Active hospital-based surveillance for meningococcal polysaccharide vaccine adverse events after an emergency mass immunization program, Edmonton, Alberta

Mass immunization programs with meningococcal polysaccharide vaccine are recommended as a control measure in meningococcal outbreaks(1) . Vaccine-associated adverse events have been documented in small clinical trial settings(2,3) or passively reported in large immunization programs(4-7) . These adverse events consist primarily of local reactions, fever, and local neurological symptoms (e.g. paresthesias). More serious adverse events are rarely reported; they include anaphylaxis and systemic allergic reactions(4,5,7,8). Hospital admissions temporally associated with meningococcal vaccine administration have involved more serious neurological conditions. Guillain Barré syndrome occurring up to 1 month after vaccine administration has been reported(7).

Active hospital-based surveillance for adverse events temporally associated with the administration of meningococcal polysaccharide vaccine has not previously been reported. We report such surveillance from a community in which an outbreak of meningococcal infection and a subsequent mass immunization program occurred. Because of the relative geographic isolation of this community, all vaccine administered and all hospitalizations for serious adverse events are likely to be captured in regional hospital-based active surveillance.

Outbreak

Neisseria meningitidis is a familiar and feared cause of sepsis and meningitis with a yearly incidence of infection of approximately 1/100 000 in Canada(9) . In late 1999 and early 2000, the health region encompassing the city of Edmonton, Alberta, and surrounding areas (population approximately 900,000), known as the Capital Health Region, had its own deadly ?Y2K bug?. The rate of infection in individuals aged 15 to 19 years exceeded 10/100,000 on 11 February, 2000. The outbreak was due to Neisseria meningitidis serogroup C, electrophoretic type 15, serotype 2a. This unique clone had not previously been described before this outbreak, and its characteristics have been documented elsewhere(10).

Community public health resources rapidly responded with a mass immunization program that was initiated on 15 February. Meningococcal quadrivalent polysaccharide vaccine was delivered at 11 locations in the Capital Health Region. Although the program was initially targeted to the high-risk, 15 to 19 age group, it was expanded on 17 February to include all individuals aged 2 to 19 years. Over the course of the immunization program, 168 000 of 207,000 individuals aged 2 to 19 (81%) in the Capital Health Region were immunized in a 14-day period (15 to 28 February).

Methods

Hospital records of all patients aged 2 to 16 years admitted as inpatients to the Stollery Children?s Hospital from 14 February, 2000, to 30 March, 2000, were reviewed. Children 2 to 16 years of age represented 83% of the population aged 2 to 19 in the region in 2000. The Stollery Children?s Hospital admits over 90% of pediatric patients for the region and is the only tertiary care centre. Adverse events observed in the 17 to 19 age group would have been passively reported to public health and were not the subject of active hospital-based surveillance in the region.

Two phases of exclusion criteria were applied. For the first phase, admissions with discharge diagnoses that were clearly not vaccine-related were excluded. These admissions comprised children admitted for elective and emergency surgery, documented infections, oncology diagnosis or treatment, management of known psychiatric conditions, or elective medical care. For the second phase, the history of meningococcal vaccine administration was determined. The hospital record was searched for documentation of meningococcal vaccine administration, and if vaccine history was not documented in the hospital record the public health records were searched. Because of the magnitude and emergent nature of the immunization program, the only records available were handwritten lists generated at the temporary emergency vaccine administration sites. Thus, confirmation of meningococcal vaccine administration was not always possible. In the case of admissions in which administration of meningococcal vaccine was documented or in which the vaccine status was unknown, the possibility that the hospitalization could be related to meningococcal vaccination was evaluated for each patient according to the timing of presentation, results of investigations, and final diagnoses.

Results

There were 297 admissions (261 patients) to the Stollery Children?s Hospital during the period studied. All of the hospital records were reviewed. As summarized in Table 1, 220 (74%) of these admissions were clearly not related to meningococcal vaccine adverse events and were excluded from further analysis. The other 77 admissions were considered possibly related to vaccine administration and were evaluated further.

The history of meningococcal vaccination for these 77 admissions was determined and categorized as “yes” given, “no” not given, or “unknown”. Table 1 summarizes the distribution of the three diagnostic categories: neurological syndrome, acute medical, and changes in chronic illness status. There was no significant difference in the distribution of the three types of diagnosis across the vaccination categories. The analysis is limited by the small sample.

Table 1. Relation of diagnostic category to history of meningococcal vaccination (MV)

Not related to MV

Possibly related to MV

Diagnostic
category

No.
(% of total)

Diagnostic
category

No.
(% of total)

MV administered

No

Yes

Unknown

Surgical

93 (42%)

Neurological syndrome

12 (16%)

2

3

7

Infection

63 (29%)

Oncology

40 (18%)

Acute medical

32 (40%)

20

4

8

Psychiatry

6 (3%)

Medical elective

18 (8%)

Chronic disease change

33 (44%)

13

4

16

Total

220

Total

77

35

11

31


For the 31 cases (40%) in which the history of meningococcal vaccination was unknown, 27 were assessed as not related to vaccine administration, primarily because the disease onset was prior to the vaccine campaign. The other four cases that could not be excluded as possibly vaccine-related were all in the neurological category. Three of these cases were admitted between 10 and 18 March, long after the immunization program was complete. The fourth admission was of a child with a chronic neurological syndrome admitted with dehydration and gradual increased frequency of seizures on 22 February. Of note is that one child was admitted on 15 March with Guillain Barré syndrome who was documented not to have received meningococcal vaccine.

Eleven admissions occurred after documented meningococcal vaccine administration. All but one of these admissions occurred> 2 days after vaccine administration (mean 10.4, range 0 to 21 days). Four admissions were assessed by the investigators as unrelated to vaccine administration: two children with chronic neurological conditions were admitted with respiratory congestion 3 days after receiving vaccine, one child had an asthma exacerbation 15 days after vaccine, and one child had abdominal pain 21 days after vaccine. Six admissions were assessed as having an unknown relation to vaccine administration. These cases all had different diagnoses for which they were admitted at different times after vaccine administration: nephrotic syndrome, 3 days after vaccination; rash and fever, 7 days; recurrent seizures, 11 days; sickle cell crisis, 12 days; syncope, 19 days; pancreatitis, 20 days. Finally, one admission occurred as a direct consequence of an adverse event after meningococcal vaccine administration. A detailed description is given in the case report.

Case Report

One hospital admission was triggered by an event that occurred in close temporal proximity to the administration of meningo- coccal vaccine. A 14-year-old child with developmental delay experienced a first seizure-like episode 45 minutes after receiving meningococcal vaccine. The child had had chronic headaches for 3 years. The headache worsened just before the seizure began. There were multiple generalized tonic movements described. The patient was conscious at the time of presentation and had no neurological deficit on physical examination. The electroencephalogram, cranial computed tomography scan, and cerebrospinal fluid examinations were all normal. The child was discharged after l day in hospital with no apparent neurological deficit and without anticonvulsant medication. The discharge diagnosis was seizure likely secondary to migraine headache. However, on long-term follow-up the final diagnosis is conversion reaction and, the child is being followed by psychiatric services.

Discussion

We are confident that this surveillance methodology comprehensively identified all potential serious adverse events requiring hospitalization in children 2 to 16 years of age, since all hospital admissions were reviewed, and the hospital normally admits> 90% of pediatric patients, including 100% of children with serious illnesses or neurological symptoms. The search was extended for 30 days after the immunization program ended to capture possible late consequences of vaccine administration, in particular the onset of Guillain Barré syndrome for which meningo- coccal vaccine may have been the trigger. Most of the admissions during this time were for conditions clearly not related to vaccine administration.

A limitation of the methodology was the significant proportion of admissions with an unknown vaccination history. Of the 77 admissions that were investigated further, 40% had an unknown vaccination history after hospital and public health records had been searched. These children were likely not vaccinated; the finding that in 27 patients (87%) the disease causing admission began before the start of the vaccination program further validated this assumption. The three neurological admissions with unknown vaccine history that occurred late after vaccine administration did not involve conditions usually associated with delayed onset. The ascertainment of vaccine history could have been improved by prospective surveillance initiated at the time of the vaccine program, but given the emergent nature of the mass immunization program this would have been difficult.

Of the 11 cases in which meningococcal vaccination was known to have occurred, there were six admissions for diseases of unknown etiology. These admissions were considered possibly but not likely related to vaccine administration because the timing was not compatible (e.g. nephrotic syndrome too soon, was probably pre-existing; and recurrent seizures and syncope too late) and causality did not seem biologically plausible (sickle cell crisis and pancreatitis). There was no clustering of diagnoses to suggest a relation with vaccine administration. The one admission that occurred in close temporal association with vaccine administration was likely triggered by a psychosomatic reaction to the injection event. We believe that the anxiety related to the injection triggered the severe migraine and pseudoseizure conversion reaction and resulted in hospital admission. The components of the vaccine itself were unlikely to have been the trigger.

Conclusion

This first report of active hospital-based surveillance for adverse events associated with meningococcal polysaccharide vaccine supports the safety of this vaccine. Ongoing active hospital-based surveillance should be maintained during future meningococcal polysaccharide vaccination programs to confirm a lack of relation between vaccine administration and the onset of diseases of unknown etiology. Even during an emergency mass immunization program, careful record-keeping of vaccine administration is essential for the accurate assessment of vaccine adverse events.

Acknowledgements

The authors acknowledge the support and assistance of Dr. M. Johnson, Deputy Medical Officer of Health for the Capital Health Region, Edmonton, Alberta, and Dr. G. Tyrrell, Director of the National Centre for Streptococcus, Provincial Laboratory of Public Health for Northern Alberta, Edmonton, Alberta. This study was financially supported by a grant from Alberta Health and Wellness.

References

  1. Centers for Disease Control and Prevention. Control and prevention of serogroup C meningococcal disease: Evaluation and management of suspected outbreaks: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(RR-5):13-21.

  2. Lepow ML, Beeler J, Randolph M et al. Reactogenicity and immunogenicity of a quadrivalent combined meningococcal polysaccharide vaccine in children. J Infect Dis 1986;154:1033-36.

  3. Scheifele DW, Bjornson G, Boraston S. Local adverse effects of meningococcal vaccine. Can Med Assoc J 1994;150:14-15.

  4. Roberts JS, Bryett KA. Incidence of reactions to meningococcal A&C vaccine among U.K. schoolchildren. Public Health 1988;102:471-76.

  5. Yergeau A, Alain L, Pless R et al. Adverse events temporally associated with meningococcal vaccines. Can Med Assoc J 1996;154:503-7.

  6. Hood DA, Edwards IR. Meningococcal vaccine ? do some children experience side effects? NZ Med J 1989;102:65-7.

  7. Ball R, Miles Braun M, Mootrey GT, and the Vaccine Adverse Event Reporting System Working Group. Safety data on meningococcal polysaccharide vaccine from the Vaccine Adverse Event Reporting System. Clin Infect Dis 2001;32:1273-80.

  8. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(RR-7):1-10.

  9. National Advisory Committee on Immunization. Statement on recommended use of meningococcal vaccines. CCDR 2001;27(ACS-6):2-36.

  10. Tyrrell G, Chui L, Johnson M et al. Outbreak of Neisseria meningitidis, in Edmonton, Alberta, Canada. Emerg Infect Dis 2002;8(5):519-21.

Source: W Vaudry, MD, A Roth, RN, BE Lee, MD, D Spady, MD, Department of Pediatrics, University of Alberta, Edmonton.


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