Study Design

We conducted a matched case–control study in which patients with Bell's palsy (case patients) and control patients were matched according to age, date of their clinic visit, and physician. Since about 74,000 doses of the intranasal vaccine, or more than 80 percent of the intranasal-vaccine supply, were distributed in the 19 German-speaking regions of Switzerland, this region was defined as the study area. To gain a better understanding of the timing of the risk for Bell's palsy after administration of the intranasal vaccine, we assessed the onset intervals (i.e., the intervals from the date of the first dose of the vaccine to the date of the first visit to a physician for Bell's palsy) in a larger series of patients, a method referred to as case-series analysis.

The study protocol was approved by the ethics committees of the regions involved in the study. All the patients gave written informed consent, except for a small minority with additional cases reported by physicians anonymously. The academic investigators had access to all the study data, took responsibility for designing and conducting the analysis, and had authority over the manuscript preparation and the decisions concerning publication.

Selection of Case Patients and Controls

All 4891 primary care physicians, ear, nose, and throat specialists, and neurologists in the study area were invited twice to report cases of Bell's palsy first diagnosed between October 1, 2000, and April 30, 2001. The overall response rate was 81.1 percent. Subsequently, the physicians who had reported cases of Bell's palsy were asked to document the date of the visit and information pertinent to the study's inclusion and exclusion criteria and to select, from among their patients without Bell's palsy, three controls sequentially from their registration log. The controls were matched with the case patients according to age (within five years), date of the clinic visit (within four days), and physician. Trained study monitors contacted the physicians and reviewed the selection forms regularly to ensure consistency in the selection of controls. At this point, participating physicians had not been made aware of the exposure to be investigated (influenza vaccination). Thereafter, questionnaires requesting clinical information about the case patients and controls were sent together with informed-consent forms to both the physicians and their patients. The patients' questionnaires were used primarily for validation of the information provided by the physicians. When there was a discrepancy, both the patient and the physician were contacted for clarification.

Patients with Bell's palsy were eligible for the study if they were at least 18 years of age and if they had complete or incomplete unilateral weakness of the facial muscles. The onset of weakness had to be sudden, and the progression of facial palsy had to reach a maximum within one week after the onset of the first symptoms. Exclusion criteria were head trauma within two months before enrollment and a history of brain tumor, cerebrovascular accident, ipsilateral ear disease or surgery, or the Guillain–Barré syndrome. Patients were not selected as controls if they met the same exclusion criteria or if they received a clinical diagnosis of influenza at the index visit. The exclusion of patients with influenza as controls was a measure taken in an effort to prevent an overrepresentation of patients with influenza as controls during the winter season. Physicians who were unwilling to select controls were still asked to document any cases.

Exposure to Influenza Vaccines

Physicians were asked to document the dates of administration and the brand name and type of influenza vaccine (parenteral or intranasal) used during the study period. Other vaccine exposures during the study period and the preceding two months were also documented. Since in all 43 sentinel cases reported in the study area the onset of Bell's palsy occurred within 91 days after intranasal vaccination, we defined the period of 1 to 91 days as the postexposure risk period.

For 10 exposed case patients and 1 exposed control, we were unable to calculate the onset interval because the date of vaccination was unknown. We decided to include them in the conditional logistic-regression analysis on the assumption that they had an onset interval of 1 to 91 days, because including them would provide a more conservative estimate of the adjusted odds ratio for Bell's palsy with use of the intranasal vaccine than would excluding them.

Covariates

Additional information, including potential risk factors for Bell's palsy,11-21 was obtained from physicians and patients. Documented information at the time of enrollment included sex, nationality, pregnancy status, smoking status, current infectious diseases (upper respiratory infections, influenza, herpes simplex, other herpes infections, borreliosis, human immunodeficiency virus infection, and Mycoplasma pneumoniae infection), chronic diseases (diabetes, cardiovascular diseases, hypertension, asthma, allergies, and neoplasm), and a personal or family history of Bell's palsy.

Statistical Analysis

Matched Case–Control Study

The date of the first visit to a physician for Bell's palsy was used as the index date and was documented for all the case patients. The date of administration of the first dose of the intranasal vaccine was defined as the exposure date. Conditional logistic regression (SAS version 8, SAS Institute) was performed to estimate the risk of Bell's palsy during the period from 1 to 91 days after vaccination (the predefined risk period), with adjustment for the potential risk factors defined as covariates.

Case-Series Analysis

To determine which exposure periods after vaccination were associated with the highest risk of Bell's palsy, we performed a case-series analysis.22,23 The case series included 412 case patients (250 from the case–control study and 162 from the group of case patients without controls). We compared the risk of Bell's palsy during various periods after intranasal or parenteral vaccination (1 to 30, 31 to 60, and 61 to 91 days, as compared with 92 or more days).

Risk Assessment after Adjustment for Biases

To assess the presence and the magnitude of selection bias, we compared the number of case patients who had been exposed to the intranasal vaccine during the case–control study with the number of the sentinel case patients and with the series of case patients for whom there were no matched controls. In addition, we estimated the relative and excess risks based on the risk in the adult population and the number of doses of the intranasal vaccine distributed in the study area.