Volume 28- 23
1 December 2002

[Table of Contents]

INFLUENZA VACCINE-ASSOCIATED ADVERSE EVENTS: RESULTS OF PASSIVE SURVEILLANCE, CANADA 2001-2002

Influenza vaccination is the cornerstone of the prevention and control of influenza and its complications, and is an important component of pandemic preparation. In most Canadian provinces/territories, influenza vaccination is offered as a publicly funded program for people at high risk; in Ontario and the Yukon Territories, it is offered free of charge to all individuals. In addition, there are also privately funded programs, most of which are associated with a work place. The immunogenicity of influenza vaccine and the adverse events associated with it are important to public health programs, especially as the vaccine contains different strains each year. Additionally, health care workers in Canada have expressed concern about mandatory vaccination programs, at least in part because of perceived vaccine safety issues.

In March of each year, the World Health Organization recommends three vaccine strains for the Northern Hemisphere influenza vaccine for the coming season. For the 2001-2002 influenza season, the strains were A/New Caledonia/20/99-like, A/Panama/2007/99-like, and B/Johannesburg/5/99-like or B/Victoria/504/2000-like.

This paper presents a summary of the adverse events reported following administration of influenza vaccine in the 2001-2002 influenza season.

Methods

In Canada, the reporting of vaccine associated adverse events (VAAE) by health care providers is done on a passive voluntary basis in most provinces and territories. In addition, 12 pediatric hospitals in Canada perform active surveillance under the program called IMPACT (Immunization Monitoring Program, Active).

Reports on VAAEs flow from the person vaccinated to Health Canada, as depicted in Figure 1. At Health Canada the reports are coded and entered into a VAAE database.

The reporting form consists of 25 predetermined adverse events of public health interest (known as VACART), which were developed mainly for the pediatric community. For information not captured by the list of VACART items there is also a section for the verbatim reporting of adverse events, from which information is then coded with the use of a reaction term thesaurus (WHOART) developed by the World Health Organization. For each report, a symptom can be coded only as a VACART or as a WHOART term, but not both.

During the 2000-2001 season, Health Canada received a large number of reports of red eyes, respiratory symptoms (cough, sore throat, difficulty breathing, chest tightness, and wheezing), and facial edema following influenza immunization, a cluster of symptoms now called oculo-respiratory syndrome (ORS). ORS is defined as the presence of bilateral red eyes or at least one of the following respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing or sore throat, or facial edema⁽¹⁾ . For the 2000-2001 influenza season, ORS was identified if the symptoms occurred within 2 to 24 hours of influenza vaccination and resolved within 48 hours. For subsequent seasons, the time restrictions were removed from the definition.

During the 2001-2002 season, these reports prompted the health authorities to undertake enhanced surveillance of influenza VAAEs. Health Canada, in consultation with the provinces and territories, decided to continue enhanced surveillance of influenza VAAEs. For this purpose, a supplementary questionnaire, intended to be completed for all influenza VAAEs, was developed for use by the provinces/ territories in addition to the usual VAAEs report form.

Figure 1. Reporting of VAAEs in Canada

Results

The data will be presented as a percentage of all reports received of influenza VAAEs as well as a rate per million doses of vaccine distributed for two sets of mutually exclusive adverse event codes, VACART and WHOART (Table 1).

During the 2001-2002 influenza season, a total number of 9,842,601 doses of influenza vaccine were distributed to health care providers in Canada, although the exact number of doses administered is unknown. Health Canada received 1,800 reports of people experiencing adverse events following influenza vaccine, for a rate of 183 reports per 1 million doses distributed.

Of reported cases, 75.7% were females, and 47.0% were >= 50 years (Figure 2); 1,704 (94.7%) had received only influenza vaccine, and 96 (5.3%) had received influenza vaccine in combination with other vaccines. The rates of adverse events reported by those who had received influenza vaccine only as compared with those who had received it in combination with other vaccines were similar.

The most frequently reported adverse event was ORS, which was experienced by 502 individuals (27.9% of all reports). The median onset of red eyes was 8 hours after vaccination, and the median duration of this symptom was 24 hours. The median onset of respiratory symptoms ranged from 6 to12 hours, and the median duration ranged from 16 to 36 hours. Other frequently reported adverse events included chest pain (22.6%), fatigue (20.2%), headache (16.8%), fever (16.4%), allergic reactions (15.2%), rigors (15.0%), myalgia (12.5%), local reaction (11.1%), and nausea (10.1%) (Table 1). The incidence of reported adverse events per million doses distributed was ORS 51.0, chest pain 41.4, fatigue 36.9, headache 36.8, fever 30.3, and allergic reaction 27.5.

Some symptoms, such as allergic reaction, arthritis, rash, and fever, can potentially be coded as either VACART or WHOART terms. For a symptom to be included as a VACART term, it has to meet the national definition. For example, allergic reaction with onset within 30 minutes is coded as a VACART term, whereas allergic reaction with onset after 30 minutes is coded as a WHOART term. Table 1 shows that there were 271 cases of allergic reaction (including hives, urticaria, pruritis, and shortness of breath) following influenza vaccination. Out of these, 207 people developed an allergic reaction within 30 minutes of administration of influenza vaccine, hence they were included in VACART categories; the remaining 64 cases had onset after 24 hours, hence these were included in a WHOART category. Another example is that arthritis or arthralgia lasting >= 24 hours was included in the VACART classification (59 reports), and cases lasting < 24 hours (14 cases) were included in the WHOART classification.

Reported symptoms were self-limiting in most cases, although nearly 20.7 % of cases consulted a health care provider (nurse, pharmacist, or physician). Of the reported cases, 25 (1.4%) were hospitalized for >= 3 days.

The serious adverse events reported were anaphylaxis (9 per 10 million doses distributed), Guillain-Barré syndrome (1 per 3 million doses distributed), convulsions (1 per 3 million doses distributed), paralysis (1 per 2.5 million doses distributed), and meningitis/encephalopathy (1 per 3 million doses distributed).

There were two deaths among the reported cases of influenza VAAEs, the first being a male in his 70s known to have Alzheimer's disease, type II diabetes, and congenital heart disease. The second was a male in his 60s with a history of chronic atrial fibrillation with a possible diagnosis of thrombolytic thrombocytopenic purpura/disseminated intravascular coagulation, presumably secondary to an infection. In both cases, the cause of death is not known.

Figure 2. Age distribution of influenza VAAEs reported in Canada 2001-2002 season

Discussion

The mechanism of ORS remains unknown. Because of the possibility that ORS, whether as a real or perceived risk, may adversely affect influenza prevention and control programs, special efforts were put in place to ensure that there was full reporting of ORS-related symptoms⁽²⁾.

In general, most of the reported adverse events following influenza immunization include local reactions and systemic side effects^{(3- 6)}. Females, young adults (aged < 40 years), and people with concomitant upper respiratory tract infections are more likely to experience these symptoms⁽⁴⁾. Allergic reactions have also been reported⁽⁷⁾. Serious adverse reactions include Guillain-Barré syndrome, although no causal association has been documented⁽⁸⁾. Other neurologic disorders following influenza vaccination include encephalopathy, facial paralysis, paresthesia, and convulsions⁽⁹⁾. There have been occasional reports of Bell's palsy and ocular effects⁽¹⁰⁾. There was increased reporting of ocular and respiratory symptoms following influenza vaccination in 2001-2002 in Canada, but the rate was lower than that observed during 2000-2001⁽¹⁾.

The vaccine associated adverse event surveillance (VAAES) system is mostly based on voluntary participation, and the reporting rate of adverse events varies greatly among provinces and territories, and among different regions within provinces and territories. Therefore, these rates of adverse events need to be interpreted with caution. In addition, the supplementary questionnaire for the influenza vaccine was not completed for all VAAES reports, and hence a considerable amount of information was missing.

It must be remembered that the reporting of an adverse event after a vaccination does not mean that it is causally related to the particular vaccine. Furthermore, the strains used for influenza vaccine development differ yearly, and the likelihood of a change in the type of events reported cannot be ruled out.

In conclusion, there are no major concerns with the safety profile of influenza vaccines; however, post-marketing surveillance of adverse events after influenza vaccination remains of considerable importance.

* Total number of reports: 1,800
** Percentage not calculated because symptoms categories are not mutually exclusive.

References

1. National Advisory Committee on Immunization. Supplementary statement for the 2001-2002 season: influenza vaccination of persons who experienced oculo-respiratory syndrome following previous influenza vaccination. CCDR 2001;27(ACS-7):1-8.

2. National Advisory Committee on Immunization. Supplementary statement for the 2002-2003 season: update on oculo-respiratory syndrome in association with influenza vaccination. CCDR 2002;28(ASC-6):1-8.

3. Fluviral. In: Compendium of pharmaceuticals and specialties. Ottawa: Canadian Pharmaceutical Association, 2001:588-89.

4. Nichol KL, Margolis KL, Lind A et al. Side effects associated with influenza vaccination in healthy working adults. A randomized, placebo- controlled trial. Arch Intern Med 1996;156:1546-550.

5. Scheifele DW, Bjornson G, Johnston G et al. Evaluation of adverse events after influenza vaccination in hospital personnel. Can Med Assoc J 1990;142:127-30.

6. Barry DW, Mayner RE, Staton E et al. Comparative trial of influenza vaccines. II. Adverse reactions in children and adults. Am J Epidemiol 1976;104:47-59.

7. Vaxigrip. Compendium of Pharmaceuticals and Specialties, 2001:1654-656.

8. Lasky T, Terracciano GJ, Magder L et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339:1797-802.

9. Margolis KL, Nichol KL, Poland GA et al. Adverse reactions to influenza vaccine in elderly people : randomised double blind placebo controlled trial. BMJ 1993;307:988-90.

10. Solomon A, Siganos CS, Frucht-Pery J. Adverse ocular effects following influenza vaccination. Eye 1999;13(Pt 3a):381-82.

Source: Y Choudhri, MD, MPH, W Walop, PhD, Immunization and Respiratory Infections Division, Centre for Infectious Disease Prevention and Control, Health Canada, Ottawa, Ontario.