A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis

The Advisory Committee on Immunization Practices currently recommends annual influenza immunization for persons at increased risk for complications of the disease. ^[1] It further encourages consideration of vaccination for anyone wishing to avoid illness. However, the decision whether to recommend influenza immunization to patients with MS remains highly controversial. Neurologic dysfunction has been anecdotally associated with a variety of vaccines. ^[2,3] Thus, many practitioners advise against influenza immunization because of fear that it will precipitate an exacerbation of MS, despite previous studies that suggest no increased risk. ^[4-6] We postulated that patients could safely receive influenza immunization and might benefit from a reduction in additional neurologic dysfunction as a result of decreases in pseudoexacerbations, associated with the fever of influenza, as well as true attacks precipitated by the viral illness. We report here the results of a multicenter, double-blind, randomized, placebo-controlled trial of influenza immunization versus placebo vaccination that we conducted during the influenza season of 1993.

Methods.

In the autumn of 1993, 104 patients at five MS centers were randomized to receive either standard influenza immunization (Wyeth-Ayerst, Philadelphia, PA) or placebo injection, consisting of the vaccine diluent. Randomization sequence was assigned separately for each center. Patients were eligible for inclusion if they had clinically definite relapsing-remitting MS with a Kurtzke expanded disability status score ^[7] of less than 6.5 (i.e., ambulatory with no more than a unilateral aid). Patients were excluded if they had experienced an acute exacerbation or treatment with corticosteroids in the previous 4 weeks. Eligible patients had not been treated with immunosuppressive medications, interferon-beta, or copolymer 1 within the preceding 6 months. Patients were also excluded if they had a history of a prior adverse reaction to influenza vaccine or were allergic to egg products.

Patients were then followed for 6 months for evaluation of neurologic status and the occurrence of influenza. Influenza was operationally defined as fever >or=to38 degrees C in the presence of coryza, cough, or sore throat at a time when the disease was known to be present in the community. Exacerbations of MS were operationally defined as an objective change on the neurologic examination resulting in an increase of at least 0.5 on the expanded disability status scale (EDSS) or an increase of at least one grade on the scores of two or more of the Kurtzke functional system scores (FSS) or two grades on one of the FSS. Symptoms must have persisted for more than 24 hours, and the neurologic changes must have occurred in the absence of fever or lasted for more than 48 hours beyond the existence of fever of >or=to38 degrees C. Symptoms were scored by the blinded neurologist as pseudoexacerbations on the basis of telephone assessment if subjective deterioration of neurologic status occurred in the context of fever >or=to38 degrees C lasting >or=to24 hours.

Patients were examined by the blinded neurologist at 4 weeks and 6 months after inoculation and were contacted by telephone at 1 week and 3 months by the blinded study nurse. They were also examined at times of possible attacks but were not seen when they were sick with flu-like illness.

Sample size calculation, assuming an alpha of 0.05 with a two-tailed test and a power of 80%, was determined assuming a moderate effect size (i.e., equivalent to one half of an SD) with a frequency of attacks similar to published figures. A moderate effect size was chosen because it was believed to be the smallest effect size having clinical significance in the context of the goals of the study. Sample size calculations were performed using a computer program for statistical power analysis. ^[8]

Comparison of attacks in the first 28 days after vaccine was performed using Fisher's exact test. Attack incidence of 6 months was compared using chi square analysis. Comparison of the incidence of influenza was performed using Fisher's exact test. The number of patients worsening over 6 months was compared using chi square. The comparison of mean change in EDSS was performed using the t test for independent samples.

Results.

Forty-nine patients received influenza vaccine and 54 patients received placebo. The groups did not differ significantly in age, gender, or disability. During the 28 days after inoculation, three vaccine patients and two placebo patients experienced MS exacerbations (no significant difference). Over the 6-month follow-up period, vaccine patients experienced 11 attacks (annual rate 0.45) and placebo patients, 6 attacks (annual rate 0.22). The difference in attack rates was not statistically significant. The mean time of onset of relapse after flu vaccine (91.5 days) exceeded that for placebo patients (55.3 days), further substantiating the lack of association between flu vaccine and MS exacerbations (Table 1). Using the operational definition of influenza, surprisingly, seven immunized patients were scored as experiencing the illness, compared with three in the placebo group, but this difference was not significant. There was no significant difference in the numbers of patients who worsened in the 6-month study period (8, vaccine; 10, placebo), nor in the mean change in EDSS (0.02, vaccine; 0.09, placebo). Pseudoexacerbations occurred in three patients (27%) who were scored as experiencing influenza.

Discussion.

This is the largest prospective study examining the effect of influenza immunization of MS patients and the first to follow patients through an entire influenza season. The results confirm previous studies and indicate that influenza vaccination is safe for MS patients because it is not associated with an increased risk of exacerbation. After a previous retrospective review of influenza vaccination had suggested it was well-tolerated with no increase in relapse rate, Bamford et al. ^[5] conducted a prospective, but uncontrolled and unblinded, study in which MS patients receiving vaccine had no increase in relapse rate compared with the unimmunized control subjects during 4 weeks of study. Myers et al. ^[6] reported a prospective, double-blind, placebo-controlled study in which 33 patients receiving swine influenza vaccine experienced two relapses, compared with four attacks in 33 placebo-treated patients and two attacks in 22 untreated control subjects during the 3 weeks after immunization. Over a 3-month follow-up period, four relapses occurred in each group. There were no significant differences among these results.

Recent clinical trials of interferon-beta 1b, ^[9] beta 1a, ^[10] and copolymer 1 ^[11] in patients with active relapsing-remitting disease reported exacerbation rates among placebo-treated patients ranging from 0.82 to 1.31 annually. A previous natural history study by Goodkin et al, ^[12] noted an attack rate of 0.6 annually. Based on a comparison with these data, our immunized patients experienced an attack rate lower than expected at both 4 weeks and 6 months after inoculation.

The apparent occurrence of more influenza cases in the vaccine group than in the placebo group, although not statistically significant, was surprising. Most cases probably reflect either noninfluenza respiratory illnesses or significantly attenuated influenza infections. This is supported by many cases scored as influenza being minor illnesses in which fever was low or brief, and the usual myalgias that accompany influenza were absent.

In conclusion, influenza immunization appears to be safe in patients with relapsing-remitting MS. It is not associated with a significantly increased attack rate in the postimmunization period nor with an increased rate of MS progression. In view of the demonstrated safety of influenza immunization, we believe vaccination can be recommended to MS patients.