Do Corticosteroids Prevent Biphasic Anaphylaxis?

Clinical Commentary Review

Do Corticosteroids Prevent Biphasic Anaphylaxis? Waleed Alqurashi, MD, MSc, FAAP, FRCPCa, and Anne K. Ellis, MD, MSc, FRCPC, FAAAAIb Ottawa and Kingston, Ontario, Canada

INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

List of Design Committee Members: Waleed Alqurashi, MD, MSc, FAAP, FRCPC, and Anne K. Ellis, MD, MSc, FRCPC, FAAAAI (authors); Scott H. Sicherer, MD (editor) Learning objectives:

Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaciinpractice.org/. Fax or other copies will not be accepted. Date of Original Release: September 1, 2017. Credit may be obtained for these courses until August 31, 2018. Copyright Statement: Copyright Ó 2017-2019. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for 1.00 AMA PRA Category 1 CreditÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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

a

Division of Emergency Medicine, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada b Division of Allergy & Immunology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Conflicts of interest: A. K. Ellis has received research support and consultancy/speaker fees from Pfizer; has received consultancy fees from ALK Abello, Merck, and Novartis; has received research support from Circassia Ltd, Green Cross, GlaxoSmithKline, Merck, Novartis, Sanofi, and SunPharma Advance Research Corporation; and has received lecture fees from Aralez, AstraZeneca, Merck, Novartis, Pfizer, and Takeda. W. Alqurashi declares no relevant conflicts of interest. Received for publication February 28, 2017; revised May 11, 2017; accepted for publication May 24, 2017. Corresponding author: Anne K. Ellis, MD, MSc, FRCPC, FAAAAI, Watkins 1D, Kingston General Hospital, 76 Stuart St, Kingston, ON, Canada K7L 2V7. E-mail: [email protected]. 2213-2198 Ó 2017 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2017.05.022

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1. To discuss incidence, nature, and predictors of biphasic anaphylaxis. 2. To describe potential pathophysiologic mechanisms of biphasic anaphylactic reactions. 3. To discuss rationale for the use of corticosteroids in anaphylaxis. 4. To discuss data for and against the use of corticosteroids in the setting of anaphylaxis. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Relevant Financial Relationships with Commercial Interests: A. K. Ellis has received research support and consultancy/speaker fees from Pfizer; has received consultancy fees from ALK Abello, Merck, and Novartis; has received research support from Circassia Ltd, Green Cross, GlaxoSmithKline, Merck, Novartis, Sanofi, and SunPharma Advance Research Corporation; and has received lecture fees from Aralez, AstraZeneca, Merck, Novartis, Pfizer, and Takeda. W. Alqurashi declares no relevant conflicts of interest. S. H. Sicherer disclosed no relevant financial relationships.

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. Ó 2017 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:1194-205) Key words: Anaphylaxis; Biphasic anaphylaxis; Epinephrine; Corticosteroids

Anaphylaxis is a severe hypersensitivity reaction that is rapid in onset and can result in death.1 The population-based prevalence of anaphylaxis from all triggers is unknown.1,2 However, the

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Abbreviation used ED- emergency department PAF- platelet-activating factor

lifetime prevalence estimates range from 0.3% to 5.1%, and it appears to be increasing globally, particularly among children.3-6 The pattern of an anaphylactic reaction can be uniphasic (or monophasic), biphasic (also called delayed or late phase), or refractory in nature.7 The most widely cited definition of biphasic anaphylaxis is a recurrence of anaphylactic symptoms after initial resolution despite no further exposure to the trigger.8,9 However, the reported definition from published clinical studies to date have been inconsistent. Furthermore, the reported incidence of biphasic anaphylaxis also varies widely, ranging from 3% to 23%.7,10-34 Nevertheless, biphasic anaphylaxis can be associated with severe outcomes. Previous case series of fatal and near-fatal anaphylaxis among food-allergic children reported 3 cases of fatal biphasic reactions.35 Although reports of fatal biphasic reactions are rare in recent literature, severe late reactions that require advanced airway intervention, extracorporeal membrane oxygenation resuscitation, and intensive care monitoring continue to be reported.25,36-38 Corticosteroids are thought by some to prevent the development of biphasic symptoms and, therefore, commonly used in the emergency treatment of anaphylaxis. Despite their wide clinical use, there is no compelling evidence to support their use.9,35 This lack of evidence is thought to contribute to the variation in practice among clinicians. As a result, many patients receive therapies of unknown efficacy, and are hospitalized or monitored in the emergency department (ED) for long hours following an anaphylactic reaction due to concerns of biphasic responses.21,39-41 In this clinical commentary, we review the risk factors and pathophysiology of biphasic anaphylaxis, summarize the literature supporting and opposing the use of corticosteroids in anaphylaxis, and provide recommendations for research studies to overcome current knowledge gaps.

METHODS We defined a biphasic anaphylactic reaction as the recurrence or new symptoms of anaphylaxis after an anaphylactic event without reexposure to the trigger, following an asymptomatic interval of at least 1 hour. Studies that clearly documented reactions meeting this definition were included. We included relevant case series, prospective and retrospective cohort studies, and clinical trials. Studies that did not describe biphasic reactions and isolated case reports were excluded. We followed the search strategy previously described by Lee et al,42 and included the following databases: Ovid MEDLINE (1946 to February 2017), Ovid EMBASE (1988 to February 2017), Web of Science (inception to February 2017), and Scopus (inception to February 2017). We also reviewed the bibliographies of included articles and previously published narrative and systematic reviews to identify potentially relevant articles.

Critical appraisal results Table I provide a list of the studies that attempt to explore prognostic factors associated with biphasic anaphylaxis and, if reported, the treatment effect of corticosteroids. Because of lack of randomized clinical trials addressing therapy and harm of

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corticosteroids in biphasic anaphylaxis, we based our discussion on the available evidence from observational studies. These studies vary considerably in their design (prospective vs retrospective), enrolled population (adults vs children or mixed), and definition and severity of anaphylaxis and biphasic reaction.21,42 These epidemiological factors should be carefully considered when making data comparisons. In addition to the significant heterogeneity between these studies, some were not primarily designed to answer a causal question, nor they were appropriately analyzed to minimize confounding factors.46,47 We also found few studies that were large enough to derive a predictive model for biphasic anaphylaxis.19,21,45 However, there are several limitations of these models including lack of validation.48,49

Pathophysiology of biphasic anaphylaxis Three important characteristics emerge from our critical review of all observational studies to date: patient or host characteristics, disease characteristics, and treatment characteristics. The wide range of time intervals leads to the supposition that biphasic reactions are likely due to a number of different mechanisms (ie, earlier onset suggesting medication “wear-off,” insufficient treatment, or secondary absorption of antigen, whereas those occurring 12-24 hours later could well be a late-phase response from the initial IgEmediated reaction). Table II provides a summary of the potential predictive factors in the studies we reviewed; a detailed discussion of these factors is beyond the scope of this review. However, below we discuss prognostic factors that have been consistently reproduced by multiple studies, and inform our understanding of the disease process and their relation to pharmacologic therapies.

Association with disease severity. Although early reports were too small to detect a statistically powered association, the association between biphasic anaphylaxis and the severity of the initial reaction has been quite consistent. It should be noted that the definition of severity used in previous studies is inconsistent and mainly based on severe clinical manifestations such as hypotension or required therapeutic interventions such as multiple epinephrine treatments.21 A summary of the studies that described this link is provided in Tables I and II. To date, one of the most robust reports demonstrating a “doseresponse” effect of disease severity by incorporating a clinical severity scoring was published by Brown et al.19 In their prospective cohort study of adults with anaphylaxis, delayed anaphylaxis was associated with the severity of the initial reaction. Hypotension was also identified as a predictor of biphasic anaphylaxis in a recent metanalysis.42 The largest pediatric study on biphasic anaphylaxis to date showed similar findings. Children with biphasic reactions had a higher triage acuity score, had manifestation of anaphylactic shock with wide pulse pressure, needed multiple epinephrine treatments for their initial reaction, and had significant respiratory distress that required treatment with inhaled b-agonists compared with those with uniphasic reactions.21 Among children who had double-blind, placebo-controlled food challenge, the risk of late reactions was significantly higher in children with initially severe reactions after the challenge (Table I).45 Impact of epinephrine treatment. Epinephrine is the firstline therapy, and the single most important agent in anaphylaxis treatment. Timely epinephrine administration plays a significant role in the prevention of severe and fatal anaphylaxis.50-53 Prospective data from the Cross-Canada Anaphylaxis REgistry found that epinephrine administration before arrival to the ED was the only

Reference/year

Design

Settings and subjects Incidence (%)

Adult 3 cases (all M)

Stark and Sullivan,12 1986

Prospective

Sampson et al,35 1992

Case series

Douglas et al,7 1994

Retrospective Adults ED, inpatients, and outpatient allergy clinic 4 of 59 had BR (1 F, 3 M)

Brady et al,10 1997

Retrospective Adults ED visits 2 of 67 developed BR (1 F, 1 M)

Trigger

Time to onset (h)*

Not reported

A

22-52

1 immunotherapy 1 insect bite 1 rabies vaccine in patient with egg allergy

3-4

Adults Inpatients and ED 5 of 25 developed BR (3 F, 2 M)

20%

A

21-67

4 drugs (antibiotics), 1–8 1 radiocontrast media

13 children 3 developed fatal BR (2 F, 1 M)

23%

A

8-15

Food 1-2 (1 peanuts, 2 tree nuts)

7%

2 A, 2 NA

20-77

2 drugs, 2 food (shrimp)

Mean, 30 (range, 1-72)

3%

NA

19-21

Hymenoptera envenomation

Mean, 33 (range, 26-40)

Risk factors

Not reported

Association with corticosteroids

Not reported (2 patients received steroids for the initial reaction) Route: IV Time: not reported Anaphylaxis provoked NAI Route: IV by oral trigger. Time: within 1 h of Delay of
30 min arrival to ED between exposure to trigger and development of initial reaction. Severe initial symptoms not predictive of BR All patients with BR Not reported had asthma. Delay in administration of first epinephrine after ingestion of allergen for all 3 patients NAI No clinical features Route and time: not distinguished reported patients with UR from patients with BR. However, 50% of the patients with BR had hypotension that required treatment with IV fluids compared with 16% of those with UR None NAI Route: IV/PO Time: not reported

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Case series

Age (y)

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Popa and Lerner,11 1984

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TABLE I. Summary of previous studies on biphasic anaphylaxis

Retrospective Adults, ED visits 6 of 34 developed BR

Lee and Greenes,18 2000

Retrospective Children Hospital admissions 6 of 105 developed BR (3 F, 3 M) Retrospective Adult and children ED visits 15 of 282 developed BR (5 F, 10 M)

Smit et al,29 2005

18%

6%

5.3%

A

Not reported

3 insect bites, 1 food (nuts), 2 drugs

Mean, 16.3 (range, 4.5-29.5)

3 A, 3 NA

1-13

2 drugs, 2 food (fish, nuts), 2 bee stings

Mean, 10.1 (range, 1.3-28.4)

3 A, 12 NA

6-80

5 4 5 1

Mean, 8 (range, 1.4-23)

food (seafood) drugs unknown insect bite

Poachanukoon and Retrospective Adult and children Paopairochan-akorn,13 Hospital admissions 2006 8 of 52 developed BR (4 F, 4 M)

15%

Not reported

Not reported

Not reported

Not reported

Retrospective Hospitalized mixed population 5 of 101 developed BR 2007 Prospective Adult and children ED visits and hospital admissions 20 of 103 developed BR (9 F, 11 M)

5%

Not reported

Not reported

Not reported

Not reported

A

4-73

7 5 6 1 1

Mean, 10 (range, 1.5-38)

NA

25-66

Immunotherapy

Jirapongsananuruk et al,30 2007

Ellis and Day,44

Scranton et al,14 2009 Prospective

23%

unknown Hymenoptera food drug immunotherapy

Mean, 7.2 (range, 2-24)

Delay in presentation to ED (1 h for UR vs 3 h for BR) 20% of patients with BR had unstable vital signs on initial presentation to ED Time interval between the onset of initial reaction and the first epinephrine was longer for patients with BR Not reported

Patients with BR received less total epinephrine dose and less systemic steroids treatment for their initial reactions Patients in the BR group were more likely to require multiple epinephrine treatments for the initial reaction

NAI Route: IV Mean time to treatment, 7.57  5.46 h

NAI Route and time: not reported

NAI Route and time: not reported Biphasic reactors received less corticosteroid (P ¼ .06) Route and time: not reported NAI Route: oral Time: not reported

(continued)

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Adult and children Allergy clinic 14 of 60 developed BR (13 F, 1 M)

19.4%

Not reported Patients with BR required larger doses of epinephrine to treat their initial reaction Delay in epinephrine NAI administration Route and time: not reported

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Brazil and MacNamara,43 1998

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Reference/year

Design

Settings and subjects Incidence (%)

Retrospective Children ED visits 12 of 109 developed BR (4 F, 8 M)

Confino-Cohen and Goldberg,34 2010

Prospective

Adult and children Allergy clinic 10 of 112 developed BR (7 F, 3 M)

11%

9%

Age (y)

Trigger

5 A, 7 NA

0.2-17

9 food 2 unknown 1 drug

Mean, 9.5 (range, 1.2-20.5)

NA

14-48

Immunotherapy

3-24

Mean, 8 (range, 2-13)

Lertnawapan and Retrospective Adult and pediatric Maek-a-nantawat,15 ED visits 2011 13 of 208 developed BR (9 F, 4 M)

6.3%

A

Median 18

4 2 2 1 4

Orhan et al,32 2011

3.1%

A

Median 3

3.3%

A

4-7.5

3 food 2 drugs 1 immunotherapy 1 Hymenoptera Not reported

Retrospective Pediatric clinic 7 of 224 developed BR

sea food fried insect as food immunotherapy insecticide unknown

1.5-6

12-18

Risk factors

Children who received >1 dose of epinephrine and/or a fluid bolus treatment of their initial anaphylactic reaction were at increased risk of BR Relatively low peak expiratory flow (PEF) (regardless of asthma history) at baseline and concomitant asthma are possible risk factors for BR Median time from onset of the initial reaction to hospital arrival and to first epinephrine treatment was significantly longer in patient with BR compared with those with UR Not reported

Association with corticosteroids

NAI Route: PO/IV Median time to administration, 108 min (IQR, 20-260)

Not reported

NAI Route and time: not reported

Not reported Route and time: not reported

NAI Patients who developed BR were Route: IV/PO more likely to have Time: not reported experienced syncope, vomiting, and treatment with >1 dose of epinephrine for their initial reactions

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Inoue and Retrospective Children Yamamoto,16 2013 Inpatient and outpatient visits 2 of 61 developed BR (1 F, 1 M)

Time to onset (h)*

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Mehr et al,31 2009

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TABLE I. (Continued)

Retrospective Pediatric allergy clinic 9 of 614 developed BR (4 F, 5 M)

Nagano et al,23 2013

Retrospective Pediatric ED 3 of 340 developed BR Prospective Pediatric allergy clinic 5 of 96 developed BR (3 F, 2 M)

Vezir et al,22 2013

Liew et al,33 2013

Retrospective Pediatric ED/allergy clinic 4 of 108 developed BR

Brown et al,19 2013

Prospective

Grunau et al,20 2014 Rohacek et al,24

Adult ED 55 of 412 developed BR

Adult ED, 2 of 496 developed BR (2 M) 2014 Retrospective Adult ED, 25 of 532 developed BR (19 F, 6 M)

1.5%

4 A, 5 NA

0.2-17

Oral food challenge to 2-24 milk, egg, and peanut

A

Median 3

Not reported

3-28

5.2%

Not reported

<5 y ¼ 1 >5y ¼ 4

3 drugs 2 Hymenoptera

0.5-9

3.7%

Not reported

Not reported

Not reported

All within 24 h

29 A Not (treated reported with epinephrine) NA 37-38

Not reported

0.2-30.4

1 food 1 drug

0.26-3.3

All patients with BR had received fluid therapy for their initial reaction, which was severe in 4 of them Three patients required intensive care unit stay for hypotension at presentation Preexisting lung disease and initially severe reactions (hypotension) None identified

<1%

13%

0.4%

Patients with BR were significantly more likely to have received steroids for their initial reaction. BR seem to be associated with the severity of the initial reaction Not reported

12 A 13 NA

Mean, 9 food 42.3  15.2 6 drugs 3 Hymenoptera 7 unknown

12 (1-36)

None identified

Median, 41 4 food (IQR, 31-51) 5 drugs 1 Hymenoptera 9 unknown 2 other Mean, 3 food 31  27.5 3 drugs 1 Hymenoptera

Median, 7 (range, 1-72)

Prior anaphylaxis, unknown trigger, wheezing, and diarrhea

Median, 8

Not reported

Lee et al,25 2014

Retrospective Adult ED, 21 of 541 developed BR (13 F, 8 M)

3.9%

A

Oya et al,27 2014

Retrospective Hospitalized patients from adults ED 7 of 114 developed BR (4 F, 3 M)

6.1%

3A 4 NA

NAI Route: IV/PO Time: not reported NAI Route and time: not reported

Not reported

NAI Route and time: not reported NAI Route: IV Time: not reported NAI (In subset of patients with initial anaphylactic reaction) Route and time: not reported NAI Route and time: not reported

NAI Route and time: not reported

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(continued)

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4.7%

NAI Route: PO Time: not reported

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Lee et al,17 2013

Reference/year

Design

Settings and subjects Incidence (%)

Manuyakorn et al,28 2015

Retrospective Hospitalized children 15 of 172 developed BR (5 F, 10 M)

8.7%

Alqurashi et al,21 2015

Retrospective Pediatric ED 71 of 484 developed BR (20 F, 51 M)

14.7%

Ko et al,36 2015

Retrospective Adult ED 9 of 415 developed BR (7 F, 2 M)

2.2%

Adult ED, 10 of 47 developed BR (7 F, 3 M)

21.3%

Trigger

9 NA 1A

Mean, 38  11.57

4 food 4 drugs 2 insect

Not reported

Mean, 6.5  4.6

2 food 10 drugs 3 blood products

49 A

Median, 6 (2.7-10.1)

47 food 3 drugs 1 bee sting 1 exercise 15 unspecified

A

Median, 41 (range, 24-60)

4 food 5 drugs

Time to onset (h)*

Median, 21.7 (range, 4.5-47)

Risk factors

Initial symptoms of abdominal pain. Lower risk in anaphylaxis patient with lower respiratory rate Not reported Patients with BR tended to be younger than those with UR (6.47  4.65 y vs 8.87  4.59 y), have more severe initial reaction, and less likely to be treated with epinephrine Lower risk in patient with anaphylaxis to known previous triggers Before ED discharge: Age 6-9 y, 4.7 (3.3-6) Delay in presentation After ED discharge: to ED or 18.5 (9.2-25.2) epinephrine administration for >90 min from the onset of the initial reaction. Wide pulse pressure at triage. Treatment of initial reaction with >1 dose of epinephrine. Administration of inhaled b-agonists in ED 15 (range, 1-45) History of anaphylaxis from resolution to drugs of initial symptoms

Association with corticosteroids

NAI Route: not reported Median time (min), 2.17 (0.67-15.75)

NAI Route and time: not reported

NAI Route: IV/PO Median time (min) to first dose, 120 (IQR. 87-256)

Not reported (only anaphylaxis patients treated with steroids were included in the study)

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Prospective

Age (y)

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Sricharoen et al,26 2015

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TABLE I. (Continued)

A, Anaphylactic; BR, biphasic reaction; F, female; IQR, interquartile range; M, male; NA, nonanaphylactic; NAI, no association identified; PO, per os (by mouth); UR, uniphasic reaction. *Time from onset of the initial reaction. †A total of 400 of 1141 developed late reaction: 53 (4.6%) reported late reactions both on the active challenge day and on the placebo challenge day, 237 (20.8%) reported late reactions only on the active challenge day, and 110 children (9.6%) reported late reactions only on the placebo challenge day. Only data of the active challenge day group reported above.

Saleh-Langenberg et al,45 2016

Retrospective Pediatric allergy clinic 171 of 1142 developed both immediate and BR†

14.9%

67 A (moderate Mean, 5.7  4.2 to severe index severity score)

Oral food challenge to milk, egg, peanut, cashew, and hazelnut

Mean, 3.5  7.6

BRs are associated with severe initial reactions after the challenge

Not reported

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factor associated with a reduced risk of multiple epinephrine administration in the ED (odds ratio, 0.2; 95% CI, 0.0-0.6).54 Similarly, Fleming et al55 found that children with food-induced anaphylaxis who received epinephrine before arrival to the ED were less likely to be hospitalized (17% vs 43%; P < .001) or to require antihistamines, corticosteroids, or inhaled b-agonists compared with those who received epinephrine in the ED. Epinephrine also plays an important role in the prevention of biphasic anaphylaxis.56 Ellis and Day44 found that early treatment of the initial anaphylactic reactions with epinephrine was associated with a lower risk of developing biphasic reactions. Several observational studies found that epinephrine treatment for initial anaphylaxis was either underused or delayed in patients who developed biphasic anaphylaxis (Table I).15,18,21,28,31 Studies investigating the role of platelet-activating factor (PAF) in human anaphylaxis have indicated that serum PAF levels are significantly increased and correlate directly with the severity of anaphylaxis.19,57 Data reveal that PAF is a highly injurious and potentially lethal mediator of anaphylaxis.58 The only therapies that have been shown to counter the effect of PAF are epinephrine or a combination of epinephrine with methylene blue.59 This mediator peaks within 60 to 90 minutes from the onset of anaphylaxis.60 Vadas and Perelman61 examined the effect of the timing of epinephrine addition on the action of PAF and found that epinephrine was most effective when administered before stimulation with PAF but was progressively less effective with time after PAF stimulation. Therefore, early administration of epinephrine is most effective in slowing or stopping the progression of anaphylaxis, whereas delayed administration of epinephrine neither interferes with PAF signaling nor favorably alters the natural history of anaphylaxis.58

Corticosteroids in anaphylaxis. Previous studies showed that corticosteroids are more frequently used than epinephrine when treating anaphylaxis. In a multicenter registry of more than 2000 patients with severe anaphylaxis from several European countries, Grabenhenrich et al62 found that less than 15% of the cohort received epinephrine compared with nearly 50% who received corticosteroids in the ED.63 Corticosteroids have 2 hypothetical effects. First, there is the possibility that using corticosteroid in the treatment of the initial phase could reduce the severity of the reaction. Second, and more feasibly, is the thought that corticosteroids could prevent or reduce the risk of biphasic reactions.64 Role of corticosteroids in the initial phase. The rationale behind the use of corticosteroids in the initial phase of anaphylaxis is an extrapolation from their effectiveness in acute exacerbations of asthma and croup, where they have been shown to reduce the need for admission to hospital and to prevent relapses.65-67 Data from fatal anaphylaxis indicate that the median time to cardiac or respiratory arrest is as follows based on the inciting antigen: 5 minutes for drugs, 15 minutes for venom (insect sting), and 30 minutes for food-triggered reactions.64 Previous studies looking at bioavailability showed that the median time to reach maximum serum concentration for oral hydrocortisone is approximately 1 to 2 hours after administration.68 Thus, based on their pharmacodynamic activity, corticosteroids are highly unlikely to prevent immediate death from anaphylaxis, or to reduce the severity of the initial reaction. Furthermore, there is no evidence from randomized controlled trials to confirm the effectiveness of corticosteroids in the treatment of anaphylaxis.69,70 Therefore, and not

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Systemic corticosteroids44

Presence of severe symptoms12 Respiratory manifestations29 Lower respiratory rate26 Anaphylaxis induced by known previous triggers28

Systemic corticosteroids7,10-31

Delay in administration of first epinephrine13,15,18,21,35 Delay in presentation to ED15,21,29

Anaphylaxis triggered by food42 No effect

Protective factors

Treatment with >1 epinephrine dose11,14,16,17,21,31,43 No treatment with epinephrine or low total dose21,28,44 Fluid bolus22,31 Hypotension or wide pulse pressure Unstable vital signs29 Syncope16 Gastrointestinal symptoms: vomiting, diarrhea, abdominal pain16,25,26 Multiple organ involvement17 Severe initial reaction17,22,28,29,45 Respiratory distress, wheezing or hypoxia21,25 Unknown trigger25,42 Oral allergen History of asthma11,35,34 Low peak expiratory flow (PEF) at baseline34 Delay of
30 min between exposure to trigger and development of initial reaction12 Age: young age, age 6-9 y21,28,45 Previous anaphylaxis25 Previous anaphylaxis to drugs36 Preexisting lung disease19 Allergic rhinitis45 Risk factors

12

Patients’ characteristics

TABLE II. Identified potential predictors from previous studies

Disease characteristics

7,16,33

Treatment characteristics

surprisingly, the updated practice parameters for anaphylaxis noted that “corticosteroids have no role in the acute management of anaphylaxis.”71

Role of corticosteroids in biphasic anaphylaxis. Out of 22 studies that examined the association of corticosteroids with biphasic anaphylaxis only 1 study seems to support the use of corticosteroids for this indication (Table I). Ellis and Day44 found that fewer biphasic reactors received corticosteroids (35% vs 55%), and, when treated, lower doses (31 mg vs 63 mg prednisone equivalents) were prescribed, though these associations were not statistically significant. However, none of the remaining 21 studies found any preventive association between corticosteroids and biphasic anaphylaxis (Table I). Furthermore, among more than 5000 children who were diagnosed with anaphylaxis at 35 American children’s hospitals between 2009 and 2013, corticosteroid administration was not associated with a reduction in ED revisit for allergic reaction within 72 hours from the initial visit (adjusted odds ratio, 1.01; 95% CI, 0.50-2.05).41 Adding to the body of evidence, Lee et al42 conducted a systematic review to evaluate predictors of biphasic anaphylaxis. The metanalysis included 17 studies and found no significant association between steroid treatment (pooled odds ratio, 1.52, 95% CI, 0.962.43) and biphasic reactions. In fact, one might argue that the pooled analysis indicates a trend toward increased risk of biphasic anaphylaxis. However, these data should be interpreted carefully because of the significant clinical and statistical heterogeneity between pooled studies (I2 ¼ 65%). Moreover, this trend is likely secondary to confounding by indication. As noted above, patients who developed a delayed reaction tend to present with more severe anaphylaxis and, therefore, more likely to receive multiple therapies including corticosteroids.21,72 It is not clear from the current literature whether the formulation or the administered dose of systemic corticosteroids has any impact on the risk of biphasic anaphylaxis. However, several studies examined the association of biphasic anaphylaxis with different formulations (dexamethasone vs prednisone vs hydrocortisone) and doses, and found no association.21,24,26,31,43 Similarly, the time from the onset of the reaction to corticosteroid administration was also assessed by few pediatric and adult studies and was not found to influence the outcome.21,31,38,44 The updated guidelines deemphasized the role of corticosteroids and moved them from being considered in all patients to being an “optional” second- or even third-line agents, and recommended against delaying epinephrine to administer them.2,71,73,74 Role of corticosteroids in the prevention of anaphylaxis. The utility of corticosteroids in the prevention of anaphylaxis has been called into question recently.70 de Silva et al75 conducted a factorial designed randomized trial to investigate the efficacy of premedication with epinephrine, antihistamine, and hydrocortisone in the prevention of snake anti-venome induced anaphylaxis in more than 1000 patients. It concluded that neither antihistamine nor hydrocortisone alone was effective in preventing serious adverse reactions. Adding antihistamines or hydrocortisone to the epinephrine (low prophylactic dose) did not increase its effectiveness. Even more concerning, hydrocortisone appeared to negate the effect of epinephrine and increased the risk of severe reaction. Another open-labeled randomized controlled trial found that intravenous hydrocortisone showed no difference in the timing, rate, or severity of adverse drug reactions to snake antivenom when administered simultaneously and

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up to 4 hours before antivenom.76 Davenport and Cohan77 recently reviewed the literature for the utility of corticosteroids in the prevention of anaphylaxis to iodinated contrast media. They found that pretreatment with corticosteroids did not prevent all contrast-related allergic reactions, and are unlikely to reduce the severity of subsequent reactions. Of note, however, anaphylaxis due to iodinated contrast media is not IgE mediated, and thus this study’s results should be interpreted with caution as one that should be applied widely to all cases of anaphylaxis.

Safety of corticosteroids. Patients at risk of anaphylaxis are more likely to have other atopic and immunologic diseases that require repeated courses of corticosteroids and therefore at higher risk of experiencing adverse side effects, even with short therapeutic courses. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing syndrome, psychiatric disturbances, and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods.78 Corticosteroids have also been associated with growth suppression and mood changes in children, and substantial cost and indirect harm in high-risk adults.78-80 Clinicians should also be aware that these agents have also been reported to cause immediate hypersensitivity reactions.81 CONCLUSIONS 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. Recommendations for future research Finally, we would like to reflect on the concluding remarks of Dr Lieberman who authored the first extensive review on biphasic anaphylaxis over a decade ago. He wrote: “Although we have made some progress in understanding the biphasic anaphylactic response since Popa and Lerner’s original article, we are yet a great distance from being able to predict those who will experience it or what will prevent it. The solutions to these clinical problems await further knowledge of the underlying pathogenesis of the biphasic anaphylactic response.”8 Since that review, more than 20 original studies have been published on biphasic anaphylaxis. The collective findings from these studies have certainly added a reasonable contribution to our understanding of the disease process and who will experience it. These studies also informed our rationale for therapeutic choices. Because corticosteroids do not seem to influence critical patient or disease characteristics, these studies questioned our previous enthusiasm for corticosteroids. It is clear that ultimately the field of anaphylaxis management would be guided by a prospective randomized controlled trial of corticosteroids versus placebo in the management of acute anaphylaxis, which would be ethically justifiable assuming the criterion standard, intramuscular epinephrine, was given to all patients.82 It is quite likely that such a study could give a more definitive answer to questions such as whether there is a subgroup of patients who may benefit from corticosteroids (eg, patients with asthma, or with marked upper airway symptoms), or whether steroids, while not preventing biphasic reactions,

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possibly reduce the severity of biphasic reaction. However, efficacy trials are unlikely to be conducted for a disease that is hard to accurately predict, and does not have a standard definition or validated severity grading across all age groups.70,83 As noted by several international organizations, these gaps need to be filled urgently.74,82,84 To increase value and reduce waste in future research, efforts should be focused on well-designed, multidisciplinary, prospective cohort trials that aim to accurately estimate the rate of biphasic anaphylaxis, and provide a robustly derived and validated predictive model.85 These studies should incorporate research findings from the rest of the anaphylaxis field, particularly factors associated with severe anaphylaxis.86,87 REFERENCES 1. Simons FER, Ardusso LRF, Bilò MB, El-Gamal YM, Ledford DK, Ring J, et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13-37. 2. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:442-77. 3. CIHI. Anaphylaxis and allergy in the emergency department. 2015. Available from: https://secure.cihi.ca/free_products/Anaphylaxis_Infosheet_en.pdf. Accessed December 18, 2015. 4. Sheikh A, Hippisley-Cox J, Newton J, Fenty J. Trends in national incidence, lifetime prevalence and adrenaline prescribing for anaphylaxis in England. J R Soc Med 2008;101:139-43. 5. Wood RA, Camargo CA Jr, Lieberman P, Sampson HA, Schwartz LB, Zitt M, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol 2014;133:461-7. 6. Tejedor-Alonso MA, Moro Moro M, Múgica-García M. Epidemiology of anaphylaxis: contributions from the last 10 years. J Investig Allergol Clin Immunol 2015;25:163-75. 7. Douglas DM, Sukenick E, Andrade WP, Brown JS. Biphasic systemic anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol 1994;93:977-85. 8. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217-26, 258. 9. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin North Am 2007;27:309-26, viii. 10. Brady WJ Jr, Luber S, Carter CT, Guertler A, Lindbeck G. Multiphasic anaphylaxis: an uncommon event in the emergency department. Acad Emerg Med 1997;4:193-7. 11. Popa VT, Lerner SA. Biphasic systemic anaphylactic reaction: three illustrative cases. Ann Allergy 1984;53:151-5. 12. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986;78:76-83. 13. Poachanukoon O, Paopairochanakorn C. Incidence of anaphylaxis in the emergency department: a 1-year study in a university hospital. Asian Pac J Allergy Immunol 2006;24:111-6. 14. Scranton SE, Gonzalez EG, Waibel KH. Incidence and characteristics of biphasic reactions after allergen immunotherapy. J Allergy Clin Immunol 2009;123:493-8. 15. Lertnawapan R, Maek-a-nantawat W. Anaphylaxis and biphasic phase in Thailand: 4-year observation. Allergol Int 2011;60:283-9. 16. Inoue N, Yamamoto A. Clinical evaluation of pediatric anaphylaxis and the necessity for multiple doses of epinephrine. Asia Pac Allergy 2013;3:106-14. 17. Lee J, Garrett JP, Brown-Whitehorn T, Spergel JM. Biphasic reactions in children undergoing oral food challenges. Allergy Asthma Proc 2013;34:220-6. 18. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762-6. 19. Brown SG, Stone SF, Fatovich DM, Burrows SA, Holdgate A, Celenza A, et al. Anaphylaxis: clinical patterns, mediator release, and severity. J Allergy Clin Immunol 2013;132:1141-1149.e5. 20. Grunau BE, Li J, Yi TW, Stenstrom R, Grafstein E, Wiens MO, et al. Incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis. Ann Emerg Med 2014;63:736-744.e2. 21. Alqurashi W, Stiell I, Chan K, Neto G, Alsadoon A, Wells G. Epidemiology and clinical predictors of biphasic reactions in children with anaphylaxis. Ann Allergy Asthma Immunol 2015;115:217-223.e2. 22. Vezir E, Erkoçoglu M, Kaya A, Toyran M, Özcan C, Akan A, et al. Characteristics of anaphylaxis in children referred to a tertiary care center. Allergy Asthma Proc 2013;34:239-46.

1204

ALQURASHI AND ELLIS

23. Nagano C, Ishiguro A, Yotani N, Sakai H, Fujiwara T, Ohya Y. Anaphylaxis and biphasic reaction in a children hospital [in Japanese]. Arerugi 2013;62:163-70. 24. Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions: occurrence and mortality. Allergy 2014;69:791-7. 25. Lee S, Bellolio MF, Hess EP, Campbell RL. Predictors of biphasic reactions in the emergency department for patients with anaphylaxis. J Allergy Clin Immunol Pract 2014;2:281-7. 26. Sricharoen P, Sittichanbuncha Y, Wibulpolprasert A, Srabongkosh E, Sawanyawisuth K. What clinical factors are associated with biphasic anaphylaxis in Thai adult patients? Asian Pacific J Allergy Immunol 2015;33:8-13. 27. Oya S, Nakamori T, Kinoshita H. Incidence and characteristics of biphasic and protracted anaphylaxis: evaluation of 114 inpatients. Acute Med Surg 2014;1: 228-33. 28. Manuyakorn W, Benjaponpitak S, Kamchaisatian W, Vilaiyuk S, Sasisakulporn C, Jotikasthira W. Pediatric anaphylaxis: triggers, clinical features, and treatment in a tertiary-care hospital. Asian Pacific J Allergy Immunol 2015;33:281-8. 29. Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28:381-8. 30. Jirapongsananuruk O, Bunsawansong W, Piyaphanee N, Visitsunthorn N, Thongngarm T, Vichyanond P. Features of patients with anaphylaxis admitted to a university hospital. Ann Allergy Asthma Immunol 2007;98:157-62. 31. Mehr S, Liew WK, Tey D, Tang ML. Clinical predictors for biphasic reactions in children presenting with anaphylaxis. Clin Exp Allergy 2009;39:1390-6. 32. Orhan F, Canitez Y, Bakirtas A, Yilmaz O, Boz AB, Can D, et al. Anaphylaxis in Turkish children: a multi-centre, retrospective, case study. Clin Exp Allergy 2011;41:1767-76. 33. Liew WK, Chiang WC, Goh AE, Lim HH, Chay OM, Chang S, et al. Paediatric anaphylaxis in a Singaporean children cohort: changing food allergy triggers over time. Asia Pac Allergy 2013;3:29-34. 34. Confino-Cohen R, Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Ann Allergy Asthma Immunol 2010;104:73-8. 35. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380-4. 36. Ko BS, Kim WY, Ryoo SM, Ahn S, Sohn CH, Seo DW, et al. Biphasic reactions in patients with anaphylaxis treated with corticosteroids. Ann Allergy Asthma Immunol 2015;115:312-6. 37. Sugiura A, Nakayama T, Takahara M, Sugimoto K, Hattori N, Abe R, et al. Combined use of ECMO and hemodialysis in the case of contrast-induced biphasic anaphylactic shock. Am J Emerg Med 2016;34:1919.e1-2. 38. Niggemann B, Yürek S, Beyer K. Severe anaphylaxis requiring intensive care during oral food challenge—it is not always peanuts. Pediatr Allergy Immunol 2017;28:201-3. 39. Grabenhenrich LB, Dölle S, Moneret-Vautrin A, Köhli A, Lange L, Spindler T, et al. Anaphylaxis in children and adolescents: the European Anaphylaxis Registry. J Allergy Clin Immunol 2016;137:1128-1137.e1. 40. Altman AM, Camargo CA Jr, Simons FER, Lieberman P, Sampson HA, Schwartz LB, et al. Anaphylaxis in America: a national physician survey. J Allergy Clin Immunol 2015;135:830-3. 41. Michelson KA, Monuteaux MC, Neuman MI. Glucocorticoids and hospital length of stay for children with anaphylaxis: a retrospective study. J Pediatr 2015;167:713-9. 42. Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of onset and predictors of biphasic anaphylactic reactions: a systematic review and metaanalysis. J Allergy Clin Immunol Pract 2015;3:402-8. 43. Brazil E, MacNamara AF. “Not so immediate” hypersensitivityethe danger of biphasic anaphylactic reactions. J Accid Emerg Med 1998;15:252-3. 44. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol 2007;98:64-9. 45. Saleh-Langenberg J, Flokstra-De Blok BMJ, Alagla N, Kollen BJ, Dubois AEJ. Late reactions in food-allergic children and adolescents after double-blind, placebo-controlled food challenges. Allergy 2016;71:1069-73. 46. Goodman SN, Schneeweiss S, Baiocchi M. Using design thinking to differentiate useful from misleading evidence in observational research. JAMA 2017; 317:705-7. 47. Agoritsas T, Merglen A, Shah ND, O’Donnell M, Guyatt GH. Adjusted analyses in studies addressing therapy and harm: users’ guides to the medical literature. JAMA 2017;317:748-59. 48. Grady D, Berkowitz S. Why is a good clinical prediction rule so hard to find? Arch Intern Med 2011;171:1701-2. 49. Wynants L, Collins GS, Van Calster B. Key steps and common pitfalls in developing and validating risk models. BJOG 2017;124:423-32.

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50. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol 2007;119: 1016-8. 51. Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy Clin Immunol 2007;119:1018-9. 52. Simons FE, Clark S, Camargo CA Jr. Anaphylaxis in the community: learning from the survivors. J Allergy Clin Immunol 2009;124:301-6. 53. Ko BS, Kim JY, Seo D-W, Kim WY, Lee JH, Sheikh A, et al. Should adrenaline be used in patients with hemodynamically stable anaphylaxis? Incident case control study nested within a retrospective cohort study. Sci Rep 2016;6:20168. 54. Hochstadter E, Clarke A, De Schryver S, LaVieille S, Alizadehfar R, Joseph L, et al. Increasing visits for anaphylaxis and the benefits of early epinephrine administration: a 4-year study at a pediatric emergency department in Montreal, Canada. J Allergy Clin Immunol 2016;137:1888-1890.e4. 55. Fleming JT, Clark S, Camargo CA Jr, Rudders SA. Early treatment of foodinduced anaphylaxis with epinephrine is associated with a lower risk of hospitalization. J Allergy Clin Immunol Pract 2015;3:57-62. 56. Ellis AK. Priority role of epinephrine in anaphylaxis further underscoredethe impact on biphasic anaphylaxis. Ann Allergy Asthma Immunol 2015;115:165. 57. Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T, et al. Plateletactivating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med 2008;358:28-35. 58. Vadas P. The platelet-activating factor pathway in food allergy and anaphylaxis. Ann Allergy Asthma Immunol 2016;117:455-7. 59. Zheng F, Barthel G, Collange O, Montémont C, Thornton SN, Longrois D, et al. Methylene blue and epinephrine: a synergetic association for anaphylactic shock treatment. Crit Care Med 2013;41:195-204. 60. Vadas P, Perelman B, Liss G. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol 2013;131:144-9. 61. Vadas P, Perelman B. Effect of epinephrine on platelet-activating factor-stimulated human vascular smooth muscle cells. J Allergy Clin Immunol 2012;129:1329-33. 62. Grabenhenrich L, Hompes S, Gough H, Ruëff F, Scherer K, Pföhler C, et al. Implementation of anaphylaxis management guidelines: a register-based study. PLoS One 2012;7:e35778. 63. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, et al. First European data from the network of severe allergic reactions (NORA). Allergy 2014;69:1397-404. 64. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000;30:1144-50. 65. Santos AF, Lack G. Commentary on “Glucocorticoids for the treatment of anaphylaxis”. Evidence-Based Child Health 2013;8:1295-6. 66. Russell KF, Liang Y, O’Gorman K, Johnson DW, Klassen TP. Glucocorticoids for croup. In: Klassen TP, editor. Cochrane database of systematic reviews. Chichester, UK: John Wiley & Sons, Ltd; 2011. p. CD001955. 67. Rowe BH, Spooner C, Ducharme F, Bretzlaff J, Bota G. Corticosteroids for preventing relapse following acute exacerbations of asthma. In: Rowe BH, editor. Cochrane database of systematic reviews. Chichester, UK: John Wiley & Sons, Ltd; 2007. p. CD000195. 68. Charmandari E, Johnston A, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol 2001;169:65-70. 69. Choo KJL, Simons FER, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev 2012;4. 70. Sheikh A. Glucocorticosteroids for the treatment and prevention of anaphylaxis. Curr Opin Allergy Clin Immunol 2013;13:263-7. 71. Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, et al. Anaphylaxis—a practice parameter update 2015. Ann Allergy Asthma Immunol 2015;115:341-84. 72. Matsui EC, Keet CA. Weighing the evidence: bias and confounding in epidemiologic studies in allergy/immunology. J Allergy Clin Immunol 2017;139: 448-50. 73. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary reportesecond National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med 2006;47:391-7. 74. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69:1026-45. 75. de Silva HA, Pathmeswaran A, Ranasinha CD, Jayamanne S, Samarakoon SB, Hittharage A, et al. Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial. PLoS Med 2011;8: e1000435.

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76. Kularatne SAM, Weerakoon K, Silva A, Maduwage K, Walathara C, Rathnayake I, et al. Efficacy of intravenous hydrocortisone administered 2-4 h prior to antivenom as prophylaxis against adverse drug reactions to snake antivenom in Sri Lanka: an open labelled randomized controlled trial. Toxicon 2016;120:159-65. 77. Davenport MS, Cohan RH. The evidence for and against corticosteroid prophylaxis in at-risk patients. Radiol Clin North Am 2017;55:413-21. 78. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013;9:30. 79. Kayani S, Shannon DC. Adverse behavioral effects of treatment for acute exacerbation of asthma in children: a comparison of two doses of oral steroids. Chest 2002;122:624-8. 80. Davenport MS, Mervak BM, Ellis JH, Dillman JR, Dunnick NR, Cohan RH. Indirect cost and harm attributable to oral 13-hour inpatient corticosteroid prophylaxis before contrast-enhanced CT. Radiology 2016;279:492-501. 81. Patel A, Bahna SL. Immediate hypersensitivity reactions to corticosteroids. Ann Allergy Asthma Immunol 2015;115:178-182.e3.

ALQURASHI AND ELLIS

1205

82. Simons FE, Ardusso LR, Bilò MB, Cardona V, Ebisawa M, El-Gamal YM, et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J 2014;7:9. 83. Niggemann B, Beyer K. Time for a new grading system for allergic reactions? Allergy 2016;71:135-6. 84. National Institute for Health and Clinical Excellence. Anaphylaxis: assessment and referral after emergency treatment j Guidance and guidelines j NICE. 2016. Available from: https://www.nice.org.uk/guidance/cg134/chapter/4-Researchrecommendations#the-frequency-and-effects-of-biphasic-reactions. Accessed December 12, 2016. 85. Ioannidis JP, Greenland S, Hlatky MA, Khoury MJ, Macleod MR, Moher D, et al. Increasing value and reducing waste in research design, conduct, and analysis. Lancet 2014;383:166-75. 86. Smith PK, Hourihane JO, Lieberman P. Risk multipliers for severe food anaphylaxis. World Allergy Organ J 2015;8:30. 87. Turner PJ, Baumert JL, Beyer K, Boyle RJ, Chan CH, Clark AT, et al. Can we identify patients at risk of life-threatening allergic reactions to food? Allergy 2016;71:1241-55.