Reimmunization was recommended to 27/31 patients with an ISR, 3 patients did not require further doses, and a recommendation was deferred in one case. At the time of this analysis, 17/27 were eligible for reimmunization, of whom 14/17 (82%) have been reimmunized and 3/17 (18%) remain unimmunized for other reasons or were lost to follow up. The ISR was of high impact or serious in 2/3 patients who have not been reimmunized versus 2/14 patients who were reimmunized (P = 0.1). Six of 14 patients who were reimmunized (43%) experienced a recurrent ISR; five events occurred after TIV and one occurred after PCV13. All 6 patients reported that the AEFI was less severe than the initial occurrence and did not affect their daily activities.
Among the 42 patients referred for ALE, 14 (33%) were diagnosed with immediate hypersensitivity without anaphylaxis, 8 (19%) with idiopathic urticaria/angioedema, 3 (7%) with anaphylaxis and 17 (40%) with other allergic events (eg, serum sickness, erythema multiforme). The median interval from immunization to onset of allergic symptoms was 2 hours (IQR 0.2–24 hours) (Table 2). As with ISR, most events were of low to moderate impact, with only 3 cases reported as high impact or serious. One or more vaccines were considered to be causally associated with the ALE in 50% of cases, most commonly DTaP/Tdap and pneumococcal conjugate vaccine (PCV; Table 3).
Allergy testing was conducted on 18/42 patients. Skin prick testing with the vaccine was performed on 17 patients, 13 of whom also underwent intradermal testing. One patient underwent intradermal testing to the vaccine without a prior skin prick test. Four of 18 patients also underwent skin prick testing to one or more vaccine excipients (eg, latex, formaldehyde) or other allergens (eg, egg protein). The results of allergy testing were negative in 16/18 patients. One patient with a positive skin prick test to influenza vaccine was reimmunized without recurrence. One patient had positive intradermal tests to influenza vaccine and latex. The patient was advised to receive influenza immunization in graded doses, but has not been reimmunized to date. Reimmunization was recommended to 16/18 patients who underwent skin prick or intradermal testing, of whom 11 have been reimmunized. One patient with a negative skin prick test experienced a mild recurrence of the AEFI, a pruritic erythematous rash at both injection sites, after reimmunization with hepatitis A and B and quadrivalent human papillomavirus vaccines. Among the 24 patients who did not undergo skin prick testing, 19 were offered reimmunization and 10 had been reimmunized at the time of the analysis (Table 4). One patient developed a recurrence of erythematous rash and edema of the hands and feet 12 hours after reimmunization with MMRV, which was coadministered with DTaP-IPV-Hib. Reimmunization was contraindicated for 2 patients: one patient developed erythema multiforme 15 days after MMR immunization and the other patient developed symptoms of serum sickness (rash with target-like lesions, fever, arthritis) with onset 2 days after DTaP-IPV. Although definitive evidence of a causal association with the vaccine was lacking in both cases, the risk of severe AEFI was determined to outweigh the benefit of reimmunization. AEFI severity did not differ significantly between patients who were revaccinated and those were not revaccinated.
There were 20 patients seen with neurologic events that had their onset after immunization, including 4 with Guillain-Barré syndrome, 4 with encephalitis, myelitis or acute disseminated encephalomyelitis, 3 with febrile seizures, 1 with peripheral neuropathy and 8 with other neurologic symptoms. The median interval from immunization to onset of neurologic symptoms was 24 hours (IQR 12 hours–14 days) (Table 2). The majority of neurologic events were either serious (45%; 9/20) or high impact (40%; 8/20). However, the role of the vaccine in causing the adverse event was indeterminate in 13/20 cases. The vaccine was reported to be causally associated with the event in 2 cases: one patient developed febrile seizures after DTaP at 16 months and after MMR at 5 years of age, and the other patient developed Bell’s palsy 4 days after hepatitis A and B and yellow fever vaccines.
Reimmunization was recommended in 13/20 cases (Table 4). Four patients have been reimmunized without recurrence. Four patients refused immunization, 2 were not due for immunization at the time of the analysis, and 3 were not vaccinated for other reasons or were lost to follow-up. AEFI severity and determination of causality did not differ between patients who were reimmunized and those who were eligible but remain unimmunized. Reimmunization with one or more vaccines was contraindicated in 3 patients. The patient with Bell’s palsy mentioned above was advised not to receive yellow fever vaccine in the future. The second patient developed Guillain-Barré Syndrome <6 weeks after influenza, MMRV, PCV and meningococcal conjugate serogroup C (MenC-C) immunizations, and was advised against future influenza immunization. The third patient had a remote history of left-sided hemiparesis and possible encephalitis after MMR vaccine.
Other Systemic Events
Thirty-nine patients experienced a range of systemic symptoms after immunization: fever ≥40.5°C (8 patients), hypotonic-hyporesponsive episode (7), thrombocytopenia (5), persistent crying >3 hours (4), vasovagal or anxiety reactions (3), other systemic reactions (12) [nonspecific rash (5), pain, malaise, Kawasaki disease, gastrointestinal symptoms, aplastic anemia, glomerulonephritis, nephrotic syndrome]. Most of these events had a low to moderate impact on health and daily activities (Table 2). All 7 patients with hypotonic-hyporesponsive episodes had received a DTaP-containing vaccine and PCV. Three patients had also received rotavirus vaccine, 1 had received rotavirus and MenC-C, and 1 had received influenza and multicomponent meningococcal B vaccine. The 4 children with persistent crying had all received a DTaP-containing vaccine; 2 had also received PCV and a third had received PCV and rotavirus vaccine. In 16/39 cases, the vaccine was considered to be causally associated with the event and in 18 cases a causal association was indeterminate. DTaP and PCV were the vaccines most often reported to be causally associated with systemic events (Table 3). Reimmunization was recommended for 34 patients (87%) and was contraindicated in only 2 cases (Table 4). Of 21 patients who have been revaccinated to date, 3 experienced a recurrence of the AEFI. The first patient developed a recurrence of fever, diarrhea and erythema at the injection site after TIV. The second patient developed fever, vomiting and nonspecific rash after reimmunization with DTaP-IPV-Hib coadministered with MenC-C and MMRV. The third patient, a child with periodic fever syndrome, developed recurrence of high fever after PCV13 coadministered with MenC-C and MMR; this recurrence was more severe than the first event.
Patients With Contraindications to Immunization
Nineteen patients were assessed for underlying conditions that may alter immunization recommendations; they ranged in age from 1.2 to 16.4 years. Ten patients were seen for pretransplant evaluation but had no immediate contraindication to immunization; no AEFI were subsequently reported from this group. The clinical characteristics of the 9 patients who were seen for possible contraindications to immunization are shown in Table 5. Seven patients were immunocompromised because of immunosuppressive medication or splenectomy. Two patients were assessed for fibrodysplasia ossificans progressiva, a rare genetic condition in which patients develop painful inflammatory soft tissue swellings that lead to heterotopic ossification at sites of trauma to muscle and connective tissue.18 Both patients were advised against receiving any intramuscular injections. They tolerated varicella vaccine (administered subcutaneously) well. Practices varied between sites, with one site recommending deferral of all immunizations for a patient with vasculitis on prednisone (dose unknown), while another patient on sirolimus for lymphangiectasia was vaccinated with live and inactivated vaccines after immunologic assessment (all vaccines were well tolerated).
This report from the Canadian SICs Network demonstrates the breadth of referrals received for patients with AEFI and potential contraindications to immunization. ALEs after DTaP/Tdap and ISRs after influenza vaccines were the most common events seen in the clinics. Although most events were of low to moderate impact, 13% of events were serious and 15% were of high impact, indicating a need for urgent medical attention and/or >4 days of disability. Of 60 patients with AEFI who were revaccinated with at least one vaccine that was temporally associated with the primary event, 11 (18%) had a recurrence of the primary adverse event. However, the recurrence was of similar or lesser severity than the first event in 10/11 patients. The one patient for whom the recurrence was more severe than the first event had high fever in the setting of an underlying autoinflammatory syndrome. None of the recurrences were considered serious adverse events.
Patients with ISR had the highest risk of recurrence (43%). Previous studies have reported similar recurrence risks of 10%–72%.19–22 These patients need to be counseled regarding the risk of recurrence, but the findings suggest that they can be reassured that such events are likely to be mild and not limit daily activities. None of the patients with ISR refused reimmunization despite their prior experiences, suggesting a high level of support for immunization in this group.
Most patients with ALE did not appear to have IgE-mediated reactions. Although skin testing was conducted in 18/42 patients, 14 of whom underwent intradermal testing, only 2 patients had a positive skin-prick or intradermal test suggestive of an IgE-mediated reaction to a vaccine or vaccine component. Therefore, it was not surprising that only 10% of patients who were reimmunized experienced a recurrence of their allergic symptoms. Furthermore, there were no cases of anaphylaxis after reimmunization. These findings are consistent with those of prior studies of ALE after immunization,23–25 and provide further reassurance that among patients who present with symptoms of immediate hypersensitivity after immunization, the risk of a subsequent severe allergic reaction is low.
Neurologic events after immunization were the most serious type of AEFI seen in the SIC network, but they were also the events associated with the greatest degree of uncertainty regarding the causal role of the vaccine. Reimmunization of patients with neurologic events was contraindicated in 3 patients, while 4 patients refused reimmunization, perhaps reflecting the severity of the AEFIs and the uncertainty surrounding these events. In some cases, early referral after the AEFI or during the acute event might have permitted a more complete evaluation to confirm the diagnosis and search for other causes of the event (eg, infection). Such information might have informed the causality assessment and immunization recommendations.
Overall, reimmunization was recommended to over 80% of patients, of whom only 11% refused reimmunization. To date, 60 patients have been reimmunized without any serious AEFI occurring and only 3 patients experienced a recurrent AEFI severe enough to limit their daily activities or to lead them to seek medical attention. These findings are consistent with reports from specialized immunization services in Australia, Italy and the United Kingdom, in regards to the high acceptance of immunization among these patients and the safety of reimmunization.7–10 Studies have found that the experience of an AEFI can negatively impact patient perceptions of vaccine safety, which could contribute to a reluctance to proceed with future immunizations.26,27 SICs have a role to play in alleviating these concerns and promoting safe immunization practices for “high-risk” patients.
This study had limitations. Patients required a referral by a healthcare provider and there was likely referral bias related to the travel distance to the nearest SIC, differences in public health policy and capacity for managing patients with AEFI, and local awareness of the existence of the SIC. Recruitment rates differed by study site and province. Few adults were referred to SICs and those who were referred were more likely to decline participation than patients <18 years of age, limiting our ability to draw conclusions regarding their outcomes after reimmunization. The AEFI diagnosis was made retrospectively based on the SIC physician’s assessment, which often occurred months to years after the initial AEFI. This may have contributed to uncertainty regarding the final diagnosis and assessment of causality. Finally, the number of patients with high impact or serious AEFI was low and overall, fewer than 50% of these patients have been reimmunized. Therefore, we have limited data on which to draw conclusions regarding the risk of recurrence of clinically significant AEFI.
Based on our findings, patients with low to moderate impact AEFI can be reassured that their risk of a recurrent adverse event that limits their daily activities is low. However, data concerning the outcomes of patients with AEFI or with potential contraindications to immunization remain limited. Large numbers of patients are needed to determine the risk of recurrence of specific AEFI after specific immunizations and to identify which patients are at increased risk of recurrence. Specialized immunization clinics are an ideal platform for systematically evaluating patients and following them after reimmunization. Such clinics exist in several locales but few have published their data. Clinicians and public health officials should be encouraged to refer high-risk patients to specialized immunization clinics, where available, and physicians operating these clinics should be encouraged to systematically collect and publish their data on outcomes after reimmunization. Only by pooling data from multiple clinics, will sufficient data be collected to support the development of immunization guidelines for patients with prior AEFI and potential contraindications to immunization.
The authors gratefully acknowledge the expert assistance of the SIC nurse coordinators and Dany Laverdière at the Institut national de santé publique du Québec. Special Immunization Clinic Network Investigators and co-investigators participating in this project are as follows: K. Top, MD MS, S. Halperin, MD, G. Rex, MD, IWK Health Centre, Halifax, NS; G. Lacuesta, MD, S. A. McNeil, MD, Nova Scotia Health Authority, Halifax, NS; F. D. Boucher, MD, J. P. Drolet, MD, Centre hospitalier universitaire de Québec, Québec, QC; G. De Serres, MD PhD, Institut national de santé publique du Québec, Québec, QC; C. Quach, MD, MSc, Marie-Noelle Primeau MD, The Montreal Children’s Hospital, Montreal, QC; A. Carignan, MD, MSc; Louis Valiquette, MD, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC; A. Pham-Huy, MD, S. Hotte, MD, Children’s Hospital of Eastern Ontario, Ottawa, ON; D. Tran, MD, MSc, Hospital for Sick Children, Toronto, ON; J. M. Pernica, MD, Z. Abdurrahman, MD, McMaster Children’s Hospital, Hamilton, ON; J. Ohayon, MD, McMaster University, Hamilton, ON; F. Diaz-Mitoma, MD, J. McElhaney, MD, Advanced Medical Research Institute of Canada and Health Sciences North, Sudbury, ON; A. McConnell, MD, Royal University Hospital, Saskatoon, SK; T. Jadavji, MD, Alberta Children’s Hospital, Calgary AB; W. Vaudry, MD, Yarden Yanishevsky, MD, Stollery Children’s Hospital, Edmonton, AB; S. Dobson, MD, British Columbia Children’s Hospital, Vancouver, BC.
1. Andre FE, Booy R, Bock HL, et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull World Health Organ. 2008;86:140–146.
2. Barlow WE, Davis RL, Glasser JW, et al; Centers for Disease Control and Prevention Vaccine Safety Datalink Working Group. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med. 2001;345:656–661.
3. Le Saux N, Barrowman NJ, Moore DL, et al; Canadian Paediatric Society/ Health Canada Immunization
Monitoring Program-Active (IMPACT). Decrease in hospital admissions for febrile seizures and reports of hypotonic-hyporesponsive episodes presenting to hospital emergency departments since switching to acellular pertussis vaccine in Canada: a report from IMPACT. Pediatrics. 2003;112:e348.
4. Erlewyn-Lajeunesse M, Hunt LP, Heath PT, et al. Anaphylaxis as an adverse event following immunisation in the UK and Ireland. Arch Dis Child. 2012;97:487–490.
5. McNeil MM, Weintraub ES, Duffy J, et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol. 2016;137:868–878.
6. Williams SE, Edwards KM, Baxter RP, et al. Comprehensive assessment of serious adverse events following immunization
by health care providers. J Pediatr. 2013;162:1276–81, 1281.e1.
7. Ko ML, Rao M, Teare L, et al. Outcome of referrals to a district immunisation advisory clinic. Commun Dis Rep CDR Rev. 1995;5:R146–R149.
8. Gold M, Goodwin H, Botham S, et al. Re-vaccination of 421 children with a past history of an adverse vaccine reaction in a special immunisation service. Arch Dis Child. 2000;83:128–131.
9. Micheletti F, Moretti U, Tridente G, et al. Consultancy and surveillance of post-immunisation adverse events in the Veneto region of Italy for 1992-2008. Hum Vaccin. 2011;7 Suppl:234–239.
10. Baxter D, Ghebrehewet S, Falconer M. Referrals to a pediatric immunization
service: findings from a practice-based audit of a UK specialist immunization
clinic. Hum Vaccin. 2010;6:420–424.
11. Top KA, Zafack J, De Serres G, et al. Canadian paediatricians’ approaches to managing patients with adverse events following immunization
: the role of the Special Immunization
Clinic network. Paediatr Child Health. 2014;19:310–314.
12. National Advisory Committee on Immunization
. Canadian Immunization
Guide: Evergreen Edition. 2012.Ottawa, ON: Public Health Agency of Canada.
13. Zanoni G, Ferro A, Valsecchi M, et al. The “Green Channel” of the Veneto region as a model for vaccine safety monitoring in Italy. Vaccine. 2005;23:2354–2358.
14. Kelso JM, Greenhawt MJ, Li JT, et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol. 2012;130:25–43.
15. Wood RA, Berger M, Dreskin SC, et al; Hypersensitivity Working Group of the Clinical Immunization
Safety Assessment (CISA) Network. An algorithm for treatment of patients with hypersensitivity reactions after vaccines. Pediatrics. 2008;122:e771–e777.
16. Tozzi AE, Asturias EJ, Balakrishnan MR, et al. Assessment of causality of individual adverse events following immunization
(AEFI): a WHO tool for global use. Vaccine. 2013;31:5041–5046.
17. Statistics Canada. Estimates of Population, by age group and sex for July 1, Canada, provinces and territories. September 29, 2015. Available at: http://www5.statcan.gc.ca/cansim/a26
. Accessed 25 February, 2016.
18. Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008;22:191–205.
19. Baraff LJ, Cherry JD, Cody CL, et al. DTP vaccine reactions: effect of prior reactions on rate of subsequent reactions. Dev Biol Stand. 1985;61:423–428.
20. Marshall HS, Gold MS, Gent R, et al. Ultrasound examination of extensive limb swelling reactions after diphtheria-tetanus-acellular pertussis or reduced-antigen content diphtheria-tetanus-acellular pertussis immunization
in preschool-aged children. Pediatrics. 2006;118:1501–1509.
21. Quinn P, Gold M, Royle J, et al. Recurrence of extensive injection site reactions following DTPa or dTpa vaccine in children 4-6 years old. Vaccine. 2011;29:4230–4237.
22. Rennels MB, Black S, Woo EJ, et al. Safety of a fifth dose of diphtheria and tetanus toxoid and acellular pertussis vaccine in children experiencing extensive, local reactions to the fourth dose. Pediatr Infect Dis J. 2008;27:464–465.
23. Rouleau I, De Serres G, Drolet JP, et al; Public Health Agency of Canada–Canadian Institutes for Health Research Influenza Research Network. Allergic symptoms after pandemic influenza vaccination rarely mediated by vaccine-specific IgE. J Allergy Clin Immunol. 2012;130:1423–1426.
24. Micheletti F, Peroni D, Piacentini G, et al. Vaccine allergy evaluation and management at the specialized Green Channel Consultation
Clinic. Clin Exp Allergy. 2012;42:1088–1096.
25. Seitz CS, Bröcker EB, Trautmann A. Vaccination-associated anaphylaxis in adults: diagnostic testing ruling out IgE-mediated vaccine allergy. Vaccine. 2009;27:3885–3889.
26. Parrella A, Gold M, Marshall H, et al. Parental perspectives of vaccine safety and experience of adverse events following immunisation. Vaccine. 2013;31:2067–2074.
27. Parrella A, Gold M, Marshall H, et al. Parental views on vaccine safety and future vaccinations of children who experienced an adverse event following routine or seasonal influenza vaccination in 2010. Hum Vaccin Immunother. 2012;8:662–667.
Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
adverse event following immunization; immunization; consultation