Document text
National Center for Immunization & Respiratory Diseases
Influenza Vaccination of Persons with Egg Allergy:
Evidence to Recommendations Discussion and Work Group Considerations
Lenee H. Blanton
Lisa A. Grohskopf
Influenza Division, CDC/NCIRD
Advisory Committee on Immunization Practices
June 21, 2023
•Donna Hummell
•Karen Broder
•Pedro Moro
•Geta Aynalem
•Shashi Sharma
•Elaine Miller
•Andrew Leidner
•Rebecca Morgan
•Doug Campos -OutcaltAcknowledgements
2
Background
•Affects approximately 1 -3% of children by age 3 years.1,2
•Resolves for many during later childhood and adolescence .
–In one study,3
›4% developed tolerance by age 4 years,
›12% by age 6 years,
›37% by age 10 years,
›68% by age 16 years.
•Reactions range from mild to life -threatening.
•Diagnosis:
–Clear history of immediate allergic reaction to egg or egg -containing foods.2
–Skin prick testing (SPT) or estimation of egg -specific IgE levels.2Egg Allergy
1. Eggesbo M et al. Allergy 2001;56(5):403 -411
2. Erlewyn -Lajeunesse M et al. BMJ 2009;339:b3680.3. Savage JH et al. J Allergy Clin Immunol 2007;120(6):1413 -7.
4
Ovalbumin Content of U.S. Influenza Vaccines, 2022 -23
Vaccine (manufacturer) Approved age
indicationOvalbumin, mcg/dose*
(per package insert)
Egg-based
Afluria Quadrivalent (Seqirus) ≥6 mos <1
Fluarix Quadrivalent (GSK) ≥6 mos ≤0.05
FluLaval Quadrivalent (GSK) ≥6 mos ≤0.3
Fluzone Quadrivalent (Sanofi Pasteur) ≥6 mos Not stated
FluMist Quadrivalent (AstraZeneca) 2 through 49 yrs <0.024
Fluad Quadrivalent (Seqirus) ≥65 yrs ≤1
Fluzone High -Dose Quadrivalent (Sanofi Pasteur) ≥65 yrs Not stated
Egg-free
Flucelvax Quadrivalent (Seqirus) ≥6 mos Egg-free
Flublok Quadrivalent (Sanofi Pasteur) ≥18 yrs Egg-free
* 0.5 mL for injectable vaccines and 0.2 mL for LAIV 5
•Persons with a history of egg allergy of any severity should receive influenza vaccine.
•Any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is
otherwise appropriate can be used.
•For persons with previous reactions to egg involving symptoms other than urticaria:
–“If a vaccine other than ccIIV4 or RIV4 is used, the selected vaccine should be
administered in an inpatient or outpatient medical setting, including but not
necessarily limited to hospitals, clinics, health departments, and physician
offices. Vaccine administration should be supervised by a health care provider
who is able to recognize and manage severe allergic reactions.”
•No specific observation period recommended.Current ACIP Recommendations1
1. CDC/ACIP . MMWR Recomm Rep 2022;71(No. RR -1):1–28. IIV4= quadrivalent inactivated influenza vaccine
LAIV4=quadrivalent live attenuated influenza vaccine
ccIIV4=quadrivalent cell culture based inactivated influenza vaccine
RIV4= quadrivalent recombinant influenza vaccine6
•American Academy of Pediatrics
–Since 2016 -17, no additional measures recommended for persons with egg allergy.1
–“Children with egg allergy can receive any influenza vaccine without any additional precautions
beyond those recommended for all vaccines.”2
–Measures related to use of specific vaccines, observation periods, or restricting vaccination to
specific medical settings not warranted and constitute a barrier to vaccination.3
–Not necessary to inquire about or screen for egg allergy prior to influenza vaccination.3
•Joint Task Force, AAAAI/ACAAI
–“No special precautions beyond those recommended for the administration of any vaccine to
any patient are necessary for administration of influenza vaccine to egg allergic individuals.”4Influenza Vaccines and Egg Allergy: Other Guidance
1. Recommendations for Prevention and Control of Influenza in Children, 2016 –2017 | Pediatrics | American Academy of Pediatrics (aa p.org)
2. Recommendations for Prevention and Control of Influenza in Children, 2022 –2023 | Pediatrics | American Academy of Pediatrics (aa p.org) .
3. AAP . Technical Report for the 2022 -23 Recommendations for the Prevention and Control of Influenza in Children, 2022 -23
4. Greenhawt M et al . Ann Allergy Asthma Immunol 2018;120:49 -52. 7
•From chapter titled “Preventing and Managing Adverse Reactions”:
–“Although allergic reactions are a common concern for vaccine providers, these
reactions are uncommon and anaphylaxis following vaccines is rare, occurring at
a rate of approximately one per million doses for many vaccines. Epinephrine
and equipment for managing an airway should be available for immediate use.”General Best Practices Guidelines for Immunization1
1. Kroger AT et al. https://www.cdc.gov/vaccines/hcp/acip -recs/general -recs/index.html
8
•Vaccine skin testing prior to vaccination.1,2
–Skin prick and/or intradermal testing with dilution of vaccine
–If positive, vaccination deferred or administered via alternative dosing protocol
•Graded administration of vaccine.3
–Incrementally increasing volumes, often in 5 to 6 steps; sometimes with dilutions in early steps
–E.g., 0.05 mL of 1:100 dilution →0.05 mL of 1:10 dilution →0.05 mL→0.1 mL→0.15 mL→0.2 mL,
with observation periods after each dose (e.g., 15 minutes).
•Split dosing of vaccine.4
–Most commonly 10% of dose volume →observation period →remaining 90% of dose volume,
often with additional observation after final dose.Past Approaches to Influenza Vaccination of Persons with
Egg Allergy (Not Currently Recommended)
1. Bierman CW et al. J Infect Dis 1977;136:S652 -S655.
2. Miller JR et al. J Allergy Clin Immunol 1983;71:568 -173.3. Murphy KR et al. J Pediatr 1985;106(6):931 -933.
4. James JM et al. J Pediatr 1998;133:624 -628.
9
•Whether t o no longer recommend additional safety measures for
persons with egg allergy of any severity, beyond what is recommended
forany other persons presenting for influenza vaccination.
–In the discussion that follows, the proposed intervention is to no longer make
the recommendation regarding vaccination setting for those with a history of
severe allergic reaction to egg.Policy Question
1
0
EtR Domain 1: Public Health Importance
•Egg allergy more common in younger children, and often co -exists with asthma:
–In a cross -sectional survey of 38,408 children,1
›Egg allergy prevalence was 0.9% overall; 1.3% for those <5 yrs.
›Asthma prevalence higher with egg allergy (46.5%) with other 8 most common food allergies (33.2%).
•Younger children and people with asthma are at increased risk of severe influenza
illness.Is Vaccination of Egg -Allergic Persons an Issue of Public
Health Importance?
1.Samady W, Warren C, Wang J, et al. Egg allergy in US children. J Allergy Clin Immunol Pract. 2020;8(9):3066 -73. 12
Public Health Importance: WG Considerations
•Current recommendations might be
a real or perceived barrier to
vaccination (e.g., by promoting
hesitancy based on safety concerns,
or providing a reason to decline
vaccination).
-No data specifically examining or
confirming that current
recommendations are a barrier found,
but existence of real or perceived
barriers is plausible.
13•Current recommendations might be
less of a barrier now, since cell -
based (egg -free) inactivated vaccine
is approved for ages ≥6 mos.
-However, there is only one such vaccine
licensed for children <18 years, compared
with four egg -based vaccines available for
this age group.
Is Vaccination of Egg -Allergic Persons an Issue of Public
Health Importance?
14
0
6
33
61
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
EtR Domain 2: Benefits and Harms
•Does the available evidence concerning the safety of influenza vaccines
in persons with a history of egg allergy favor routine vaccination without
additional safety measures, regardless of severity of previous allergic
reaction to egg?
–Review focused on Harms (safety) —did not include review of
effectiveness/efficacy data.Review Question
16
Population, Intervention, and Comparators
▪Population: Persons of any age with a history of allergy to eggs, or who
have had an allergic reaction to influenza vaccine believed to be
secondary to egg allergy.
▪Intervention: Any influenza vaccine.
▪Comparators: Placebo, non egg -based influenza vaccine, non -influenza
control vaccine, no vaccine, no comparator
17
Outcomes
Important
•Allergic reaction symptoms
requiring outpatient or emergency
department medical attention†
•Allergic reaction including
cardiovascular symptoms,
respiratory symptoms, angioedema,
or generalized urticariaCritical
•Death
•Anaphylaxis meeting Brighton
criteria Levels 1 -3*
•Anaphylaxis otherwise
classified*
•Allergic symptoms requiring
hospitalization
* These two outcomes are combined in the tables that follow.
† Includes instances treated with medications, without explicit mention of outpatient or emergency department care .18Within 4 hours of vaccination:
Study Designs, Vaccines, and Comparison Groups
▪47 reports describing 52 studies.
•1 randomized study (compared full -dose with 10%/90% split dose).
•1 VAERS report summary.
•Remainder retrospective/prospective cohort studies and case series.
•2 involved only recombinant vaccine (egg -free).
▪No studies include a relevant comparison group (e.g., an alternative or no vaccine).
▪14 abstracts only (no related paper found).
▪All studies were reviewed descriptively.
▪28 reports (31 studies) included in GRADE:
•Egg-based vaccines only (seasonal and monovalent).
•Full-dose or split -dose administration.
•For the randomized study, full -and split -dose groups combined; treated as a cohort study.
•Data with unknown/unclear vaccine type, unspecified administration protocol, graded (≥3 steps)
dosing, and/or unknown denominator excluded.
•Since there are no comparators, data are summarized as frequencies. 19
Summary of Events by Vaccine Type: Egg Allergy of All severities
Outcome Seasonal IIVs* Monovalent IIVs* LAIV Importance Certainty
Death 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Anaphylaxis 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Reaction requiring hospitalization 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Reaction requiring outpatient/ED
attention (includes those given
symptomatic medications)3/1591 (0.2%) 77/5235 (1.5%) 0/1129 (0%) Important Very low
Allergic reaction including
cardiovascular symptoms, respiratory
symptoms, angioedema, or
generalized urticaria5/1591 (0.3%) † 33/5235 (0.6%) 10/1129 (0.8%) Important Very low
20*Includes several papers for which vaccine type not explicitly stated, but presumed based upon season, study
location, and/or use of graded/split dosing. Seasonal IIV data include one paper describing a virosomal vaccine.
†One study reported 6 instances of reactions including “wheezing, eczema exacerbation, or hives on chest”, but
not specifying number with each symptom. If assumed that all six included wheezing, frequency would be
11/1591=0.7%
Summary of Events by Vaccine Type: Persons with Anaphylaxis to Egg
Outcome Seasonal IIVs* Monovalent IIVs* LAIV Importance Certainty
Death 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Anaphylaxis 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Reaction requiring hospitalization 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Reaction requiring outpatient/ED attention 0/295 (0%) 0/68 (0%) 0/412 (0%) Important Very low
Allergic reaction including cardiovascular
symptoms, respiratory symptoms,
angioedema, or generalized urticaria0/291 (0%) 0/68 (0%) 0/27 (0%) Important Very low
21*Includes several papers for which vaccine type not explicitly stated, but presumed to be IIV based upon season,
study location, and/or use of graded/split dosing.
Summary of Evidence for Outcomes of Interest
Outcome Importance Included in
profileCertainty
Death Critical Yes Very low
Anaphylaxis Critical Yes Very low
Allergic reaction symptoms requiring hospitalization Critical Yes Very low
Allergic reaction symptoms requiring outpatient or
emergency department medical attentionImportant Yes Very low
Allergic reaction including cardiovascular symptoms,
respiratory symptoms, angioedema, or generalized urticariaImportant Yes Very low
22
Report of Brighton Level 1 Anaphylaxis
▪One report of Brighton Level 1 anaphylaxis in person with “possible” egg allergy
within 30 minutes of receiving monovalent vaccine.
•In paper summarizing VAERS reports following monovalent pandemic influenza vaccine during
2009 -10 season.1
•Unclear from paper whether documented to be egg -allergic.
▪Doses administered that season unknown
•Reaction not included in counts in GRADE evidence profiles (as denominator undefined).
▪Paper states approximately 127 million doses distributed that season.
▪Other reactions:
•2 of respiratory hypersensitivity
•1 sensation of throat closure
1. Halsey NA, et al. Vaccine. 2013 Dec 9;31(51):6107 -12. doi: 10.1016/j.vaccine.2013.09.066. Epub 2013 Oct 8. PMID: 24120547 .
Descriptions Of Reactions Following Egg -free Vaccines
24•Woo et al 2015, 2017: summaries of VAERS reports following
recombinant influenza vaccine (RIV):
•Reports of serious allergic reactions following RIV, some of which occurred
among persons with egg allergy.
•RIV is egg, gelatin, antibiotic, and preservative -free.
•Authors note that the occurrence of such reactions might reflect an
underlying predisposition to atopy.
•Reports also highlight unpredictability of severe allergic reactions, and
importance of being prepared in all vaccination settings, for all
recipients, and with all vaccines.
Limitations and WG Considerations
▪Observational data with no comparator groups meeting criteria.
▪Some data only available from abstracts.
▪Many (particularly older) studies employed skin testing with egg proteins and/or
vaccine prior to decision to vaccinate.
▪Considerable variability in level of detail in which outcomes are described.
▪Observation time post -vaccination varied; time elapsed post -vaccination not often
reported for delayed reactions.
•Observation for immediate reactions under 4 hours for most studies; generally 30 min to 2 hours.
▪Ovalbumin content was not reported/unknown in most instances.
•In most instances where noted, was <1µg/dose; in some cases substantially less.
•Difficult to know how this compares with current vaccines, since expressed as an upper limit.
▪Data specifically for persons with anaphylaxis to egg were limited.
•Not all studies specified that persons with severe egg allergy were included.
•Where included, not all studies reported reactions specifically for this subgroup. 25
Egg Allergy and Anaphylaxis Reports after IIVs in
VAERS, 2017 -2022
•178 anaphylaxis reports after any IIV
•18 had an egg allergy (based on VAERS report)
•Clinical review revealed 7 reports of anaphylaxis and egg allergy (all in 2017 -18):
•4 in children (ages 2, 4, 9, 11 yrs); 3 in adults (ages 21, 52, 61 yrs)
•4 Brighton level 1; 1 Brighton level 3; 2 did not meet Brighton
•Influenza vaccines:
›Fluarix quadrivalent: 2
›Fluzone quadrivalent: 2
›Fluvirin trivalent: 1
›Flucelvax quadrivalent: 1
›Flublok quadrivalent: 1
•Difficult to assess if reaction was due to egg protein due to limited laboratory data.
26 Vaccine Adverse Event Reporting System (VAERS) (hhs.gov)
How Substantial are the Undesirable Anticipated Effects?
27
39
44
6
0
11
0Minimal
Small
Moderate
Large
Varies
Don't Know% ofrespondents (N=18)
EtR Domain 3: Values
•No direct evidence found.
•Change in recommendations might be reassuring to some who have
wanted to be vaccinated but were hesitant/perceived it is unsafe;
•Or might be source of concern.
–WG member expressed that change might be viewed unfavorably if it is
perceived as trade -off between safety vs. increasing coverage/reducing missed
opportunities for vaccination.Does the Target Population Feel that the Desirable Effects
are Large Relative To Undesirable Effects?
29
Does the Target Population Feel that the Desirable Effects
are Large Relative To Undesirable Effects?
30
0
6
22
17
6
50No
Probably no
Probably yes
Yes
Varies
Don't Know% of respondents (N=18)
•No direct evidence found.
–Presumably, greater value attached to the more serious outcomes (death,
anaphylaxis, hospitalization).Is There Important Uncertainty About, or Variability In, How
Much People Value the Main Outcomes?
31
Is there important uncertainty about, or variability in, how
much people value the main outcomes?
32
0
28
67
6
0Important uncertainty or variability
Probably important uncertainty or
variability
Probably not important uncertainty or
variability
No important uncertainty or variability
No known undesirable outcomes% of respondents (N=18)
EtR Domain 4: Acceptability
•No direct evidence found.
•Several US professional societies (AAP , AAAAI, ACAAI) already recommend no special
measures (screening, observation periods, selection of specific vaccines, specific
vaccination settings) for those with egg allergy.
•As of 2022 -23, package inserts for egg -based vaccines continue to carry a
contraindication of severe hypersensitivity reaction to any vaccine components.
–However, ACIP has previously recommended influenza vaccination with any appropriate vaccine
(egg -based or not), regardless of severity of reaction to egg.Is the Intervention Acceptable to Key Stakeholders?
34
Acceptability: WG Considerations
•Alignment of recommendations
among public health organizations
and professional societies facilitates
consistent messaging to providers
and patients.
35•Concern that some settings might
not be prepared to manage severe
reactions (e.g., retail).
•Acceptability will be severely
impacted if anaphylaxis occurs in a
setting unprepared to manage it.
-Importance of stressing that every
setting must be able to manage
anaphylaxis, or should not administer
any vaccines to any recipient.
•Concer n for potential liability issues.
Is the Intervention Acceptable to Key Stakeholders?
36
0
0
56
44
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
EtR Domain 5: Resource Use
•No economic analysis was conducted.
–The target population is small.
–Lack of data for some factors.
›No reliable estimate of the proportion of those with egg allergy who have had
severe reaction to egg.
›Proportions of individuals with egg allergy by age uncertain.
›Proportions of persons receiving egg -based vs. egg -free vaccines uncertain.
•Primary emphasis of assessment was safety rather than cost.Is the Intervention a Reasonable and Efficient Allocation of
Resources?
38
•CMS payment allowances and VFC costs higher for egg -free vaccines that are approved for children
(rounded to nearest dollar):Relative Costs of Egg -Based vs. Egg -Free Influenza Vaccines
39Vaccine (based on 0.5mL dose) CMS Rate 2022 -231 VFC List 2023 -242
Egg-based
Average for egg -based vaccines for ≥6 mos: Multidose $20.00 $20.00
Average for egg -based vaccines for ≥6 mos: Preservative -free $22.00 (IIV4s)
$27.00 (LAIV4)$21.00 (IIV4s)
$24.00 (LAIV4)
Fluzone High -Dose Quadrivalent: Preservative -free (≥65 yrs only) $70.00 -
Fluad Quadrivalent: Preservative -free (≥65 yrs only) $72.00 -
Egg-free
Flucelvax Quadrivalent: Multidose (≥6 mos) $31.00 $29.00
Preservative -free (≥6 mos) $32.00 $30.00
Flublok Quadrivalent Preservative -free (≥18 yrs only) $70.00 -
1.https://www.cms.gov/Medicare/Medicare -Fee-for-Service -Part-B-Drugs/McrPartBDrugAvgSalesPrice/VaccinesPricing
2.CDC Vaccine Price List (Private sector cost per dose)
Resource Use: WG Considerations
•Removing existing restrictions
could result more efficient
allocation of resources, if data
suggest no or minimal increase in
adverse events.
40•Change in recommendations and
lower cost of egg -based vaccines
might lead to their increased use,
which might be associated with
increased costs if these is an
increase in reactions requiring
medical attention.
Is the Intervention a Reasonable and Efficient Allocation of
Resources?
41
0
0
24
76
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=17)*
* Answer from one respondent who selected “Probably yes” and “Yes” excluded
EtR Domain 6: Equity
•No direct evidence found.
•Some racial/ethnic groups at increased risk for severe influenza illness, highlighting
importance of vaccination:
–Influenza associated hospitalization and ICU admission rates higher among Black, Hispanic, and
American Indian/Alaska Native children <4 yrs of age compared with White children.1
–Black children were disproportionately represented among children with egg allergy in one
series (23.4%, relative to comprising 13.2% of the U.S. pediatric population).2
–If current recommendations are a barrier to vaccination, the intervention could improve equity
with regard to risk of severe influenza illness.What Would Be the Impact on Health Equity?
431.O’Halloran et al J AMA Netw Open. 2021 Aug 2;4(8):e2121880
2.Samady W et al. J Allergy Clin Immunol Pract. 2020 Oct;8(9):3066 -3073.e6. doi: 10.1016/j.jaip.2020.04.058 .
•Issues related to trust in the healthcare system, from the patient’s
perspective :
–A change in recommendations might mean vaccination occurs more widely in
more settings than previously, and perhaps increased use of egg -based vaccines
rather than egg -free vaccines in some settings.
–The fact that egg -based vaccines are less expensive might reinforce belief that
providers/ healthcare systems do not care to use the necessary resources to
provide a potentially safer vaccine.Equity: WG Considerations
44
What Would Be the Impact on Health Equity?
45
0
17
11
50
0
6
17Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don't know% of respondents (N=18)
EtR Domain 7: Feasibility
Is the Intervention Feasible to Implement?
•Considerations favoring feasibility:
-The proposed change i s a simplification
of the previous recommendation.
-It does not specify particular vaccines.
-It does not change recommendations
for emergency equipment and
resources.
›The General Best Practices indicate that
epinephrine and equipment to manage
an airway should be available in all
vaccination settings.1
47•Consideration against feasibility:
-Vaccination settings not already
prepared to manage severe allergic
reactions would need to address
these needs.
›However, all settings are already
recommended to be prepared for
severe allergic reactions when
administering any vaccine to any
recipient.1
1. Kroger AT et al. https://www.cdc.gov/vaccines/hcp/acip -recs/general -recs/index.html.
Is the Intervention Feasible to Implement?
48
0
0
11
89
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
Balance of Consequences and Sufficiency
of Information
Balance of Consequences
50
0
0
0
39
61
0Undesirable consequences clearly outweigh desirable consequences
in most settings
Undesirable consequences probably outweigh desirable consequences
in most settings
The balance between desirable and undesirable consequences is
closely balanced or uncertain
Desirable consequences probably outweigh undesirable consequences
in most settings
Desirable consequences clearly outweigh undesirable consequences
in most settings
There is insufficient evidence to determine the balance of consequences0 10 20 30 40 50 60 70 80 90 100% of respondents (N=18)
Is There Sufficient Information to Move Forward With a
Recommendation?
51•Of 18 respondents,
–18 responded “Yes”
–0 responded “No”
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY: 1 -888-232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.
Search
•First search 03 -14-2019; updated search 10 -26-2022.
•Medline, Embase, PsycInfo, CINAHL, NTIS, Scopus, Cochrane Library,
ClinicalTrials.gov; no date or language restriction.
Included reports
•Randomized Controlled trials, Observational studies, Case reports, Case series,
Safety surveillance system reports (including Vaccine Adverse Event Reporting
System and other safety surveillance system reports).
•Abstracts for which no papers found were included.
Excluded reports
•Animal studies, duplicate reports, reviews*, clinical trial registry summaries.*Literature Search, Inclusion/Exclusion Criteria
* Used to help identify other potentially relevant reports 53
PRISMA Diagram
381 reports excluded
•255 review/other non -primary source
•67 wrong study design
•20 wrong patient population
•16 abstract (paper found) or registry summary
•6 wrong intervention
•3 wrong outcomes
•14 insufficient information477 reports retrieved
47 reports abstracted428 full -text reports assessed454 reports screened23 duplicates removed
26 studies irrelevant
19 reports excluded from GRADE
•12 unclear dosing protocol
• 4 unclear vaccine
• 2 egg -free vaccine
• 1 graded dosing only28reports included in GRADE
54
1. Question and PICO
Policy
question:Whether available evidence concerning safety of influenza vaccines in persons with a history of
egg allergy favors routine vaccination without additional safety measures, regardless of severity of
previous allergic reaction to egg.
Population Persons of any age with a history of allergy to eggs, or who have had an allergic reaction to
influenza vaccine believed to be secondary to egg allergy.
Intervention Receipt of any influenza vaccine.
Comparison Placebo, nonegg -based influenza vaccine, non -influenza control vaccine, no vaccine, no
comparator.
Outcomes Critical:
•Death
•Anaphylaxis meeting Brighton criteria Levels 1 -3*
•Anaphylaxis otherwise classified*
•Allergic reaction symptoms requiring hospitalization
Important:
•Allergic reaction symptoms requiring outpatient or emergency department medical attention†
•Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or
generalized urticaria
*These outcomes are combined in the evidence profile tables.
†Includes instances treated with medications, without explicit mention of outpatient or emergency department care. 55
2. Outcomes and Rankings
Outcome Importance Included in
evidence profile
Death Critical Yes
Anaphylaxis meeting Brighton criteria Levels 1 -3* Critical Yes
Anaphylaxis otherwise classified* Critical Yes
Allergic reaction symptoms requiring hospitalization Critical Yes
Allergic reaction symptoms requiring outpatient or
emergency department medical attention†Important Yes
Allergic reaction including cardiovascular symptoms,
respiratory symptoms, angioedema, or generalized urticariaImportant Yes
56*These outcomes are combined in the evidence profile tables.
†Includes instances treated with medications, without explicit mention of outpatient or emergency department care.
3a. Summary of Studies and Outcomes —Seasonal IIV (1)
*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62. Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Anvari 2011 Not specified 86 None None Unclear
Chung 2010 Skin test group:
Average 6.2
(95%CI 5.1 -7.2) yrs
Non -skin test
group: Average 3.9
(95%CI 3.3 -4.5) yrs171 None None Moderate
Comeau 2016 † Not specified 88 None None Serious
Des Roches 2012 -1 <2 yrs: 27
2-4 yrs: 83
5-11 yrs: 82
>12 yrs: 37230 None None Low
DesRoches 2012 -2 <2 yrs: 29
2-4 yrs: 53
5-11 yrs: 51
>12 yrs: 4137 None None Low
Erlewyn -Lajeunesse 2010 † Not specified 16 doses None Cardiovascular, respiratory, angioedema,
or generalized urticaria: 1 Moderate
57
3a. Summary of Studies and Outcomes —Seasonal IIV (2)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern
Esposito 2008 6.03 +/ -3.33 yrs 44 Non -allergic group Outpatient or emergency department
medical attention: 1
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 1 Low
Greenhawt 2012 -1 Median 11 -12 mos 31 Comparison of full -vs.
split -dose (combined in
this review)None Low
Greenhawt 2012 -2 Median 12 mos at
diagnosis112 None None Low
Hotte 2008 † Not provided 115 None None Unclear
Howe 2011 Not specified 69 Non -allergic group None Unclear
James 1998 Median 3 (1 -46) yrs 83 Non -allergic group Outpatient or emergency department
medical attention: 2
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 3Low
Leo 2010 † Not provided 31 None None Unclear
Park 2008 † Mean 36.1 +/ -19.1
(11 to 105 mos)45 None None Unclear
Paschall 2011 † Mean 3.8 yrs 65 doses None None Unclear
Shimizu 2016 Median 15
(IQR 13 -20) mos17 None None Low
Thanik 2010 Not specified 214 doses None None Unclear
58*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62. Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
3b. Summary of Studies and Outcomes —Monovalent IIV (1)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Didenko 2010 median 4 (2 -11) yrs 6 None None Moderate
Forsdahl 2012 Mean 6.25 yrs
(10 mos -16.5 yrs)80 None Outpatient or emergency department
medical attention: 1
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 1 Moderate
Gagnon 2010 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrs830 Non -allergic group Outpatient or emergency department
medical attention: 4
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 6Low
Gagnon 2010 -2 Not specified 3460 None Outpatient or emergency department
medical attention: 68
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 26Unclear
Greenhawt 2010 Mean 5.5 (range
0.4-20.4) yrs105 Non -allergic group None Low
59*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62. Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
3b. Summary of Studies and Outcomes —Monovalent IIV (2)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Leo 2010 † Not specified 50 None None Unclear
Paschall 2011 † Mean 3.8 yrs 66 None None Unclear
Pien 2010 Mean 3.7 +/ -3.0 yrs 59 None None Moderate
Pitt 2011 Mean 5.6 (1 -27) yrs 59 None None Moderate
Schuler 2011 Mean 4.5 yrs
(10 mos -16 yrs)62 None Outpatient or emergency department
medical attention: 4Moderate
Siret -Alatrista 2010 † Unclear 53 None None Unclear
Spiegel 2010 † Range 1 -56 yrs 150 None None Unclear
Upton 2012 3-5 yrs:12
6-9 yrs:24
10-13 yrs:28
14+ yrs:1075 None None Moderate
60*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62. Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
3c. Summary of Studies and Outcomes —LAIV
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Des Roches 2015 2-16 yrs 68 Non -allergic group None Low
Turner 2015a Median 4.9 yrs
(2-17 yrs)282 None Cardiovascular symptoms, respiratory
symptoms, angioedema, or generalized
urticaria: 6Low
Turner 2015b Median 5.3 yrs
(2-18 yrs)779 None Cardiovascular symptoms, respiratory
symptoms, angioedema, or generalized
urticaria: 4Low
61*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62. Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL1. Death
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without comparator interventions, with the exception of one randomized study which compared adminis tration of full dose vs split dose. Full dose and split dose
administration are treated as equivalent in this review, and so this study is treated as a cohort study. Six of 17 are of unc lear methodological quality. Six of 17 are abstracts.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.3. Allergic reaction symptoms requiring hospitalization4a: Seasonal IIV administered full -or split -dose, egg allergy of all severities (1)
62
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone3/1591 (0.2%)
instancesVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
17Observa -
tionalSeriousaNot Serious SeriousbSeriouscNone5/15 91 (0.3%)†
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d
included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Re porting.
† One study reported 6 instances of reactions included “wheezing, eczema exacerbation, or hives on chest”, but not specifying number with each symptom. These are
excluded here. If assumed that all six included wheezing, frequency would be 10/1591=0.6%
a. All are cohort studies without comparator interventions, with the exception of one randomized study which compared adminis tration of full dose vs split dose. Full
dose and split dose administration are treated as equivalent in this review, and so this study is treated as a cohort study. Sixof 17 are of unclear methodological
quality. Six of 17 are abstracts.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4a: Seasonal IIV administered full -or split -dose, egg allergy of all severities (2)
63
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
10a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/322 (0%)
instancesVery Low CRITICAL1. Death
10a Observa -
tionalSeriousbNot serious Not seriousbSeriouscNone0/322 (0%)
instancesVery Low CRITICAL
10a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/322 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
a. Includes only studies which explicitly mentioned inclusion of egg -anaphylactic patients for whom data are specifically report ed.
b. All are cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) protocols. Two of 10 studies are abstracts, and 3 of 10 have
uncertain methodological quality.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but wh ichdid not indicate whether these occurred in a person with a
history of anaphylaxis to egg. 4b: Seasonal IIV administered full -or split -dose, persons with anaphylaxis to egg (1)
64
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
9a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/295 (0%)
instancesdVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
a. Includes only studies which explicitly mentioned inclusion of egg -anaphylactic patients for whom data are specifically report ed.
b. All are cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) protocols. Two of 10 studies are abstracts, and 3 of 10 have
uncertain methodological quality.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but wh ichdid not indicate whether these occurred in a person with a
history of anaphylaxis to egg. 8a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/291 (0%)
instancesdVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria 4b: Seasonal IIV administered full -or split -dose, persons with anaphylaxis to egg (2)
65
4c: Monovalent IIV administered full -or split -dose, egg allergy of all severities (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instancesVery Low CRITICAL1. Death
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instances dVery Low CRITICAL
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All were cohort studies without comparator intervention groups, including administration via either full dose or split -dose ( 2-step) protocols. Concerns regarding methodological quality were
"Low" for only two studies, moderate for 6, and unclear for 4. History of egg allergy was by self report only for the larges t study (n=3640).
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without confidence intervals; however some degree of imprecision must b e assumed.
d. One instance of Brighton Level 1 anaphylaxis was reported in a VAERS surveillance data summary from the 2009 -10 influenza sea son. This instance is not represented in the table as no
denominator is available for this paper. However, it was reported that 127,075,320 doses of monovalent influenza vaccine were distributed in the United States for the season. 66
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone77/5235 (1.5%)
instancesVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
13Observa -
tionalSeriousaNot serious SeriousbSeriouscNone33/5235 (0.6%)
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All were cohort studies without comparator intervention groups, including administration via either full dose or split -dose ( 2-step) protocols. Concerns regarding methodological quality were
"Low" for only two studies, moderate for 6, and unclear for 4.
b. Only 143 of total participants reported to have a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without confidence intervals; however some degree of imprecision must b e assumed.
d. One instance of Brighton Level 1 anaphylaxis was reported in a VAERS surveillance data summary from the 2009 -10 influenza sea son. This instance is not represented in the table as no
denominator is available for this paper. However, it was reported that 127,075,320 doses of monovalent influenza vaccine were distributed in the United States for the season. 4c: Monovalent IIV administered full -or split -dose, egg allergy of all severities (2)
67
4d: Monovalent IIV administered full -or split -dose, persons with anaphylaxis to egg (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone0/68 (0%)
InstancesVery Low CRITICAL1. Death
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low CRITICAL
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. Cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) p rotocols.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.68
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. Cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) p rotocols.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4d: Monovalent IIV administered full -or split -dose, persons with anaphylaxis to egg (2)
69
4e. Seasonal LAIV, egg allergy of all severities (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL1. Death
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without a comparison intervention.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.70
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone10/1129 (0.8%)
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without a comparison intervention.
b. Majority of persons in each study did not have history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4e. Seasonal LAIV, egg allergy of all severities (2)
71
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL1. Death
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies with no comparison groups.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed. Very low denominator count. 4f. Seasonal LAIV, persons with anaphylaxis to egg (1)
72
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
1Observa -
tionalSeriousaNot serious Not seriousVery
seriousc None 0/27 instances Very Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60 -62 [51]. Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies with no comparison groups.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed. Very low denominator count.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but which did not indicate whether these occurred in a person with a
history of anaphylaxis to egg. 4f. Seasonal LAIV, persons with anaphylaxis to egg (2)
73
Appendix 1. Event Summary: Death
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
74
Appendix 2. Event Summary: Anaphylaxis
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
75
Appendix 3. Event Summary: Hospitalization
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
76
Appendix 4. Event Summary: Outpatient/Emergency Care (1)
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
eggEvents
Esposito 2008 Mean 6.03 +/ -3.33 Seasonal
virosomal44 11 •1 bronchospasm in mildly
allergic child, treated with
bronchodilator and
steroid.
James 1998 Mean 6.25
(10mos -16.5 years)Seasonal IIV 83 27 •1 delayed (>1 hour post -
vaccination) emesis, mild
cough, wheeze treated
with nebulizer.*
•1 delayed (>1 hour post -
vaccination) erythema at
injection site treated.*
*Uncertain whether occurred in individual with anaphylaxis to egg.
77
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Forsdahl 2012 Mean 6.25 yrs
(10 mos -16.5 yrs)Monovalent IIV 80 19 •1 wheal on lip, diffuse
rash, and loose stools a
few minutes after 90%
step; treated with
antihistamine.
Gagnon 2010 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrsMonovalent IIV 830 - •1 wheeze treated with
bronchodilator.
•1 hives treated with
antihistamines
•1 ocular pruritis treated
with antihistamines
•1 angioedema treated
with antihistamines.Appendix 4. Event Summary: Outpatient/Emergency Care (2)
78
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Gagnon 2010 -2 Not provided Monovalent IIV 3460 - •1 mouth/throat tingling 10 -15 min
post -vaccination; received two
doses epinephrine and observed in
emergency department; recovered.
•1 continuous crying with wheezing
30 min post -vaccination. Received
epinephrine and bronchodilator (6
treatments), observed 4 hours,
recovered.
•66 skin and respiratory symptoms,
treated with antihistamines
•42 with skin involvement
•17 with throat
tingling/tightening
•7 with cough (4 also treated
with bronchodilator)Appendix 4. Event Summary: Outpatient/Emergency Care (3)
79
Author
Publication yearAge Vaccine N egg
allergicN anaphylaxis to
egg/severe allergyEvents
Schuler 2011 Mean 4.5 yrs
(10 mos -16 yrs)Monovalent IIV 62 - •1 vasovagal response requiring
symptomatic management.
•1 hyporesponsive episode;
referred to emergency
department.
•2 hives treated with
antihistamines.Appendix 4. Event Summary: Outpatient/Emergency Care (4)
80
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis
to egg/severe
allergyEvents
Erlewyn -
Lajeunesse 2010 Children Seasonal IIV 16 doses 4 •1 instance subjective wheeze*
Esposito 2008 Mean 6.03 +/ -3.33 Seasonal IIV 44 11 •1 instance bronchospasm in mildly
allergic child, treated with
bronchodilator and steroid.
James 1998 Mean 6.25
(10mos -16.5 years)Seasonal IIV 83 27 •1 with mild throat itching, cough,
and wheeze.*
•1 delayed (>1 hour post -vaccination)
emesis, mild cough, wheeze treated
with nebulizer.*
•1 mild URI symptoms.*
*Uncertain whether occurred in individual with anaphylaxis to egg.Appendix 5. Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (1)
81
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Forsdahl 2012 Mean 6.25 yrs
(10 mos -16.5 yrs)Monovalent IIV 80 19 •1 sneezing without
bronchospasm.
Gagnon 2010 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrsMonovalent IIV 830 - •1 sensation of throat
closure
•1 hoarse voice
•1 angioedema
•1 bilateral wheeze
•2 generalized urticariaAppendix 5. Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (2)
82
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Gagnon 2010 -2 Not provided Monovalent IIV 3460 - •1 mouth/throat tingling 10 -15
min post -vaccination;
received two doses
epinephrine and observed in
emergency department;
recovered.
•1 continuous crying with
wheezing 30 min post -
vaccination. Received
epinephrine and
bronchodilator (6 treatments),
observed 4 hours, recovered.
•17 with throat
tingling/tightening
•7 with cough (4 also treated
with bronchodilator)Appendix 5. Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (3)
83
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Turner 2015a Median 4.9 yrs
(2-17 yrs)LAIV3 282 115 •6 rhinitis within 30 min post -
vaccination.
Turner 2015b Median 5.3 yrs
(2-18 yrs)LAIV4 779 157 •4 rhinitis within 2 hours post -
vaccination.Appendix 5. Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (4)
84
Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
Death Critical Yes Very low
Anaphylaxis Critical Yes Very low
Allergic reaction symptoms requiring hospitalization Critical Yes Very low
Allergic reaction symptoms requiring outpatient or
emergency department medical attentionImportant Yes Very low
Allergic reaction including cardiovascular symptoms,
respiratory symptoms, angioedema, or generalized
urticariaImportant Yes Very low
85
1. Anvari , S., et al., Influenza vaccine testing and administration in Egg allergic children. Journal of Investigative Medicine, 2011. 59(2): p. 477 -478.
2. Chan D. The safety of influenza vaccination in children with anaphylactic egg allergy. Internal Medicine Journal 2009; 39 (Suppl. 5): A139.
3. Chung, E.Y ., L. Huang, and L. Schneider, Safety of influenza vaccine administration in egg -allergic patients. Pediatrics, 201 0. 125(5): p. e1024 -30.
4. Comeau, J., et al., Why is Australian policy still cautious with influenza vaccination in severe egg allergic children? In ternal Medicine Journal, 2016. 46 (Supplement 4): p. 6.
5. Des Roches, A., et al., Egg -allergic patients can be safely vaccinated against influenza. Journal of Allergy & Clinical Immun ology, 2012. 130(5): p. 1213 -1216.e1.
6. Des Roches, A., et al., Safe vaccination of patients with egg allergy by using live attenuated influenza vaccine. The Jour nalof Allergy & Clinical Immunology in Practice, 2015.
3(1): p. 138 -9.
7. Didenko , I., et al., Influenza A (H1N1) vaccination in individuals with egg allergy. Revista Portuguesa de Imunoalergologia , 2010. 18(3): p. 243 -252.
8. Dona, D., et al., Special immunization service: A 14 -year experience in Italy. PLoS ONE, 2018. 13 (4) (no pagination)(e0195881).
9. Dorsey MJ. Influenza vaccine in 55 patients with egg allergy. J Allg Clin Immunol 2005: S250.
10. Erlewyn -Lajeunesse , M., et al., Multicentre audit of influenza immunisation in children allergic to egg. Allergy: European Journal of Allergy and Clinical Immunology, 2010.
92): p. 364 -365.
11. Esposito, S., et al., Safe administration of an inactivated virosomal adjuvanted influenza vaccine in asthmatic children with egg allergy. Vaccine, 2008. 26(36): p. 4664 -8.
12. Forsdahl , B.A., Reactions of Norwegian children with severe egg allergy to an egg -containing influenza A (H1N1) vaccine: a retrospective audit. BMJ Open, 2012. 2: p.
e000186.
13. Fung, I. and J.M. Spergel , Administration of influenza vaccine to pediatric patients with egg -induced anaphylaxis. Journal of Allergy & Clinical Immunolo gy, 2012. 129(4): p.
1157 -9.
14. Gagnon, R., et al., Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine. Journal of Al lergy & Clinical Immunology, 2010. 126(2): p. 317 -
23.
15. Grainger -Allen, E., et al., Safety of influenza immunisation in high risk egg allergy. Clinical and Experimental Allergy, 2013. 43 (12): p. 1433.
16. Greenhawt , M.J., et al., Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy. Annals o f Allergy, Asthma, & Immunology, 2012.
109(6): p. 426 -30.References
17. Greenhawt , M.J., et al., The safety of the H1N1 influenza A vaccine in egg allergic individuals. Annals of Allergy, Asthma, & Immunolo gy,2010. 105(5): p. 387 -93.
18. Halsey, N.A., et al., Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines : Reports to VAERS. Vaccine, 2013. 31(51): p.
6107 -6112.
19. Hotte SL. A 6 -year Experience with Influenza Vaccination in Egg Allergic Patients. J Allerg Clin Immunol 2008;121:s239.
20. Howe, L.E., et al., Safe administration of seasonal influenza vaccine to children with egg allergy of all severities. Ann alsof Allergy, Asthma, & Immunology, 2011. 106(5): p.
446-7.
21. James, J.M., et al., Safe administration of influenza vaccine to patients with egg allergy. Journal of Pediatrics, 1998. 133(5): p. 624 -8.
22. Kawahara, H., et al., [Immediate adverse reactions after administration of the influenza vaccine to patients with positiv e CAP-RAST to egg white]. Arerugi -Japanese
Journal of Allergology, 2002. 51(7): p. 559 -64.
23. Kawahara, H., et al., [Safe administration of influenza vaccine in asthmatic children]. Arerugi -Japanese Journal of Allergology, 1998. 47(7): p. 679 -86.
24. Khan, F.S., et al., Influenza vaccine administration in egg allergic children. Journal of Allergy and Clinical Immunology , 2012. 1): p. AB70.
25. Kletz , M.R., et al., Administration of egg -derived vaccines in patients with history of egg sensitivity. Annals of Allergy, 1990. 64( 6): p. 527 -9.
26. Leo, S.H., J. Dean, and E.S. Chan, Safety of H1N1 and seasonal influenza vaccines in egg allergic patients in British Col umb ia. Allergy, Asthma and Clinical Immunology.
Conference: Canadian Society of Allergy and Clinical Immunology Annual Scientific Meeting, 2010. 6(SUPPL. 2).
27. Murad, M.H., et al., Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med, 2018. 23(2 ): p. 60 -63.
28. Murphy, K.R. and R.C. Strunk, Safe administration of influenza vaccine in asthmatic children hypersensitive to egg protei ns.Journal of Pediatrics, 1985. 106(6): p. 931 -3.
29. Nickolls , C., et al., The safety of H1N1/seasonal influenza vaccination in egg allergic children -A prospective study. Internal Medicin e Journal, 2010. 4): p. 16.
30. Owens, G. and A. MacGinnitie , Higher -ovalbumin -content influenza vaccines are well tolerated in children with egg allergy. Journal of Allergy & Clinical Imm unology, 2011.
127(1): p. 264 -5.
31. Park, A., et al. Administration of influenza vaccine to patients with egg allergy. J Allergy Clin Immunol , 2008 (Februar y).p. S240.
32. Paschall, V.L., et al., Do egg -specific IgElevels predict reactions to seasonal influenza or H1N1 vaccination? Journal of Allergy and Clinical Immunology, 2011. 1): p. AB182.
33. Pien , G.C., et al., Coordination of multidisciplinary resources for vaccination of egg -allergic individuals during an H1N1 (novel) i nfluenza pandemic. Allergy & Asthma
Proceedings, 2010. 31(6): p. 507 -10.
34. Pitt, T., et al., Assessment of epicutaneous testing of a monovalent Influenza A (H1N1) 2009 vaccine in egg allergic patients. Allergy, Asthma, & Clinical Immunology :
Official Journal of the Canadian Society of Allergy & Clinical Immunology, 2011. 7(1): p. 3.
35. Schuler, J.E., et al., Administration of the adjuvanted pH1N1 vaccine in egg -allergic children at high risk for influenza A/ H1N1 disease. Can J Public Health, 2011. 102(3): p.
196-9.
36. Seyerle , J., R. Scherzer, and E.A. Erwin, Testing and administration of seasonal and pandemic influenza vaccines in egg allergic pat ients. Annals of Allergy, Asthma and
Immunology, 2010. 105 (5): p. A109.
37. Shimizu, M., et al., [Safety of Influenza Vaccination in Children with Severe Allergy to Hen's Eggs: A Prospective Case S eries Study]. Arerugi -Japanese Journal of
Allergology, 2016. 65(2): p. 128 -33.
38. Siret -Alatrista , A., et al., The 2009 -2010 H1N1 vaccination campaign for patients with egg allergy in a region of France. Allergy, 2011. 66(2): p. 298 -9.
39. Spiegel, W. and R. Anolik , Administration of H1N1 vaccine in an eggallergic population. Annals of Allergy, Asthma and Immunology, 2010. 105 (5): p. A4.
40. Thanik , E.S., A.L. Cox, and H.A. Sampson, Administration of a low egg -containing influenza vaccine [ fluarix ] in an egg -alphallergic pediatric population. Journal of Allergy
and Clinical Immunology, 2010. 1): p. AB25.
41. Tounian , P ., et al., [Vaccinations of children allergic to eggs with vaccine prepared with egg]. Archives Francaises de Pediatrie , 1993. 50(3): p. 191 -5.
42. Tozandehjani , S., et al., Safety of Inactivated Influenza Vaccine in Patients with Egg Allergy in Kurdistan Province, Iran. Iranian Journ al of Public Health, 2019. 48(4): p. 758 -
763.
43. Turner, P .J., et al., Safety of live attenuated influenza vaccine in atopic children with egg allergy. Journal of Allergy & Clinical Immunology, 2015. 136(2): p. 376 -81.
44. Turner, P .J., et al., Safety of live attenuated influenza vaccine in young people with egg allergy: multicentre prospective cohort study. BMJ, 2015. 351: p. h6291.
45. Upton, J.E., et al., No systemic reactions to influenza vaccination in egg -sensitized tertiary -care pediatric patients. Alle rgy, Asthma, & Clinical Immunology : Official Journal
of the Canadian Society of Allergy & Clinical Immunology, 2012. 8: p. 2.
46. Webb, L., et al., Single -dose influenza vaccination of patients with egg allergy in a multicenter study. Journal of Allergy & Clinical Immunology, 2011. 128(1): p. 218 -9.
47. Woo, E.J., Allergic reactions after egg -free recombinant influenza vaccine: reports to the US Vaccine Adverse Event Reportin g System. Clinical Infectious Diseases, 2015.
60(5): p. 777 -80.
48. Woo, E.J., et al., Postmarketing safety surveillance of trivalent recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. Vaccin e,2017.
35(42): p. 5618 -5621.
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