Anaphylaxis Update: Be Prepared!

OD0022
Ari R Cohen, MD, FAAP
Massachusetts General Hospital
Boston, MA
Faculty Disclosure Information (Option A)

I have no relevant financial relationships with the

manufacturer(s) of any commercial product(s) and/or
provider(s) of commercial services discussed in this
CME activity.

I do not intend to discuss an unapproved/investigative

use of a commercial product/device in my
presentation.
Learning Objectives

At the conclusion of the presentation, participants

should be able to:
1. Diagnose Anaphylaxis
2. Distinguish child and adult symptomatology
3. Differentiate myth versus science of treatment
Changes you may wish to make in practice:

1. Lower the threshold for giving IM epinephrine

2. Give epinephrine early instead of antihistamines
3. Use less steroids
Clinical Case Scenario

• 12 yo female walks into your office for an urgent care visit complaining of
rash. Rash has been present for 24 hours and is urticarial. Patient also
mentions she has had some nausea and abdominal cramping. She tried
some diphenhydramine with some relief. No respiratory symptoms,
swelling of lips or throat. No previous allergic reactions.
• What do you do next?
• A) Call EMS
• B) Give Epinephrine IM
• C) Recommend continuing antihistamine and adding H2 Blocker
• D) Prescribe steroids
Answer/Overview

• Depends on your clinic’s capabilities

• Auto-injectors versus vial 1mg/ml
• Recognizing anaphylaxis is critical and it is often under
treated
• Definition
• Pitfalls
• Science
• Myths
Definition from the 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-2005
• Anaphylaxis is a serious allergic reaction
that is rapid in onset and may cause
death
• Simple and straightforward that captures the severity of
the disease process
Anaphylaxis Basics

• Adults: Medication and stings

• Kids: Foods and stings (food allergy 8-11% of kids)
• Lifetime prevalence 1.6-5.1%
• IgE binding and cross-linking of the high affinity IgE receptor on the surface
of mast cells and basophils
• Neutrophils, monocytes, macrophages, and platelets and signaling through
mediators that include complement, leukotrienes, platelet activating factor, IL-6, IL-
10, and TNF-receptor 1.
• Prevalence of fatal anaphylaxis recently in the US/UK is between 0.47 and
0.69 per million persons
• Continued poor compliance with treatment guidelines
 The Effect of Mast Cell Activation on Different Tissues
Increased fluid Diarrhea and
Gastrointestinal secretion and
peristalsis Vomiting

Wheezing,
Mast-cell Increased airway
degranulation Respiratory edema and Coughing, Nasal
Congestion, Phlegm
mucous secretion

Increased blood Tachycardia and

Cardiovascular flow, permeability,
Hypotension
dilation

Janeway Immunobiology.
 Symptoms of Allergic Reactions

Pistiner, Lebovidge, et. al. Living Confidently With Food Allergy, Anaphylaxis Canada, 2013.
The symposium created the following criteria

• These were meant to capture 95% cases of

anaphylaxis
• If you met any of the three criteria you were
classified as anaphylaxis.
• Prospectively validated in an ED setting and had a
positive likelihood ratio of 3.26 and negative
likelihood ratio of 0.07
• sensitivity of 95% with a specificity of 71%
Campbell RL, Hagan JB, Manivannan V, 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. J Allergy
Clin Immunol.2012;129(3):748–752
 NIAID/FAAN Diagnostic Criteria for Anaphylaxis
Anaphylaxis is highly likely when any one of the 3 criteria are
fulfilled:
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)
 NIAID/FAAN Diagnostic Criteria for Anaphylaxis
Anaphylaxis is highly likely when any one of the 3 criteria are
fulfilled:
• 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)
 NIAID/FAAN Diagnostic Criteria for Anaphylaxis
Anaphylaxis is highly likely when any one of the 3 criteria are
fulfilled:
• 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 (70 + agex2)
• b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person's baseline
• Caveat: those with known severe rxn
• They have high sensitivity (96.7%), reasonable specificity (82.4%), and a high negative
predictive value (98%)
• Campbell RL, Hagan JB, Manivannan V, 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. J Allergy
Clin Immunol.2012;129(3):748–752

Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL,
Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. 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. PMID: 16461139.
2020 AAAAI Practice Parameter Update
• The 2006 criteria proposed for definition of
anaphylaxis by National Institute of Allergy and
Infectious Disease are useful framework
• But need for rapid treatment
• Poor utility of confirmatory tests
• “Fulfilling diagnostic criteria is not a prerequisite
for epinephrine administration in a patient
experiencing an acute allergic reaction.”
 Myth: Steroids are essential
• No proven benefit for acute anaphylaxis
• Acceptable second line treatment
• 50-75% get prescribed at d/c from ED
• No proven benefit at preventing biphasic
reaction
• NNT 161 and ? Increased rate of biphasic rxn with steroids in < 18yo

• No placebo-controlled trials
• ? Benefit in asthma or steroid deficient
• Will use with hx of late phase reaction or
really sick

Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, Dinakar C, Ellis A, Greenhawt M, Khan DA, Lang DM, Lang ES, Lieberman JA, Portnoy J, Rank MA, Stukus
DR, Wang J; 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. PMID: 32001253.
MYTH: antihistamines stop anaphylaxis
• Second-line treatment for anaphylaxis
• Slow onset of action
• Inability to stop mast cell degranulation
• Do not treat vasodilation or bronchospasm
• Use of antihistamines can delay the necessary use of
epinephrine
• H1 and H2 antagonists are synergistic in treating dermal
symptoms
Anaphylaxis and Hypotension

• Position- recumbent with legs elevated

• IV epi if not responsive to IM epi or if hypotension
persists
• Avoid IV bolus except in arrest
• Side-effect of arrhythmias
• Continuous low-dose infusions safest
• Rapid fluid aggressive resuscitation
• Up to 35% blood volume extravasation
• Vasodilation causing pooling
 Biphasic Reactions
• Recent studies found a 4% rate (compared to 1-20%)
• Risk factors include 1) Unknown trigger 2) Prior
anaphylaxis 3) Delayed EPI administration 4) Severe
reactions
• Median time of onset 11 hours (up to 72h)
• Consider longer period of observation for biphasic
reaction with > 1 dose epi or severe reaction
• > 6 hours
Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, Dinakar C, Ellis A, Greenhawt M, Khan DA, Lang DM, Lang ES, Lieberman JA, Portnoy J, Rank MA, Stukus
DR, Wang J; 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. PMID: 32001253.
Special Considerations

• 18-year-old and 3-year-old and 6-month-old patients

are very different
• Different presentations
• Different symptoms
• Different physiology
 Caregiver-Reported Presentation of Severe Food-
Induced Allergic Reactions in Infants and Toddlers
• The survey was completed for 374 children (193 infants, 181 toddlers).
The most common symptoms and signs reported were:
• Skin reactions (90%), facial and extremity swelling (59%), gastrointestinal
issues (51%), and coughing/wheezing (45%)

• Infants more frequently experienced skin reactions, skin

mottling/cyanosis, and ear pulling/scratching or putting fingers in ears

• Toddlers more frequently experienced throat itching and

coughing/wheezing than infants

Pistiner M, Mendez-Reyes JE, Eftekhari S, Carver M, Lieberman J, Wang J, Camargo Jr CA. Caregiver-Reported Presentation of Severe Food-Induced Allergic
Reactions in Infants and Toddlers. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Nov 18.
 Food-induced Anaphylaxis in Infants and Children

• Retrospective, chart review; 357 cases (47 infants,

43 toddlers, 96 young children and 171 school-aged children)
• Skin: 94 % of infants vs. 91 % of toddlers, 62 %
of school-aged children [Hives-70 % of infants]
• GI: 89 % of infants vs. 63 % of toddlers, 60 % of
young children and 58 % of school-aged
children [Vomiting-83 % of infants]
Waheeda Samady, Jennifer Trainor, Bridget Smith, Ruchi Gupta. Food-induced Anaphylaxis in Infants and Children. Annals of Allergy, Asthma &
Immunology, 2018; DOI: 10.1016/j.anai.2018.05.025
Food-induced Anaphylaxis in Infants and Children
• Respiratory: 17 % in infants vs. 44 % in young
children and 54 % in school-aged children [One
infant in the study with wheezing]
• Low blood pressure present in one infant

• Conclusion: Infants primarily presented with GI

and skin symptoms
Waheeda Samady, Jennifer Trainor, Bridget Smith, Ruchi Gupta. Food-induced Anaphylaxis in Infants and Children. Annals of Allergy, Asthma
& Immunology, 2018; DOI: 10.1016/j.anai.2018.05.025
Caregiver-Reported Presentation of Severe Food-
Induced Allergic Reactions in Infants and Toddlers:
• Survey using Anaphylaxis in America and Asthma and Allergy
Foundation of America Infant Toddler Anaphylaxis Study
criteria
• Dermal- 94%
• Respiratory- 60/63%
• Gastrointestinal- 51%
• Neurologic- 34%
• Cardiovascular- 17/23%
Pistiner M, Mendez-Reyes JE, Eftekhari S, Carver M, Lieberman J, Wang J, Camargo Jr CA. Caregiver-Reported Presentation of Severe
Food-Induced Allergic Reactions in Infants and Toddlers. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Nov 18.
Caregiver-Reported Presentation of Severe Food-
Induced Allergic Reactions in Infants and Toddlers:
• Survey using Anaphylaxis in America and the Asthma and Allergy
Foundation of America Infant Toddler Anaphylaxis Study criteria
• Dermal- 94%
• Respiratory- 60/63%
• Gastrointestinal- 51%
• Neurologic- 34%
• Cardiovascular- 17/23%
Pistiner M, Mendez-Reyes JE, Eftekhari S, Carver M, Lieberman J, Wang J, Camargo Jr CA. Caregiver-Reported Presentation of Severe
Food-Induced Allergic Reactions in Infants and Toddlers. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Nov 18.
NIAID/FAAN Diagnostic Criteria for Anaphylaxis
NIAID/FAAN Diagnostic Criteria for Anaphylaxis
Cardiovascular Symptoms/Signs in Infants and Toddlers
with Anaphylaxis
• Hypotension is a late phase finding of shock and signifies
decompensated shock

• Physiologically and developmentally appropriate symptoms/signs

that signify compensated shock
• Tachycardia not related to crying
• Change in mental status (lethargy, inconsolability, or hypotonia)
• Poor perfusion (cyanosis or mottling, decreased capillary refill)
• Tachypnea
Pistiner M, Handorf A, Camargo Jr C, Cohen A. Approaching Cardiovascular Symptoms/Signs in Infants and Toddlers with Anaphylaxis . The Journal of
Allergy and Clinical Immunology: In Practice. 2021 In-Press.
Kleinman ME, et. al. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and
emergency cardiovascular care. Circulation. 2010;122(18_suppl_3):S876-908.
Poor KM, Ducklow TB. Benefit of BP Measurement in Pediatric ED Patients. ISRN Nurs. 2012;2012:627354.
Cardiovascular Symptoms/Signs in Infants and Toddlers
with Anaphylaxis
• Hypotension is a late phase finding of shock and signifies
decompensated shock

• Physiologically and developmentally appropriate symptoms/signs that

signify compensated shock
• Tachycardia not related to crying
• Change in mental status (lethargy, inconsolability, or hypotonia)
• Poor perfusion (cyanosis or mottling, decreased capillary refill)
• Tachypnea
Pistiner M, Handorf A, Camargo Jr C, Cohen A. Approaching Cardiovascular Symptoms/Signs in Infants and Toddlers with Anaphylaxis .
The Journal of Allergy and Clinical Immunology: In Practice. 2021 In-Press.
Kleinman ME, et. al. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary
resuscitation and emergency cardiovascular care. Circulation. 2010;122(18_suppl_3):S876-908.
Poor KM, Ducklow TB. Benefit of BP Measurement in Pediatric ED Patients. ISRN Nurs. 2012;2012:627354.
 Cardiovascular Symptoms/Signs in Infants and
Toddlers with Anaphylaxis
• Heart rate obtained when a child is
not actively crying can be useful in
driving management decisions,
such as administration of
epinephrine and fluid

Pistiner M, Handorf A, Camargo Jr C, Cohen A. Approaching Cardiovascular Symptoms/Signs in Infants and Toddlers with Anaphylaxis . The Journal of
Allergy and Clinical Immunology: In Practice. 2021 In-Press.
Kleinman ME, et. al. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and
emergency cardiovascular care. Circulation. 2010;122(18_suppl_3):S876-908.
Poor KM, Ducklow TB. Benefit of BP Measurement in Pediatric ED Patients. ISRN Nurs. 2012;2012:627354.
Cardiovascular Symptoms/Signs in Infants and Toddlers
with Anaphylaxis
• Utilize blood pressure when decompensated
shock or hemodynamic instability are
suspected
• Hypotension may signify need for escalation
of clinical interventions
• Continuous epinephrine infusion
• Admission to PICU
• Invasive monitoring
Pistiner M, Handorf A, Camargo Jr C, Cohen A. Approaching Cardiovascular Symptoms/Signs in Infants and Toddlers with
Anaphylaxis . The Journal of Allergy and Clinical Immunology: In Practice. 2021 In-Press.
Kleinman ME, et. al. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for
cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18_suppl_3):S876-908.
Poor KM, Ducklow TB. Benefit of BP Measurement in Pediatric ED Patients. ISRN Nurs. 2012;2012:627354.
Mental Status in the Infant and Toddler
Mental Status in the Infant and Toddler

Diaper change
Feeding
Pacifier
Swaddle
Comfort

Or
Epinephrine
Mental Status in the Infant and Toddler
Discharge

• No well-defined criteria for duration of observation

• Observe until anaphylaxis resolves
• 1 h versus 4-6 h asymptomatic
• Extended observation for some
• Rx epi autoinjector-x2
• Refer to allergist (1/3 unknown trigger at
presentation)
• Provide patient info on risk of recurrence, threshold
for further care, trigger avoidance, auto-injector use
Case Scenario Continued

• Our initial case does not meet the criteria for anaphylaxis as there was
no known trigger. Had there been a known trigger the cutaneous and
GI symptoms may have met the second criteria if persistent
• As antihistamines had not resolved her symptoms, I still may have given
IM epi
• One must consider the circumstances and continue to treat the clinical
picture. If this was happening on an airplane at 30,000 feet, there
would be no question I would want to give epi.
Case scenario #2

• 8 yo old with multiple food allergies had urticaria and

vomiting after eating at a restaurant. Also associated
with throat tightness and cough which resolved after
antihistamine taken 30 min ago. Now in ED with
residual urticaria, no further vomiting nor respiratory
symptoms.
• Does this case meet the criteria for anaphylaxis?
• Do you treat with epi at this point?
• For how long do you observe this patient?
 Case scenario #2

• 8 yo old with multiple food allergies had urticaria and vomiting after eating at
a restaurant. Also associated with throat tightness and cough which resolved
after antihistamine taken 30 min ago. Now in ED with residual urticaria, no
further vomiting nor respiratory symptoms.
• Does this case meet the criteria for anaphylaxis?
• This is the easy one. YES, meets Criteria 1 and 2, even though
symptoms have resolved
• Do you treat with epi at this point?
• How long do you observe this patient for?
 Case scenario #2
• 8 yo old with multiple food allergies had urticaria and vomiting after eating at a restaurant. Also associated
with throat tightness and cough which resolved after antihistamine taken 30 min ago. Now in ED with
residual urticaria, no further vomiting nor respiratory symptoms.
• Does this case meet the criteria for anaphylaxis?
• Do you treat with epi at this point?
• Harder. Still with symptoms and 30min ago met criteria. Antihistamines
have not stopped the cascade and IM epi is the treatment of choice with
few serious side effects and delayed epi leads to worse outcomes so…
• I would still give it but do not have any literature to support this decision.
(after 60min, I would not)
• Such cases cause much variability in practice
• Lieberman JA, Camargo CA, Pistiner M, Wang J, Camargo CA Jr. Pediatrician perspectives on symptom presentation and treatment
of acute allergic reactions. Annals of Allergy, Asthma & Immunology. 2021;126

• How long do you observe this patient for?

Case scenario #2
• 8 yo old with multiple food allergies had urticaria and vomiting after eating at a restaurant.
Also associated with throat tightness and cough which resolved after antihistamine taken 30
min ago. Now in ED with residual urticaria, no further vomiting nor respiratory symptoms.
• Does this case meet the criteria for anaphylaxis?
• Do you treat with epi at this point?
• How long do you observe this patient for?
• Duration of observation is not clear especially in a case
where most symptoms have resolved. Patient had
anaphylaxis and still has dermal involvement. I would
have given IM epi, H2 blocker and observed until 4 hours
post-resolution of respiratory and GI symptoms.
 Epinephrine Summary
• First-line, treatment of choice
– IM ant-lat thigh, avoid seams

#1 • Acts where we need it to

• Will make you feel better
• Fast-acting
GIVE It, RX It, • Delays in administration increase
TEACH It risk of death
• Err on the side of caution and give it
• Safe medicine- “lower the bar”
(Sampson, JACI,134; 5; 1016–1025) NIAID 6.3.1.1.
Take Home Points
• Well established criteria to define anaphylaxis exist
• Treatment for anaphylaxis is epinephrine
• All other treatments are secondary- should not delay epi
• Biphasic reactions are rare and difficult to predict
• Be cautious in severe reactions-prolonged observation
• Delayed epinephrine treatment maybe a risk factor
• Steroids not proven to prevent
• Observe until asymptomatic at minimum
• All new cases should get epi auto-injector, educational materials, and
allergy referral
Thanks

• Special thanks to Michael Pistiner, MD MMSc,

Director of the Food Allergy Advocacy, Education and
Prevention at MGHfC
• Adaption of Dr. Pistiner’s slides in #10, 21-34
• Thanks to the rest of the Division of Allergy at MGHfC
References
For more information on this subject, see the following publications:

• Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr,
Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. 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. PMID: 16461139.
• Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, Dinakar C, Ellis A, Greenhawt M, Khan DA, Lang DM, Lang ES, Lieberman JA, Portnoy J,
Rank MA, Stukus DR, Wang J; 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. PMID: 32001253.
• Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.
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diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol.2012;129(3):748–752
• Loprinzi Brauer CE, Motosue MS, Li JT, Hagan JB, Bellolio MF, Lee S, et al. Prospective validation of the NIAID/FAAN criteria for emergency department diagnosis of
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DOI: 10.1016/j.anai.2018.05.025
• Pistiner M, Mendez-Reyes JE, Eftekhari S, Carver M, Lieberman J, Wang J, Camargo Jr CA. Caregiver-Reported Presentation of Severe Food-Induced Allergic Reactions in
Infants and Toddlers. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Nov 18.
References
For more information on this subject, see the following publications:

• Pistiner M, Handorf A, Camargo Jr C, Cohen A. Approaching Cardiovascular Symptoms/Signs in Infants and Toddlers with Anaphylaxis . The Journal of Allergy and Clinical
Immunology: In Practice. 2021 In-Press.
• Lieberman JA, Camargo CA, Pistiner M, Wang J, Camargo CA Jr. Pediatrician perspectives on symptom presentation and treatment of acute allergic reactions. Annals of
Allergy, Asthma & Immunology. 2021;126
• Sampson, H.A., Mendelson, L., and Rosen, J.P. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992 Aug 6; 327: 380–384
• Bock, S.A., Munoz-Furlong, A., and Sampson, H.A. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001 Jan; 107: 191–193
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