifestations of other forms of anaphylaxis. Treatment regimens are implemented based on the frequency and severity of patient symptoms and generally include the use of epinephrine autoinjectors, antihistamines, and steroids. The prognosis of idiopathic anaphylaxis is generally favorable with well-established treatment regimens and effective patient education.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 25841556
A M Ditto, K E Harris, J Krasnick, M A Miller, R Patterson
Idiopathic anaphylaxis: a series of 335 cases.
Ann Allergy Asthma Immunol. 1996 Oct;77(4):285-91. doi: 10.1016/S1081-1206(10)63322-4.
Abstract/Text BACKGROUND: Idiopathic anaphylaxis is anaphylaxis with no definable etiology and no trigger by exogenous allergens. Initially described in 1978, idiopathic anaphylaxis has been subsequently characterized and treatment protocols have been established.
OBJECTIVE: The demographics and course of 335 patients (225 previously reported) treated with prednisone, hydroxyzine, and albuterol are now reported.
RESULTS: Ages ranged from 5 to 83 years. There were nine new pediatric patients in this series totaling 14 (4.2%). Atopy was common (48%) with 34 new patients with asthma. The duration of symptoms prior to presentation ranged from three days to 27 years. One hundred thirty-two patients with idiopathic anaphylaxis were available for follow-up. Twenty of these are currently receiving prednisone for control of idiopathic anaphylaxis, seven of them as part of their initial therapy, and ten for control of recurrence of symptoms. Three patients required continuous alternate day prednisone for control of symptoms (corticosteroid-dependent idiopathic anaphylaxis). Of the 335 patients, there were no longer any patients with the diagnosis of malignant idiopathic anaphylaxis defined as requiring prednisone, 20 mg daily, or 60 mg every other day, for control of idiopathic anaphylaxis. Of the six patients previously diagnosed with malignant idiopathic anaphylaxis, five no longer required prednisone and one has a decreased prednisone requirement of 20 mg on alternate days. Hospital visits were significantly reduced by the management regimens. There were no fatalities from idiopathic anaphylaxis in this series.
CONCLUSIONS: The incidence of idiopathic anaphylaxis is increasing in our practice with more patients being evaluated each year. During 1104 patient years of observation (the longest period of single patient observation being 24 years), no inciting agent has been found responsible for the anaphylactic symptoms. Prognosis continues to remain good with the majority of patients achieving remission with pharmacotherapy.

PMID 8885805
M B Boxer, P A Greenberger, R Patterson
The impact of prednisone in life-threatening idiopathic anaphylaxis: reduction in acute episodes and medical costs.
Ann Allergy. 1989 Mar;62(3):201-4.
Abstract/Text Two patients with frequent episodes of well documented life-threatening idiopathic anaphylaxis were studied. Despite prior treatment with antihistamines and self-administered epinephrine, both patients continued to have episodes of anaphylaxis. At the time of presentation to the Northwestern University Allergy Service, prednisone and antihistamines with or without sympathomimetics were started. Described in this report are the substantial reductions in the frequency of hospitalizations, emergency room visits, and anaphylactic episodes after our medical management was instituted.

PMID 2564265
D A Khan, M W Yocum
Clinical course of idiopathic anaphylaxis.
Ann Allergy. 1994 Oct;73(4):370-4.
Abstract/Text BACKGROUND: Only a few groups have reported on idiopathic anaphylaxis. We analyzed our experience with idiopathic anaphylaxis, especially in regards to prognosis.
METHODS: Thirty-seven patients with the diagnosis of idiopathic anaphylaxis were retrospectively identified by a medical records search from 1989-1992. Thirty-five patients were evaluable and a telephone questionnaire was conducted to determine the current treatment and course of their idiopathic anaphylaxis since their initial evaluation.
RESULTS: Patient ages ranged from 26 to 71 years (mean 48), 72% were women, and 43% were atopic. Frequent episodes of idiopathic anaphylaxis (> 5/year) occurred in 31%. At follow-up (mean 2.5 years), 21 patients (60%) had resolution of idiopathic anaphylaxis, and the frequency of anaphylaxis was decreased in nine, increased in two, and the same in three patients. Only three patients were still having frequent episodes and two required chronic glucocorticoids. Patients with frequent idiopathic anaphylaxis treated with only antihistamines and adrenergics underwent remission or improvement as frequently as those treated with chronic glucocorticoids.
CONCLUSIONS: These results are similar to other reports of idiopathic anaphylaxis and indicate a generally favorable prognosis. Some patients with frequent idiopathic anaphylaxis improved without the need for glucocorticoids. Well controlled studies may be required to analyze the role of glucocorticoids in this disease.

PMID 7944007

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