Pediatric Anaphylactic Adverse

Vaccine 33 (2015) 1602–1607
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j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e Pediatric anaphylactic adverse events following immunization inVictoria, Australia from 2007 to 2013Daryl R. Cheng a,b,∗, Kirsten P. Perrett a,c,d , Sharon Choo d , Margie Danchin a,c,e ,Jim P. Buttery f , Nigel W. Crawford a,e,fa Department of General Medicine, The Royal Children’s Hospital, Melbourne, VIC, Australiab Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USAc Vaccine and Immunisation Research Group (VIRGo), Murdoch Childrens Research Institute and Melbourne School of Population and Global Health,The University of Melbourne, Melbourne, VIC, Australiad Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, VIC, Australiae Department of Pediatrics, The University of Melbourne, Melbourne, VIC, Australiaf SAEFVIC, Murdoch Children’s Research Institute, Melbourne, VIC, Australiaa r t i c l e i n f oArticle history:Received 10 November 2014Received in revised form 3 February 2015Accepted 4 February 2015Available online 16 February 2015Keywords:AnaphylaxisImmunizationAEFIVaccine safetya b s t r a c tBackground: Anaphylaxis is a rare life-threatening adverse event following immunization (AEFI). Vari-ability in presentation can make differentiation between anaphylaxis and other AEFI difficult. This studysummarizes pediatric anaphylaxis AEFI reported to an Australian state-based passive surveillance system.Methods: All suspected and reported pediatric (<18 years) anaphylaxis AEFI notified to SAEFVIC (Surveil-lance of Adverse Events Following Vaccination In the Community) Melbourne, Australia, between May2007 to May 2013 were analyzed. Clinical descriptions of the AEFI, using the internationally recognizedBrighton Collaboration case definition (BCCD) and final outcome were documented.Results: 93% (25/27) of AEFI classified as anaphylaxis met BCCD criteria, with 36% (9/25), assessed as thehighest level of diagnostic certainty (Level 1). Median age was 4.7 years (range 0.3–16.2); 48% of caseswere male. The vaccine antigens administered included: diphtheria, tetanus, acellular pertussis (DTaP)alone or in combination vaccines containing other antigens in 11 of 25 cases (44%); and live attenuatedmeasles mumps rubella (MMR) vaccine for six (five also had other vaccines concomitantly administered).The estimated incidence rate of anaphylaxis for DTaP vaccines was 0.36 cases per 100,000 doses, and 1.25per 100,000 doses for MMR vaccines. The majority of cases had rapid onset, but in 24% (6/25) of cases,first symptoms of anaphylaxis developed ≥30 min after immunization. In 60% (15/25) of cases, symptomsresolved ≤60 min of presentation. Intramuscular adrenaline was administered in 90% (18/25) of cases.All cases made a full recovery with no sequelae identified.Conclusion: This comprehensive case series of pediatric anaphylaxis as an AEFI identified that diagnos-tic criteria are useful when applied to a passive vaccine surveillance system when adequate clinicalinformation is available. Anaphylaxis as an AEFI is rare and usually begins within 30 min of vaccination.However, healthcare professionals and vaccinees/parents should be aware that onset of anaphylaxis canbe delayed beyond 30 min following immunization and that medical attention should be sought promptlyif anaphylaxis is suspected.© 2015 Elsevier Ltd. All rights reserved.1. IntroductionAustralia has a standardized childhood National Immunisa-tion Program (NIP) schedule approved and reviewed on a regular∗ Corresponding author at: The Royal Children’s Hospital Melbourne, 50 Fleming-ton Rd, Parkville, VIC 3052, Australia. Tel.: [phone].E-mail address: [e-mail] (D.R. Cheng).basis by the Australian Technical Advisory Group on Immunisa-tion (ATAGI) and authorized by the National Health and MedicalResearch Council (NHMRC) [1]. It includes infant and early child-hood immunization, as well as a secondary school (age 12–16 years)program for catch-up vaccines (Hepatitis B, Varicella) and newvaccines (e.g. Human papillomavirus (HPV) vaccine introduced forfemales in 2007; males in 2012) [2]. There are also specific specialrisk groups with additional vaccine requirements (e.g. Aboriginaland Torres St Islanders).
http://dx.doi.org/10.1016/j.vaccine.2015.02.008
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D.R. Cheng et al. / Vaccine 33 (2015) 1602–1607 1603
Table 1
Case vaccination demographics.
Gender Age at vaccine (years) Vaccine NAME Dose No. BCCD level Adrenaline administered
Male 8.7 Fluvax 1 Level 2 Y
Female 16.5 Gardasil 2 Level 2 N
Male 4.7 Infanrix-IPV, Priorix 4, 3 Level 2 Y
Female 16.0 Gardasil 3 Level 1 N
Male 4.1 Infanrix-IPV, Priorix 4, 2 Level 2 Y
Male 1.3 Varilrix 1 Level 2 Y
Female 1.0 Priorix 1 Level 2 N
Female 0.4 Infanrix Hexa, Prevenar, RotaTeq 2, 2, 2 Level 1 Y
Female 4.0 Infanrix-IPV, Priorix 4, 2 Level 1 Y
Male 13.4 H-B-Vax II Adult formulation 2 Level 2 Y
Female 12.8 H-B-Vax II Adult formulation, Gardasil 2, 3 Level 2 Y
Male 4.9 Infanrix-IPV, Priorix 4, 2 Level 2 Y
Male 8.4 Twinrix Junior (360/10), Typherix 1, 1 Level 2 Y
Female 7.7 Panvax H1N1 2 Level 2 Y
Female 10.6 Fluvax 1 Level 2 N
Male 13.1 H-B-Vax II Adult formulation 1 Level 2 Y
Female 9.4 Influvac 1 Level 2 Y
Female 1.3 Prevenar 13 4 Level 1 Y
Female 16.2 Boostrix 1 Level 2 Y
Male 0.6 Infanrix Hexa, Prevenar 13 2, 2 Level 1 N
Male 0.6 Infanrix Hexa 3 Level 1 Y
Female 15.3 Boostrix 1 Level 3 Y
Male 0.9 Vaxigrip Jr 1 Level 1 N
Female 0.3 Infanrix Hexa, Rotateq, Prevenar 13 2,2, 2 Level 1 N
Male 4.3 Infanrix-IPV, Priorix 4, 2 Level 1 Y
Table 2
BCCD symptom presentations of anaphylaxisa .
Category Major Minor
Dermatological/Mucosal Generalized urticaria/erythema
Angioedema (localized/generalized)
Generalized pruritus with skin rash
Generalized pruritus without skin rash
Generalized prickle sensation
Localized injection site urticaria
Red/itchy eyes
Cardiovascular Measured hypotension
Shock (clinical diagnosis with ≥3 of tachycardia, cap
refill >3 s, reduced central pulse volume, decreased
level of consciousness)
Reduced peripheral circulation (≥2 tachycardia, capillary refill >3 s
without hypotension, decreased level of consciousness)
Respiratory Bilateral wheeze
Stridor
Upper airway swelling
Respiratory distress (>2 tachypnea, accessory muscle
use, recession, cyanosis, grunting)
Persistent dry cough
Hoarse voice
Difficulty breathing without wheeze/stridor
Sensation of throat closure
Sneezing/rhinorrhea
Gastrointestinal Diarrheal
Abdominal Pain
Nausea
Vomiting
Laboratory Raised mast cell tryptasea Adapted from Gold et al. [9].As part of the NIP, any adverse event following immunization(AEFI) can be reported via appropriate state or territory procedures.All reports are forwarded to the centralized national body, the Ther-apeutic Goods Administration (TGA). Likewise, reports directly tothe TGA are redirected back to SAEFVIC for local clinic follow-up andevaluation [3]. Anaphylaxis is a rare but potentially life-threateningAEFI [4], with an estimated incidence of approximately one caseper million vaccine doses [5,6]. It can manifest in a wide constella-tion of non-specific symptoms. This variability in presentation canmake it difficult to differentiate between anaphylaxis and otherisolated allergic AEFI such as urticaria or angioedema [7]. Anaphy-laxis is usually an immediate IgE-mediated phenomenon, requiringallergy workup including skin prick and intradermal testing and ifindicated supervised vaccine challenge(s) [8] (Table 1).The Brighton Collaboration is an internationally recognizedbody who developed a case definition for anaphylaxis as an AEFI(Table 1), outlining levels of diagnostic certainty (Table 2) [9].By providing a standardized objective definition to apply to AEFIreports, it is hoped that the accuracy of reports can be verifiedand that standardized management across the pediatric populationwould prove easier to disseminate and implement.Surveillance of Adverse Events Following Vaccination In theCommunity (SAFEVIC) is a passive surveillance system monitor-ing all AEFI across the state of Victoria, Australia. Established inMay 2007, it provides specialized outpatient services for both chil-dren and adults [10]. SAEFVIC maintains a database of all reportedadverse events and the follow-up details of each case. The pop-ulation of Victoria, Australia, in 2013 included over 1.05 millionchildren under 18 years of age [11].The primary aim of this study was to accurately detail theoccurrence, diagnosis and management of anaphylaxis post-immunization by applying the Brighton case definition to allreported pediatric anaphylaxis cases in the SAFEVIC database. Asecondary aim was to review which vaccines were temporallyassociated with anaphylaxis, vaccine specific incidence rates, man-agement strategies (e.g. use of adrenaline) and outcome.

1604 D.R. Cheng et al. / Vaccine 33 (2015) 1602–1607
Table 3
BCCD level of certainty for anaphylaxis.
BCCD level of certainty Diagnostic criteria Number of cases meeting criteria
Level 1 ≥1 major dermatological AND ≥1 major cardiovascular 0
≥1 major dermatological ≥AND 1 major respiratory 9
Level 2 ≥1 major cardiovascular AND ≥1 major respiratory 0
≥1 major cardiovascular/respiratory AND ≥1 minor criterion involving ≥1 different system 3
≥1 major dermatological AND ≥1 minor cardiovascular/respiratory 12
Level 3 ≥1 minor cardiovascular OR respiratory AND ≤1 minor criteria from ≥2 different systems 1
Level 4 Reported anaphylaxis with insufficient evidence to meet case definition 12. MethodsPediatric cases (under 18 years old) with suspected anaphy-laxis AEFI reported to SAFEVIC between May 2007 to May 2013 (sixyears) were included. Search terms used to select reports for reviewincluded all terms currently within BCCD criteria such as urticar-ial, hypotension, tachycardia or angioedema. Historical events (i.e.AEFI occurring before May 2007) reported during the study periodwere excluded due to a lack of reliable and objective data availableprior to the establishment of a standardized assessment process viaSAEFVIC.All events suspected or reported as anaphylaxis were followedup within 24 h of initial report via trained SAEFVIC healthcareprofessionals. Data collected included demographic information,medical history, medications, immunization status and previousAEFI. Clinical descriptions and details surrounding the currentadverse event, including management and final outcome were alsosourced from the family and treating physician and/or hospitalmedical records. All cases were offered a specialist clinic follow-upappointment and assessment prior to any subsequent vaccina-tion. Any incomplete information was recollected from consentingreporters, parents and healthcare workers prior to final analysis.The Brighton Collaboration Case Definition (BCCD) for ana-phylaxis AEFI (Table 1) was then retrospectively applied by twoindependent reviewers (DC and NC), who were not involved in anySAEFVIC assessments at time of initial reporting, applying a level ofdiagnostic certainty for each case (Table 2).Vaccine specific dose administration data from the AustralianChildhood Immunisation Register (ACIR) and National HPV Vacci-nation Program Register were used as the denominator to calculateincidence estimates. Data was entered into a Microsoft AccessDatabase (Microsoft Corporation, Redmond, WA, USA) and ana-lyzed with STATA 12.0 (Statacorp, TX, USA). Ethics approval wasobtained from The Royal Children’s Hospital Melbourne HumanResearch Ethics Committee.3. ResultsTwenty-five patients, with a total of 27 reports of anaphylaxis,were identified in the six-year study period (Table 3). The medianage of immunization was 4.7 years (range 0.3–16.2 years), with48% of cases male. Six cases (22.2%) were ≤12 months old whenreceiving vaccination. Twenty-five of these cases met BCCD criteriafor anaphylaxis (Table 2), with a total of 37 vaccines administered.Of these cases, nine (36%) met BCCD Level 1 diagnostic certainty,15 (60%) Level 2 and one case Level 3 (4%). One case was deemedLevel 5 (not a case of anaphylaxis).Thirteen cases included vaccines that are part of the routineAustralian infant and preschool immunization schedule, which hasevolved slightly through the study period [2]. The remaining 12cases consisted of vaccines that are part of the routine Australiansecondary school immunization program. The vaccine antigensadministered included combination DTaP vaccines (DTaP com-bined with other antigen) in 9 of 25 cases (36%). Measles mumpsrubella (MMR) vaccine was received in six cases; five of whom hadconcomitant vaccines (Table 4). The majority of vaccines (93%) wereadministered at a general practitioner’s (GP) primary care practice,or at a specialist immunization nurse led local council vaccinesession. Immunization nurses also administered most secondaryschool adolescent vaccines.3.1. Anaphylaxis incidence rateVaccine coverage is approximately 91% at 12 months of age [12]and 70–75% in the school program in Victoria [13]. 197,878 dosesof Infanrix IPVTM [GSK] were administered, with an incidence of2.53 per 100,000 doses [2.43, 2.63]. Likewise, 481,297 doses of thecombination MMR vaccine were administered with an estimatedincidence of 1.25 per 100,000 doses [1.18, 1.32]. For 13-valentpneumococcal (PCV13) vaccines, there were 498,039 doses withan incidence of 0.6 per 100,000 doses [0.55, 0.65].A total of 1,092,682 vaccine doses of Infanrix HexaTM [GSK] wereadministered over the study period, yielding an estimated inci-dence rate of 0.36 cases per 100,000 doses [0.32, 0.40, 95% CI]. Aminimum of 934,255 doses of HPV vaccines were administeredto pediatric patients within the study period, indicating an esti-mated anaphylaxis incidence of 0.32 per 100,000 doses [0.29, 0.35](data courtesy of ACIR and the National HPV Vaccination ProgramRegister).3.2. History of anaphylaxis/atopyOne infant had anaphylaxis on three separate occasions, withdifferent vaccines administered each time (Infanrix Hexa, Preve-nar 13, Vaxigrip Jr). Skin tests followed by vaccine challenges wereundertaken in an allergy clinic in a hospital setting as part of acausality assessment of specific vaccines and/or components. Oneformal allergy challenge was positive, with an anaphylactic reac-tion at 40 min following Infanrix HexaTM vaccine; the challenge forPrevenar 13 only resulted in an erythematous rash.Five cases (20.5%) had a past history of anaphylaxis to fooditems such as egg, nuts or seafood. All had already been prescribedan epinephrine auto-injectable device, with three patients hav-ing utilized it on a previous occasion for food related anaphylacticepisodes; however no device was used in any of the anaphylacticAEFI cases. Eight cases had a previous history of atopic disease; fourwith asthma, six with eczema and two with hayfever.3.3. Time post-vaccinationThe time anaphylaxis occurred post-immunization is detailed inFig. 1. Anaphylaxis in 19 cases (70%) occurred ≤30 min after immu-nization. A further two cases presented between 30 to ≤60 minand the remaining three cases were greater than 120 min followingimmunization.Symptoms resolved within 60 min of presentation for 15 cases,with a further six resolved within 24 h. The remaining four hadsymptoms persisting beyond 24 h, with one case having ongoingangioedema and urticaria for the following 6-days.