Reimmunization and AEFI Recurrence: Overall Results
Among the 1731 patients included in the analyses, 1350 (78%) were reimmunized and received 78% of the 2169 required additional doses (Table 2). The majority (59%, 803/1350) of reimmunized patients were children 2 years of age or younger, and the most common category of AEFI was ALE (49%, 659/1350). Overall, a recurrence occurred in 16% (215/1350) of patients (Table 2), 41% and 18% of which were rated as equally and more severe than the initial AEFI, respectively.
Compared with patients 2 to 17 years of age or 18 years of age or older, those 2 years of age or younger were more often reimmunized (65% and 68% versus 86%; P < 0.001) and less likely to have a recurrence (23% and 29% versus 12%; P < 0.001; Table 2). Gender did not influence reimmunization (76% of males versus 81% of females; P = 0.3) or recurrence (15.6% of males versus 16.2% of females; P = 0.7; Table 2). The proportion of patients reimmunized was inversely proportional to the severity of the initial AEFI (89%, 76% and 64% of patients with mild, moderate and severe AEFIs were, respectively, reimmunized; P < 0.001), but the rate of recurrence was not significantly different whatever the severity (18%, 15% and 8% of recurrences in patients with mild, moderate and severe AEFIs, respectively; P = 0.1). Patients with SAEs were less often reimmunized than those without SAEs (60% versus 80%; RR: 0.8; 95% CI: 0.66–0.86) but had fewer recurrences (8% versus 17%; RR: 0.5; 95% CI: 0.25–0.95; Table 2).
Among all AEFIs, patients with hypotonic hyporesponsive episode (HHE) were the most likely to be reimmunized (89%; 95% CI: 78.1–96.0) and the least likely to have a recurrence (Table 2). Only 1 of 50 (2%; 95% CI: 0.1%–10.6%) patients with HHE who were reimmunized had a recurrence. This recurrence occurred in a 4-month-old boy receiving his second doses of pneumococcal conjugate vaccine (PCV) and full-content diphtheria-tetanus-acellular pertussis (DTaP)–containing vaccine.
The rate of AEFI recurrence was similar between vaccines and varied from 8% to 22%. Patients with an AEFI following full-content or reduced-antigen diphtheria-tetanus-acellular pertussis (DTaP/dTap)–containing vaccines were the most likely to be reimmunized (90%; 95% CI: 87.4–92.2), and those with an AEFI following rotavirus vaccine were the least likely to be reimmunized (53%; 95% CI: 41.9 to 63.5; Table 2) especially if they had diarrhea/vomiting. Among patients with diarrhea/vomiting, only 35% (10/29) were reimmunized with rotavirus vaccine compared with 94% (29/31) and 88% (14/16) of patients reimmunized with DTaP/dTap-containing vaccines and PCV, respectively (Table 3).
Recurrence per Type of AEFI
Among the 820 patients with ALEs, 659 (80%) were reimmunized of which 76 (12%; 95% CI: 9.2–14.2) had a recurrence (Table 2). The rate of ALE recurrence varied from 5% to 25% between vaccines (Table 3). Patients whose ALE onset occurred within an hour of immunization were as likely to be reimmunized as those with onset 1–3 hours or ≥4 hours postimmunization and had no greater rate of recurrence (Table 4). Among the 18 patients with reported anaphylaxis, 3 met the Brighton Collaboration level 1 of diagnostic certainty, 8 met level 2, 6 met level 3 and 1 did not have a description of signs and symptoms (Table, Supplemental Digital Content 3, http://links.lww.com/INF/D243). A medical assessment was done for 2, 4, 4 and 1 patients, and reimmunization performed in 0, 3, 4 and 1 patients, respectively. None of 8 reimmunized patients had a recurrence. Reimmunization was withheld in 3 patients: 1 was considered immune to the targeted vaccine preventable disease based on serum antibody titers, and 2 had positive skin testing to the vaccine.
Large local reactions recurred in 44 of 203 reimmunized patients (22%; 95% CI: 16.2–28.0; Table 2). The rate of recurrence varied from 7% to 33% between vaccines (Table 3). Large local reactions that extended beyond the nearest joint and lasted 4 days or more recurred in 6(67%) of 9 patients compared with 13% (5/39) when it did not go beyond the nearest joint and lasted <4 days (RR = 2.9; 95% CI: 1.4–5.8).
Among the 92 patients with fever, 71 (77%) were reimmunized, and recurrences occurred in 11 (15%; 95% CI: 8.0–26.0). The rate of recurrence varied from 0% to 15% between vaccines (Table 3). The proportion of patients reimmunized and the rate of fever recurrence did not differ by the recorded level of temperature (39°C–40.4°C versus ≥40.5°C).
No recurrences occurred among 11 patients with afebrile seizures who were reimmunized compared with 3 recurrences among 36 patients (8%; 95% CI: 1.8–22.5) with febrile seizures. These 3 recurrences of febrile seizures occurred among patients reimmunized with DTaP/dTap-containing vaccines administered with or without concurrent PCV. None of the 33 patients reimmunized with measles mumps rubella vaccine with or without varicella antigen (MMR±V; Table 3) had a recurrence of febrile seizure including 18 patients with onset of febrile seizures between day 5 and day 12 following their first MMR±V immunization.
Diarrhea/vomiting recurred in 18 of 74 reimmunized patients (24%; 95% CI: 15.1–35.7; Table 2). The rate of recurrence varied from 0% to 38% between vaccines (Table 3).
This is one of the largest studies to estimate the rate of AEFI recurrence per type of AEFI and vaccine, a key element for the decision regarding further immunization of patients who had a prior AEFI. Overall, 16% of patients had a recurrent AEFI, of whom 18% rated the recurrence as more severe than the initial AEFI, respectively. The rate of AEFI recurrence was similar between vaccines and between AEFIs except for large local reactions extending beyond the nearest joint and lasting 4 days or more, which were associated with the highest rate of recurrence (67%). No patient with anaphylaxis experienced a recurrence. Among patients with nonanaphylactic ALEs, 12% had a recurrence, of which 20% were considered more severe than the initial ALE. None of the 33 patients with febrile seizures following the first dose of MMR±V (recommended in Quebec at 12 months of age) had a recurrence following administration of the second dose (recommended at 18 months of age; Table, Supplemental Digital Content 2, http://links.lww.com/INF/D242).
ALEs often raise concerns about the rate of anaphylaxis upon reimmunization. Our results and those of previous studies show that while recurrence of nonanaphylactic events may happen, anaphylaxis following reimmunization is rare.4 , 11–17 This reassuring finding is likely related to 2 factors. First, most reported ALEs following immunization are mild or moderate. Based on the experience with penicillin, food and insect venom allergies mild or moderate events will either not recur18–21 or will generally result in recurrences with similar severity (stereotypic) as the first event22–27 and not in anaphylaxis. Second, most ALEs following immunization are unlikely to be IgE mediated. They usually began more than 1 hour following immunization, a timing inconsistent with an IgE-mediated hypersensitivity to vaccine components.11 , 13 , 16 , 17 This is further supported by the fact that skin tests with the vaccines temporally associated with the ALE are generally negative even in patients with reported anaphylaxis.11–13 , 16 The current management algorithms suggest that precautions (skin testing with the vaccine, graded dose reimmunization or serologic testing for immunity to the vaccine) are needed for the few patients with a severe clinical presentation9 and/or onset of their ALE within 1 to 4 hours of immunization but are generally unnecessary for other patients.11 , 28
Similar to other studies,13 , 29–31 we found that large local reactions extending beyond the nearest joint and lasting 4 days or more (referred to as extensive limb swelling) recurred frequently (67%). Fortunately, recurrent extensive limb swellings are usually not accompanied by systemic adverse events and resolve without sequelae.29 , 30 , 32 Further studies are needed to understand the mechanism of these reactions and identify interventions reducing these recurrences. For extensive limb swellings following administration of DTaP-containing vaccines, reimmunization with lower-antigen formulations (dTap) reduces the rate of recurrence.29 , 30 However, the low antigen-content formulations have been confirmed to provide protective levels of antibody in patients 4 years of age or older, but data is lacking for infants.33–35
Patients with a history of HHE were the most likely to be reimmunized. This probably results from the clear recommendations to reimmunize these children issued since 199832 , 36 after various studies showed that the condition was benign and recurred in less than 1% of children.4 , 37–39
Rotavirus vaccine was readministered to 53% of patients overall and to only 35% of those with diarrhea/vomiting. The reasons of this lower reimmunization rate were not captured in this study. However, the narrow window to complete the rotavirus series (before 8 months of age) and perceptions that rotavirus gastroenteritis is not a severe disease in Canada may be contributing factors.40 , 41
This study had limitations. It was based on a passive surveillance system that does not capture all AEFIs, and only 31% of eligible patients were followed up. While our participants may not be representative of all patients with AEFIs, they are likely representative of the rate of recurrence of those with similar conditions. Nearly 40% of patients with severe or serious AEFIs were not reimmunized, and they may have been at greater risk of recurrence than those who were. This would underestimate the rate of recurrence in this subgroup. However, it is reassuring to see that most patients with severe events can be safely reimmunized given that the 60% who were reimmunized had fewer recurrences than patients with mild or moderate events. We were not able to estimate the rate of recurrence of rare and severe AEFIs (eg, Guillain–Barré syndrome, Kawasaki disease) because information about reimmunization was available in less than 4 patients. Collection of reimmunization data was not standardized, and many reports missed information on AEFI severity. Additionally, the information on AEFI recurrence and its severity was mostly obtained from patients and relied on their memory and perception that may or may not be consistent with objective clinical severity. When several vaccines were coadministered at a given visit, it was impossible to determine which vaccine(s) caused systemic AEFIs (initial or recurrent). Difference between the formulations of vaccines associated with the initial AEFI and those used for reimmunization is also a methodologic caveat that may have underestimated the rate of recurrence of a specific systemic AEFI associated with a given vaccine/product. However, our results likely represent the rate observed in real-life practice where vaccine coadministration is frequent and various vaccine formulations are available. Given that the potential confounders of AEFI recurrence are unknown, we presented crude estimates and performed stratified analyses. It should be noted that details such as administration of analgesics/antipyretics were not recorded in the database.
Our results suggest that despite the rate of recurrence, most patients with a history of mild or moderate AEFI can be safely reimmunized. The vaccine-specific rates of recurrence of specific AEFIs we have estimated should be helpful to vaccine providers but often included a small number of patients limiting the statistical power. Additional studies are needed to improve the precision of these estimates and to better assess the rate of recurrence in patients with serious AEFIs as they are often not reimmunized.4 , 13 Rare and serious AEFIs require the surveillance of a large-source population to be identified.42 , 43 Despite their limitations, passive vaccine adverse event reporting systems may be the only way to access these patients in sufficient numbers to obtain robust estimates of their rate of recurrence. Therefore, adapting these systems to include a systematic and standardized follow up of patients with rare or serious AEFIs could be the only way to ever provide empiric data to clinicians.
The authors extend their sincere thanks to the public health unit staff across Quebec for their efforts in investigation and reporting of adverse events after immunization, which are essential to the assessment of vaccine safety. G.D.S., J.G.Z., E.T. and M.L. performed study concept and design. All authors involved in acquisition, analysis or interpretation of data. J.G.Z. and G.D.S. performed statistical analysis. J.G.Z. helped in drafting of the manuscript. All authors involved in critical review of the manuscript for intellectual content.
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vaccination; safety; adverse event; recurrence; surveillance
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