SAFETY OF REVACCINATION OF PATIENTS AFFECTED BY THE OCULO-RESPIRATORY SYNDROME (ORS) FOLLOWING INFLUENZA VACCINATION

Introduction

The oculo-respiratory syndrome (ORS), first identified in Canada in 2000, is an adverse event occurring after influenza vaccination. The clinical case definition of ORS, as defined by the National Advisory Committee on Immunization (NACI), is the onset within 24 hours of vaccination of at least one of the following symptoms: bilateral red eyes or respiratory symptoms (cough, sore throat, difficulty swallowing, wheeze, difficulty breathing, chest tightness) or facial edema (lid, face, lips)(1). ORS affected 4% to 6% of people vaccinated against influenza in 2000(2).

Many features of this syndrome are suggestive of an allergic reaction. A skin testing study of ORS patients ruled out an anaphylactic type of reaction(3) but found a nearly 50% recurrence rate upon intradermal administration of 500-fold less than the routine dose of vaccine. In a clinical trial in the fall of 2001, revaccination of ORS patients resulted in a recurrence risk of 28%(4). This rate was based on a small number of vaccinated individuals (32) because the trial was quickly aborted according to a predetermined stopping rule.

The uncertainty about the safety of revaccination of ORS patients was a major factor in cautious recommendations for re-immunization made by NACI in the fall of 2001(2). In this statement, postponement of revaccination was advised for patients with severe ORS who had no personal risk factors for influenza complications. During the following influenza vaccination campaign, the reported number of ORS cases decreased by 35%, and there were no reports of severe outcome following revaccination. A telephone survey conducted in British Columbia found that 5% of the 122 ORS patients revaccinated in the fall of 2001 had had a recurrence, and that there was no increased risk for individuals with a severe initial ORS episode(5).The study authors made the hypothesis that the large discrepancy between the results of this study and those of the clinical trial described earlier(4) was probably attributable to the fading memory of mild ORS recurrences after the 6 to 8 month delay between revaccination and interview, a as compared with the intensive search for symptoms immediately after vaccination in the clinical trial.

In the fall of 2002, NACI recommended revaccination of all ORS patients except those who had severe involvement of their lower respiratory tract(1). The published evidence on the safety of revaccination of ORS patients is based on a cumulative number of revaccinated individuals of <= 200(1,5-7). To add to this body of evidence, the objective of this study was to estimate the safety of revaccination in >= 360 patients revaccinated in fall 2001 or 2002 in the province of Quebec.

Methods

Quebec is Canada's second largest province (7.2 million people) and the one reporting the largest number of ORS cases both in 2000 and 2001. In this province, vaccine adverse events are reported to the public health units by vaccine providers and health care workers. Each case is validated by a physician or a nurse and entered into a computerized database. To be considered as ORS, cases had to meet the criteria of the NACI case definition. All cases reported in fall 2000 and fall 2001 were eligible for participation in this study, which was conducted in two parts. Patients affected by ORS in 2000 were called between July and August 2002 to investigate the outcome of their revaccination in fall 2001 (9-10 months earlier); those affected in 2001 were called in January 2003 about their revaccination in fall 2002 (1-3 months earlier).

Patients were called by physicians and nurses at their respective public health unit and were asked to respond to a standard questionnaire. For children, a parent answered the questionnaire. Patients were asked whether they had been revaccinated and whether they had experienced ORS symptoms; if so, what was the delay to onset, the duration and severity of symptoms, the comparison of that severity with the initial ORS episode, the need for medical consultation, and the intent to be revaccinated the following year. The severity was considered mild if symptoms were bothersome but did not interfere with daily activities, moderate if they interfered with but did not prevent daily activities, and severe if they prevented daily activities (including sleep).

In fall 2001 and 2002, there were primarily two different vaccines distributed in Quebec: Fluviral® (Shire Biologics) and Vaxigrip® (Aventis Pasteur). Fluviral® accounted for about two-thirds of the total for each season. Since vaccinators do not usually tell patients which brand of vaccine they use, this information was not asked of patients: they could have received either product for revaccination. The strain composition of these vaccines did not change during those 2 years. Fluviral® contained 15 mg per 0.5 mL dose of hemagglutinin antigen of each of A/New Caledonia/20/99(H1N1), A/Panama/2007/99(H3N2) and B/Victoria/504/2000, whereas Vaxigrip® strains were A/New Caledonia/20/99(H1N1), A/Panama/2007/99(H3N2) and B/Johannesburg/5/99.

Proportions were compared with chi square statistics, and a p value of 0.05 was the threshold of significance. Logistic regression was used for multivariate analysis. Data were entered and analyzed with Epi-Info 2002.

Results

In 2000 and 2001, 637 and 459 ORS cases were reported to the public health units, and 83% (527) and 87% (397) agreed to participate in this study. Among participants, 21% and 30% respectively reported that their initial ORS episode was mild, 31% and 36% that it was moderate, and 48% and 34% that it was severe.

Overall, 34% (178) of participants with ORS in 2000 and 47% (188) with ORS in 2001were revaccinated the year after their ORS episode (p < 0.001). In 2001, revaccination was significantly lower among female patients, those aged < 60 years, those who had had ORS at their first influenza vaccination, and those with the greatest severity of the original ORS (Table 1). In 2002, only patients with the most severe episode of prior ORS had a significantly lower rate of revaccination. Accordingly, significantly more female patients, patients < 60 years and those who had had ORS at their first influenza vaccination were revaccinated in 2002 as compared with 2001. In multivariate analysis, lower revaccination rates were significantly associated with a greater severity of the initial ORS episode both in 2001 and 2002, whereas having sustained ORS after a first influenza vaccination was significant only in 2001.

Table 1. Percentage of revaccination by year among patients previously affected by oculo-respiratory syndrome (ORS)

 

ORS in 2000

ORS in 2001

Total
N

Percentage revaccinated
in 2001

p
value

Total
N

Percentage revaccinated
in 2002

p
value

Total

527

34%

 

397

47%

0.00003

Sex

Female

391

32%

 

290

47%*

 

Male

135

41%

0.05

107

48%

0.9

Age

< 60 years

387

30%

 

299

46%*

 

>= 60 years

138

45%

0.001

98

53%

0.2

Number of the dose that triggered ORS

1st dose

261

27%

 

130

44%*

 

>= 2nd dose

253

42%

0.0003

239

49%

0.4

Perceived severity of initial ORS

Bothersome

111

59%

 

111

59%

 

Interfered with daily activities

161

36%

 

131

55%*

 

Prevented daily activities

250

21%

0.0000

123

28%

0.0000

* This percentage was significantly (p< 0.05) different from the previous year.

In 2001, a recurrence was reported by 14 of the 178 revaccinated patients (8%, 95% confidence interval [CI] 4.5%-13%) (Table 2). The recurrence rate was higher in 2002 (15%, 95% CI 10%-21%), occurring in 28 of the 188 revaccinated. In both years, there was no significant difference in the rates of recurrence by sex, age, number of the dose, or severity of the prior ORS episode. However, there was a significantly greater recurrence rate in 2002 as compared with 2001 among patients < 60 years, those who had had ORS after a second, or higher, dose of influenza vaccine, and among those with milder ORS. In multivariate analysis, for both years no factor was significantly associated with a greater risk of ORS.

Table 2. Percentage of oculo-respiratory syndrome (ORS) recurrence by year and characteristics of patients

 

ORS in 2000

ORS in 2001

Revaccinated in 2001
N

Percentage with ORS recurrence

p
value

Revaccinated in 2002
N

Percentage with ORS recurrence

p
value

Total

178

8%

 

188

15%*

0.03

Sex

Female

123

9%

 

137

15%

 

Male

55

6%

0.4

51

14%

0.8

Age

< 60 years

116

9%

 

136

18%*

 

>= 60 years

62

7%

0.8

52

8%

0.09

Number of the dose that triggered ORS

1st dose

71

10%

0.4

57

14%

0.7

>= 2nd dose

105

7%

 

116

16%*

 

Perceived severity of initial ORS

Bothersome/interfered with daily activities

123

7%

 

137

18%*

0.2

Prevented daily activities

53

11%

0.4

34

9%

 

* This percentage was significantly (p< 0.05) different from the previous year.

Symptoms experienced during recurrences were similar in both years (Table 3). Overall, 21% experienced two or three symptom categories. By decreasing order of frequency, respiratory symptoms only was the most frequent (64%) reported category of symptoms followed by respiratory and ocular symptoms (14%) and ocular symptoms only (12%). Recurrences prevented daily activities in 14% of patients, and 10% considered their recurrence to have been more severe than the initial ORS episode. Medical consultation was sought by 7% of cases, and none was hospitalized. Despite their recurrence, 88% of the patients expressed intent to be revaccinated during the following year. This intent was much greater in patients who had already been revaccinated once compared with those who had not (93%-94% versus 11%-14%) (Table 4). In multivariate analysis, the factors significantly affecting the intent to be revaccinated were having been revaccinated once (with or without an ORS recurrence) and, for those who experienced ORS in 2000 only, the greater the severity of the episode the lower the intention to be revaccinated.

Table 3. Recurrence of oculo-respiratory syndrome (ORS) and symptom characteristics

 

ORS recurrence

In 2001
N
= 14

In 2002
N
= 28

Total
N
= 42

Symptom category

Resp. + ocular + edema 0% 7% 5%
Resp. + ocular 21% 11% 14%
Ocular + edema 0% 4% 2%
Respiratory only 71% 61% 64%
Ocular only 7% 14% 12%

Edema only

0%

4%

2%

Severity of the recurrence

Bothersome/interfered with daily activities 79% 86% 83%

Prevented daily activities

21%

11%

14%

Comparison with the first episode of ORS

Milder 71% 71% 71%
Similar 21% 14% 17%

Worse

7%

11%

10%

Had medical consultation

7%

7%

7%

Intent to be revaccinated

Yes 86% 89% 88%
No 14% 7% 10%

Unknown

0%

4%

2%

Table 4. Proportion of oculo-respiratory syndrome (ORS) cases with a positive (+) intent to be revaccinated the following year

  ORS in 2000 ORS in 2001
N + Intent for 2002 p N + Intent for 2003 p
n % n %
Total 525 204 39%   394 204 52%  
Sex
Female 390 138 35%   288 146 51%*  
Male 135 66 49% 0.06 106 58 55% 0.5
Age
< 60 years 387 140 36%   296 148 50%*  
>= 60 years 137 64 47% 0.03 98 56 57% 0.2
Number of the dose that triggered ORS
1st dose 262 85 32%   238 126 53%*  
>= 2nd dose 252 116 46% 0.001 128 61 48% 0.33
Perceived severity of initial ORS
Bothersome 112 75 67%   110 70 64%  
Interfered with daily activities 161 68 42% 0.0001 131 76 58%* 0.4
Prevented daily activities 248 60 24% 0.0000 121 39 32% 0.0000
Revaccination
Not revaccinated 347 38 11%   206 29 14%  
Revaccinated 177 166 94% 0.0000 188 175 93% 0.0000
Without recurrence 163 154 94%   160 150 94%  
With recurrence 14 12 86%   28 25 89%  
* This proportion differs significantly from the previous year.

Discussion

This study provides additional reassurance about the safety of revaccination of ORS patients. Recurrence occurred in 8% in 2001 and 15% in 2002; most episodes were considered mild, very few required medical consultation, none led to hospitalization, and no patients had an anaphylactic reaction. The retrospective design of this study and the recall bias of data based on patients' memory are likely to underestimate the frequency of recurrence. However, severe adverse events are unlikely to have escaped detection by these patients, who were already "primed" to detect influenza vaccine adverse events. This priming is even more likely in those who suffered a severe initial episode of ORS. Despite that, these individuals reported no increased risk or severity of recurrence. Our recurrence rate in 2001 (8%) is similar to that in British Columbia in 2001 (5%) but much lower than in 2002 (15%)(5). This discrepancy can likely be explained by the longer delay between revaccination and interview in 2001 (8-10 months) than in 2002 (1-3 months).

For many, ORS may appear benign, but the fact that only one-third of the ORS patients from 2000 were revaccinated in 2001 and about half of the ORS patients from 2001 were revaccinated in 2002 suggests that ORS leaves a strong impression on those affected. Cautious recommendations about revaccinating ORS cases, in particular those who had a severe episode in 2000, may have also contributed to the low revaccination rate in 2001. Despite new recommendations in 2002 to revaccinate all ORS patients except those with severe respiratory problems (wheezing, difficulty breathing), the revaccination rate remained low. The greatest factor influencing the revaccination rate was the severity of the initial ORS episode. This understandable reluctance may be partly overcome by strong recommendations from clinicians that only a minority of patients will experience a recurrence, that most recurrences are milder (70%), and that nearly 90% of patients with a recurrence still intend to be vaccinated the following year.

The negative impact of ORS was greater in individuals < 60 years old. It is likely that these people feel at less personal risk from the effects of influenza itself; in this instance the ORS experience may be sufficient to negatively tip the appraisal of the risk-benefit balance. Similarly, patients receiving their first dose of influenza vaccine may be less convinced a priori of its safety, may feel more anxious and thus perceive a greater risk of possible adverse event.

In conclusion, revaccination of ORS patients is safe. Previously affected patients should be reassured and encouraged to be revaccinated. The risk of ORS recurrence after revaccination is minimal compared with the serious threat posed by influenza and repeated on an annual basis.

References

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

  2. National Advisory Committee on Immunization. Supplementary statement on influenza vaccination: continued use of Fluviral® influenza vaccine in the 2000-2001 season. CCDR 2001;27(ACS-1):1-3.

  3. Skowronski DM, De Serres G, Hébert J et al. Skin testing to evaluate oculo-respiratory syndrome (ORS) associated with influenza vaccination during the 2000-2001 season. Vaccine 2002;20:2713-19.

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

  5. Skowronski D, Strauss B, Kendall P et al. Low risk of recurrence of oculorespiratory syndrome following influenza revaccination. Can Med Assoc J 2002;167(8):853-58.

  6. De Serres G, Skowronski DM, Guay M et al. Risk of recurrence of oculo-respiratory syndrome (ORS) associated with two different influenza vaccines for 2002-2003. The Sixth Annual Conference on Vaccine Research, Arlington, VA, 5-7 May 2003, Abstract S33.

  7. De Serres G, Boulianne N, Duval B et al. Oculo-respiratory syndrome following influenza vaccination: evidence for occurrence with more than one influenza vaccine. Vaccine 2003;21:2346-53.

Source: J-L Grenier, MD, MSc, Department of Public Health, the Laurentides; E Toth, MSc, Quebec National Institute of Public Health of Quebec; G De Serres, MD, PhD, National Institute of Public Health of Quebec, Laval University, Quebec Department of Public Health; S Ménard, MD, Department of Public Health, Estrie; R Roussel, MD, Department of Public Health, Bas-St-Laurent; M Tremblay, MD, MSc, Montreal Department of Public Health; M Landry, MD, LLCM, Quebec National Institute of Public Health, Quebec Ministry of Health and Social Services; Y Robert, MD, MSc, Quebec National Institute of Public Health, Quebec Ministry of Health and Social Services; DM Skowronski, MD, MHSc, FRCPC, British Columbia Centre for Disease Control

Page details

Date modified: