Anaphylaxis: Translating recent studies into daily

practiceSangil Lee, MD, MS

Assistant professor, Department of emergency medicine University of Iowa Carver College of medicine

Disclosure• None

About myself…• Born and raised in Japan• Family medicine board certified• Emergency medicine board certified• Areas of interest: allergic reaction and anaphylaxis• Another area of interest: delirium and EEG

• Overall area of passion: EBM and translational research

Learning objectives 1) Recognize and diagnose anaphylaxis.2) Appropriately manage anaphylaxis patients.3) Distinguish anaphylaxis patients who should be observed after symptom

resolution4) Describe outpatient anaphylaxis management and follow up.

Anaphylaxis- History

Cited from: www.Utahallergy.com, picture from TimeRime.com, and badassofthe week.com

Scenario1• You are talking to the attending at the round and presenting a case of

allergic reaction. • …Mr. A developed rash, shortness of breath and throat swelling after

dose of Aspirin was given and required IVF, dose of IM epinephrine, prednisone, and antihistamine…• What is the current diagnostic criteria for anaphylaxis?

Scenario1

Scenario1. Definition of anaphylaxis

• Anaphylaxis is a rapid onset potentially life-threatening multisystem syndrome resulting from mediators released from mast cells and basophils. –WAO

1. Sampson, H.A., et al., Symposium on the definition and management of anaphylaxis: summary report. The Journal of allergy and clinical immunology, 2005. 115(3): p. 584-91.2. Johansson, S.G.O., et al., Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. Journal of Allergy and Clinical Immunology, 2004. 113(5): p. 832-836.

Scenario 1. NIAIDS/FAAN criteria• Anaphylaxis is highly likely when any one of the following 3 criteria is

fulfilled (cont):• 1. Acute onset of an illness (minutes to several hours) with involvement

of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)• AND AT LEAST ONE OF THE FOLLOWING• a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm,

stridor, reduced PEF, hypoxemia)• b. Reduced BP or associated symptoms of end-organ dysfunction (eg,

hypotonia [collapse], syncope, incontinence)

Scenario 1. NIAIDS/FAAN criteria• Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled

(cont):• 2. Two or more of the following that occur rapidly after exposure to a likely

allergen for that patient (minutes to several hours):• a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush,

swollen lips-tongue-uvula)• b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced

PEF, hypoxemia)• c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope,

incontinence)• d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

Scenario 1. NIAIDS/FAAN criteria• Anaphylaxis is highly likely when any one of the following 3 criteria is

fulfilled (cont):• 3. Reduced BP after exposure to known allergen for that patient

(minutes to several hours):• a. Infants and children: low systolic BP (age specific) or greater than

30% decrease in systolic BP• b. Adults: systolic BP of less than 90 mm Hg or greater than 30%

decrease from that person’s baseline

So, How good is the criteria? • Campbell, R.L., et al., Evaluation of national institute of allergy and

infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients. JACI, 2012. 129(3): p. 748-52.

NIAID/FAAN Criteria Sensitivity=97%

NIAID/FAAN Criteria Positive Predictive Value=69%

Scenario 2.• You are treating a 65 year old male with prior history of anaphylaxis presenting

with anaphylaxis to your unit (emergency department or inpatient unit). Initial symptom was controlled with prompt administration of epinephrine, H1 and H2 blocker.

• In an hour later, patient requested to be released. You are wondering if the patient can be discharged without a prolonged monitoring.

Multivariable model to predict biphasic anaphylaxis or symptom recurrence

among ED anaphylaxis patients

Sangil Lee, MD, MS

Alexa Peterson, BA

ChristiNe Lohse, MSErik P Hess, MD, MScRonna L Campbell, MD, PhD

Introduction• Anaphylaxis is most commonly treated in the Emergency Department (ED)

•Risk of biphasic reaction is rationale for observation

•Current guidelines recommend observation for 4-6 hrs

•A biphasic anaphylactic reaction was defined as recurrent anaphylaxis (meeting NIAID/FAAN criteria) without re-exposure to an inciting trigger within 72 hrs. after initial anaphylaxis resolution

• 5% rate of biphasic reaction at Saint Mary’s Hospital in Mayo Clinic Rochester

Objective

• To examine characteristics of ED anaphylaxis patients to determine which

patients are at increased risk of developing a biphasic reaction

Methods• Design: Observational study of a retrospective and prospective cohort of ED

patients. The Mayo Clinic Institutional Review Board approved the study protocol• Setting: ED of Mayo Clinic Hospital, Saint Mary’s Campus, Rochester, MN, a

tertiary care academic medical institution with 73,000 ED visits annually• Participants: Consecutive patients meeting NIAID/FAAN criteria for anaphylaxis

from 2008 to 2015 who provided consent• Patient selection:

• Retrospective cohort: Patient’s with ED diagnoses including “anaph-”, “allerg,” or “sting”, were included if NIAID/FAAN criteria were met

• Prospective cohort: Patient’s with a chief concern that included “allergic,” “reaction,” “anaphy-,” “angio-,” “sting,” “hives,” or “rash” were included if NIAID/FAAN criteria were met

Methods• Predictor variables collected: • Age and sex• History of asthma or anaphylaxis • Suspected inciting trigger• Delayed ED presentation (> 90 min

after symptom onset)• Number and timing of epinephrine

doses (prior to ED arrival vs. after)• Number of bronchodilator doses• Signs &Symptoms: syncope,

diarrhea, hypotension, wheezing

Outcomes: • Biphasic reaction meeting NIAID/FAAN

criteria• Biphasic reaction requiring any

treatment• 72 return visit due to allergy related

symptoms• Direct admission after ED discharge

within 72 hours due to allergy related symptoms

Statistical Analysis• Statistical analyses were performed using version 9.4 SAS software package • Associations of the candidate predictors with the outcomes of interest were

evaluated using univariable and multivariable logistic regression models• Summarized with odds ratios and 95% confidence intervals • All tests were two-sided and p-values <0.05 were considered statistically

significant

Results• 863 anaphylaxis-related visits met NIAID criteria among 798 patients

• Biphasic reaction meeting NIAID/FAAN criteria = 35 (4.1%) visits

• Biphasic reaction and associated adverse event = 63 (7.3%) visits• Biphasic reaction requiring any treatment (N=63, 7.3%)• 72 hr ED return visit due to allergy related symptoms (N=22, 2.6%)• Direct admission after ED discharge within 72 hrs due to allergy related symptom (N=1,

0.1%)

Table 1: Sample characteristics (n=863)

Table 2. Univariable analysis of candidate predictors for any adverse outcomes

Table 2. Univariable analysis of candidate predictors for any adverse outcomes (cont)

Table 3: Multivariable model to predict biphasic recurrence meeting NIAID/FAAN criteria and any adverse outcome, N=799

Table 4: Predicted probabilities of biphasic recurrence meeting NIAID/FAAN criteria

Main summary • A 4.1% rate of biphasic reaction meeting NIAID/FAAN criteria, and 7.3%

rate of those requiring treatment, ED return visits or direction hospitalization, were identified in this study • A history of anaphylaxis, unknown inciting trigger and first epinephrine

use after more than 60 minutes of symptom onset were identified as risk factors for a biphasic reaction• We presented the Table showing the predicted probabilities for developing

a biphasic reaction

Limitations• Infrequent event rate and wide CI• Retrospective data with possible bias• Single center study with Caucasian pt population

Discussion & Implications• Biphasic reactions are infrequent but do occur, supporting current guidelines to

observe otherwise high risk patients after anaphylaxis • A history of anaphylaxis, Inciting trigger, and timing of epinephrine are important

factors to stratify risk• These finding can be used to increase evidence based clinical management of

anaphylaxis in the ED by identifying high vs low risk patients allowing clinicians to tailor the approach to individual patients

References

• 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 Sep;115(3):217-23 e2

• 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. [Observational Study]. 2014 May-Jun;2(3):281-7.

• Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics. 2000 Oct;106(4):762-6.

• Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. [Research Support, U.S. Gov't, P.H.S.]. 1992 Aug 6;327(6):380-4.

• Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 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. Ann Emerg Med. 2006 Apr;47(4):373-80.

Scenario 3.• A 54 year old male with history of anaphylaxis presents by EMS due to

difficulty breathing and facial swelling. Patient required endotracheal intubation in the field, and was admitted to your ICU. Family asked if this will happen again, and you are being consulted to give your expert opinion about recurrence.

Rate of Recurrent Anaphylaxis and Associated Risk Factors among Olmsted County Residents: A population-based Study

• Sangil Lee, MD, MS1, 2, Curtis Bashore1, Christine M Lohse, MS3, M. Fernanda Bellolio, MD, MS1, Alanna Chamberlain, PhD3, Kumi Yuki, MD4, Erik P Hess, MD, MSc1, Ronna L Campbell, MD, PhD1

• 1Department of Emergency Medicine, Mayo Clinic, Rochester, MN, 55905• 2Department of Emergency Medicine, Mayo Clinic Health System, Mankato, MN,

56001• 3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905• 4 The REACH institute, Ney York, NY, 10001

Lee et al. Ann Allergy Asthma and Immunology: 2016 in press

Disclosure• None

Recurrent anaphylaxis• Introduction• Methods• Results• Discussion

Introduction• Anaphylaxis is a systemic allergic reaction that can be fatal. Several studies in

different populations have reported increasing incidence rates of anaphylaxis over time.

• Recurrence is reported particularly in patients with multiple allergies, but there are few studies conducted in a population level.

• Study objective: This study was designed to measure the rate and risk factors for recurrent anaphylactic reactions in the population of Olmsted County, Minnesota from 2001 to 2010.

Methods• A population-based observational cohort among residents of Olmsted County

from 2001- 2010• Patients identified with anaphylaxis from the medical record linkage system

(Rochester Epidemiology Project: REP)• Candidate selected based on ICD codes (Figure 1), followed by chart review to

confirm the diagnosis of anaphylaxis based on NIADI/FAAN criteria• Demographics, inciting triggers, signs & symptoms, eval setting and treatment

recorded• IRB approved

Methods• Demographics, inciting triggers, signs & symptoms, eval setting and treatment

recorded• Inter rater agreement calculated• Variables collected with counts and percentages• Recurrence rate was reported as event per 100 person-years• Cox proportional hazards regression model for association of features with time to

recurrence• Time estimated as index date of recurrence to the date of recurrence the date of

last follow up or 12/31 if the patient was still being followed• All tests were two sides and P<0.05 was considered statistically significant, and we

reported 95% CI • Software: SAS 9.3

Results• Inter rater agreement: kappa 0.88 (95% 0.64-1.00)• Author’s search identified 611 patients with anaphylaxis (Figure1)

from 2001-2010.

All codes representing anaphylactic shock, anaphylactic shock caused by food, anaphylactic

shock not classified elsewhere, anaphylactic shock after sting, n=613

20% of codes representing food/venom allergies (928/4668)

20% representing medication allergies (845/4242)

n=1773

Total patient records reviewed, n=2386

Study population, at least one event meeting the NIAID/FAAN criteria for anaphylaxis, anaphylaxis code (n=311), food/venom allergies code (n=49), Medication code (n=14),

Total n=375

No event meeting the NIAID/FAAN criteria for anaphylaxis, n=2011

Overall number of anaphylaxis from entire cohortanaphylaxis n=312, food/venom n=247 (0.053 x 4668), Medication n=72 (0.017 x 4242)

Total n=631 (312+ 247 + 72)

Patients with recurrence n=50One recurrence n=46Two recurrences n=3Eight recurrences n=1

No research authorization n=1No follow up date n=19

Final cohort N=611

No recurrence n=561

Figure 1: Selection process

Results: Summary of features N=611 Feature N (%)

Age at index anaphylaxis

Adult

 

463 (76)Women  299 (49)

Race/ethnicity (N=562)*

White

 

476 (85)Visit setting (N=610)

Emergency department

Urgent care

Allergy clinic

 

467 (77)

33 (5)

40 (7)Disposition (N=606)

Home

Hospital ward

 

449 (74)

85 (14)

Past medical history Asthma Allergic rhinitis Atopic dermatitis Hives

 101 (17)61 (10)21 (3)28 (5)

Inciting allergen

Food

Venom

Medication

 

223 (37)

146 (24)

130 (21)

Feature N (%)

Epinephrine as a therapy: 288 (47)

Results: Recurrence features 

• 50 patients (8%) of recurrence during the study period• Mean 1.8 years (median 0.6years, IQR 0.1 to 4.1)• Recurrence rate of 2.6 per 100 person-years• 46 experienced one recurrence, 3 experienced two, and 1

experienced a total of 8 recurrences• Also refer to the next slide

Results: summary of recurrence (N=60)Feature N (%) Pediatric

Adult

 14 (23)

46 (77)Sex

Women

 

33 (55)Race/ethnicity

White

 

52 (87)Visit setting

Emergency department

Allergy clinic/Clinic

 

52 (87)

6 (10)

Feature N (%)Disposition

Home

Hospital ward

 

45 (75)

11 (19)Inciting allergen

Food

Medication

Venom

Unknown

 

20 (33)

5 (8)

7 (12)

17 (28)

Epinephrine as a therapy 39 (65)

Results: Univariable analysis for recurrence

• TBD

Feature Hazard Ratio (95% CI) P-valuePast medical history

Asthma

Allergic rhinitis

Atopic dermatitis

Hives

1.39 (0.71-2.71)

1.86 (0.87-3.96)

3.41 (1.21-9.61)

2.12 (0.84-5.36)

0.34

0.11

0.020

0.11Inciting allergen

Food

Medication

Venom

Unknown

Contrast, latex, and other

1.0 (reference)

0.63 (0.28-1.41)

0.34 (0.14-0.84)

1.14 (0.50-2.58)

1.58 (0.67-3.72)

0.26

0.019

0.76

0.30Allergist saw patient after index anaphylaxis 0.89 (0.51-1.55) 0.67Allergy tests performed (N=608) 0.85 (0.47-1.54) 0.59Steroid provided as therapy 4.30 (1.93-9.59) <0.001Epinephrine provided as therapy 1.44 (0.82-2.52) 0.20

Results: Univariable analysis for recurrence

Results: Univariable analysis for recurrence (cont)

Results: Multivariable analysis for outcome of recurrence and candidate risk factorsFeature Hazard Ratio (95% CI) P-valueAtopic dermatitis 5.60 (1.95-16.13) 0.001

Oral pruritus 9.93 (4.25-23.21) <0.001

Chest pain 0.24 (0.07-0.79) 0.019

Cough 4.70 (2.06-10.71) <0.001

Steroid provided as therapy 5.16 (2.28-11.67) <0.001

CI: Confidence interval

Discussion- main findings• Recurrence rate 2.6 per 100 patient-years• Median time to recurrence 0.6 years• Recurrence associated with history of atopic dermatitis, presenting

signs and symptoms of cough, oral pruritus and received a steroid therapy, but…• Recurrence had decreased risk with the presence of chest pain

Discussion• Rate of recurrence was 8%. Previous studies reported 22-76%

recurrence rate in the allergy clinic patients collected by survey- likely sampling/referral bias. • The time to recurrence was about 7months- supporting the strategy

to supply epinephrine for future event. • Statistically significant but clinically difficult to utilize findings- a

history of atopic dermatitis, cough, oral pruritus, chest pain and treatment with steroid and recurrence• Availability of epinephrine auto-injector rose from 13% to 76% with

the recurrence.

Limitations• Data coding and missing data issue• Selection bias for sampling • Data accuracy from medical record• Caucasian cohort

Conclusion• Recurrence rate was 8%, and half of them experience within 7months.• The risk of recurrence with a history of atopic dermatitis and

mucocutaneous and respiratory symptoms during initial reaction. • Tailored approach for each patient to be prepared for future

recurrence, by providing epinephrine auto-injector and referral to allergist is important.

References• Sampson HA, Munoz-Furlong A, Campbell RL, et al. 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. Annals of emergency medicine 2006; 47:373-80.• Decker WW, Campbell RL, Manivannan V, et al. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. J Allergy Clin Immunol 2008; 122:1161-5.• 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.• Tejedor-Alonso M, Moro-Moro M, Mosquera Gonzales M, et al. Increased incidence of admissions for anaphylaxis in Spain 1998-2011. Allergy 2015.• Turner P, Gowland M, Sharma V, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012. J Allergy Clin Immunol 2015; 135:956-63.• Sampson HA, Munoz-Furlong A, Campbell RL, et al. 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. Ann Emerg Med 2006; 47:373-80.• Mullins RJ. Anaphylaxis: risk factors for recurrence. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2003; 33:1033-40.• Gold MS, Sainsbury R. First aid anaphylaxis management in children who were prescribed an epinephrine autoinjector device (EpiPen). The Journal of allergy and clinical immunology 2000; 106:171-6.• Kemp SF, Lockey RF, Wolf BL, Lieberman P. Anaphylaxis. A review of 266 cases. Archives of internal medicine 1995; 155:1749-54.• Melton LJ, 3rd. History of the Rochester Epidemiology Project. Mayo Clinic proceedings 1996; 71:266-74.• Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ, 3rd. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clinic proceedings 2012; 87:1202-13.• St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, 3rd, Pankratz JJ, Brue SM. Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system. International journal of epidemiology 2012; 41:1614-24.• St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, Rocca WA. Use of a Medical Records Linkage System to Enumerate a Dynamic Population Over Time: The Rochester Epidemiology Project. American Journal of Epidemiology 2011;

173:1059-68.• Lee S HE, Lohse CM, Gilani W, Chamberlain AM, Campbell RL. Trends, characteristics and incidence of anaphylaxis in 2001-2010: A population study. J Allergy Clin Immunol 2016; In press. • Decker WW, Campbell RL, Manivannan V, et al. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. The Journal of allergy and clinical immunology 2008; 122:1161-5.• Harris PT, Thielke R, Payne R, Gonzalez J, Conde NJ. Research Electronic Data Capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;

42:377-81.• Mullins R. Anaphylaxis: risk factors for recurrence. Clin Exp Allergy 2003; 33:1033-40.• Kemp SL, Wolf R, Lieberman, Phil P. Anaphylaxis: a review of 266 cases. Archives of Internal Medicine 1995; 155:1749-54.• Vetander ML, Hakansson N, Lilja G. et al. Recurrent reactions to food among children at paediatric emergency departments. Clin Exp Allergy 2013; 44:113-20.• Sampson H. Anaphylaxis and Emergency Treatment. Pediatrics 2003; 111:1601-8.• Simons FE. Epinephrine auto-injectors: first-aid treatment still out of reach for many at risk of anaphylaxis in the community. Ann Allergy Asthma Immunol 2009; 102:403-9.• Manassis K. Managing Anxiety Related to Anaphylaxis in Childhood: A Systematic Review. Journal of Allergy 2012; 2012.• Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115:584-91 Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis

and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126:477-80 e1-42.

Summary• Diagnosis of anaphylaxis remains clinical• Clinical suspicion is sufficient to use epinephrine• Biphasic reaction is infrequent but does occur• Post anaphylaxis care requires a careful follow up as outpatient and

prescription of epinephrine

Question? Thank you! Sangil-lee@uiowa.edu• Acknowledgement: Daniel Cabrera, MD who graciously shared his

slides on anaphylaxis.