Immunization and MS

Identification of topics for literature search.

Topics were identified by the Immunization Panel of the MS Council for Clinical Practice Guidelines and the methodological advisory panel of the Center for Clinical Health Policy Research at Duke University.

Two topic questions were formulated to address the need to vaccinate patients with MS: 1) Are vaccine-preventable infectious diseases more frequent in patients with MS than in the general population? 2) Do vaccine-preventable infectious diseases increase the risk of MS exacerbations?

Two other topic questions addressed the risks and the benefits of immunizing patients with MS: 3) Does vaccination increase the risk of exacerbations of MS, and is there a difference in this risk between live attenuated and inactivated vaccines? 4) Are vaccines as effective in patients with MS as in the general population?

Search strategy and inclusion process.

We reviewed English language MEDLINE (from 1966 to January 2001; U.S. National Library of Medicine, Bethesda, MD) and two other online bibliographic databases, HealthSTAR and Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Cinahl Information Systems, Glendale, CA), and the reference lists of all included articles and review articles. Search strategies included index terms and text words for “MS,” “transverse myelitis,” and index terms for “optic neuritis,” “encephalomyelitis,” “demyelinating diseases,” and for general and specific terms relating to vaccination and related infectious diseases. Six hundred and sixty-seven citations were obtained and 280 full-text articles were screened for inclusion by two independent reviewers according to criteria developed by the methodologists guided by the expert panel. One hundred and thirty articles were included; 53 experimental or observational studies were abstracted in evidence tables, and 77 case reports were summarized in a summary table. Twenty-five articles addressed the four first topic questions.

Assessment of the quality of available evidence.

Each included and abstracted study was evaluated and rated for quality of evidence using the classification scheme developed by the American Academy of Neurology (table 1).

When feasible, data were pooled and analyzed in meta-analysis using Comprehensive Meta-Analysis software for Windows (version 1.09; Biostat, Englewood, NJ).

Are potentially vaccine-preventable infectious diseases more frequent in patients with MS than in the general population?

One prospective cohort study (Class II evidence)5 and two case-control studies (Class IV evidence)6,7⇓ were identified. The first study showed that viral infections including cold, influenza, enteric, and herpetic infections were significantly less frequent in patients with MS than in control subjects.5 The second showed no difference in the monthly cold frequency comparing 39 patients with MS with 39 community control subjects.6 In contrast, the third study reported a significantly higher rate of sinusitis in patients with MS than in control subjects.7

Thus, there is conflicting evidence on the risk of common infectious diseases in the MS population compared with control populations (Level U Recommendation).

Do potentially vaccine-preventable infectious diseases increase the risk of MS exacerbations?

Six cohort studies (Class II, Class IV evidence)3,5,8-11⇓⇓⇓⇓⇓ and two case-control studies (Class IV evidence)6,7⇓ were identified. In a prospective cohort of 60 patients with MS, the annual number of infections was 3.50 in the group of 46 patients who had one or more relapses, compared with 2.34 in the group of 14 patients who did not experience a relapse (p < 0.01) (Class II evidence).3 In a 4-week period beginning 1 week before the infection and ending 3 weeks after the infection, the relative risk of relapse was 1.3 (p = 0.0477) compared with all other periods.

In another prospective cohort of 41 patients, the attack rate of clinical exacerbations was 3.3 during “at risk” periods, defined as periods from 2 weeks before to 2 weeks after an upper respiratory tract infection, compared with 1.6 in “not at risk” periods (OR: 2.0, 95% CI: 1.3 to 3.2) (Class II evidence).8

In a third cohort of 30 patients, nearly two-thirds of exacerbations were observed during at risk period (from 1 week before an episode of upper respiratory tract infection to 5 weeks after), and one-third of infections were associated with exacerbations. Attack rates of exacerbations were 2.92 per year during at risk periods compared with 1.16 during not at risk periods (p < 0.001) (Class II evidence).9

The incidence of viral infections and the relation between infections and MS exacerbations was studied in a cohort of 170 patients with MS with 134 concurrent control subjects (Class II evidence).5 Viral infections were significantly less frequent in patients with MS than in control subjects. The overall exacerbation rates were almost three times greater during at risk (−2 weeks to +3 weeks around the infection) periods (0.64/year, 95% CI: 0.49 to 0.79) compared with not at risk periods (0.23/year, 95% CI: 0.19 to 0.26).

Serum antibody levels to various viruses were prospectively determined in 34 patients with MS. (Class II evidence).10 There were no significant changes in measles, adenovirus, or mumps antibody levels. Three patients had significant changes in herpes simplex and three others in respiratory syncytial virus antibodies. For both viruses, the increase was related to an MS attack in one patient. Thirty-four other patients with MS were prospectively followed for a period of 461 patient-months (Class II evidence).10 During this period, 48% of 69 MS attacks were associated with infections, and 40% of infections were associated with exacerbations.

In a cohort of 233 patients, influenza episodes were recorded in 36 patients with relapsing-remitting MS (Class IV evidence).11 Thirteen (36%) of these episodes were associated with an exacerbation. Four patients with the progressive form of MS had symptoms of influenza illness with an increase in fatigue in two patients.

In a case–control study, the rate of nasopharyngeal infections was determined in a group of 92 patients with MS and compared with control subjects (Class IV evidence).7 The rate of sinusitis was significantly higher in the MS group than in the control group (up to four-fold higher). The rate of MS attacks was 0.025 per patient per year during the at risk periods (from 2 months before to 6 months after an episode of sinusitis), compared with 0.012 during not at risk periods.

In another case–control study, the monthly cold frequency was 13.3% in 39 patients with MS and 13.7% in 39 control subjects (Class IV evidence).6 During a 294 patient–months period, 19 MS exacerbations were observed, and six occurred in association with colds; the rate of exacerbation was more than three times higher in cold months than in noncold months (p = 0.028).

Thus, there is definitive evidence for an increased risk of MS exacerbations during the weeks around an infectious episode (Level A Recommendation).

Does vaccination increase the risk of exacerbations of MS, and is there a difference in this risk between live attenuated and inactivated vaccines?

Influenza.

Three randomized, placebo-controlled trials (Class I, Class II evidence),20-22⇓⇓ one case–crossover (Class III evidence),19 and seven cohort studies (Class II, Class IV evidence)10,11,23-28⇓⇓⇓⇓⇓⇓⇓ were identified (see table 2). For each of the three randomized, controlled trials, the rate difference for early MS exacerbation (3 to 4 weeks after vaccine/placebo), for late exacerbation (4 to 6 months after vaccine/placebo), and for occurrence of influenza was estimated and combined in a meta-analysis (figure). Within the limits of the few studies included in the analysis, no heterogeneity was found (p = 0.58). Rate difference for early MS exacerbation ranged from −6.1% to 2.0%, with an overall rate difference of 0% (95% CI: −6.9% to 6.9%). For late exacerbation, the rate difference ranged from 0% to 11.3%, with a pooled rate difference of 6.1% (95% CI: −4.1 to 16.3%). Finally, the rate difference for influenza during the 6 months after the intervention range from 5.7% to 8.7%, with a pooled rate difference of 8.4% (95% CI: −2.5% to 19.3%). Although these negative studies are reassuring, they do not definitely exclude a slight risk of increase of exacerbation after immunization. Nevertheless, the 95% CI excludes an absolute increase in exacerbation rate beyond 0.08 per patient per year.

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Figure. Differences in exacerbation and influenza rates after vaccine or placebo.

Thus, there is definitive evidence against a substantial increased risk of MS exacerbation after influenza vaccine (Level A Recommendation).

Are vaccines as effective in patients with MS as in the general population?

Four experimental trials reported efficacy data (Class I, Class II evidence).10,17,20,21⇓⇓⇓ Two randomized controlled trials on influenza vaccine reported influenza episodes during a 6-month follow-up after immunization (see table 2). None of these studies reported data regarding antibody response to vaccine.

The immune response to a live attenuated poliovirus vaccine was explored in 20 patients with MS and 18 control subjects.10 Eleven patients with MS (55%) and eight control subjects (44%) were considered as “infected” after immunization.

In a pilot trial of varicella immunization in 50 patients with MS, a significant rise in varicella antibodies after vaccination was observed in all patients and persisted for 7 to 12 months.17

Thus, there is insufficient evidence regarding the efficacy of immunization in patients with MS (Level U Recommendation).

Disclaimer.

This statement is provided as an educational service of the American Academy of Neurology. It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.