Details of Clinical Exacerbations in Adults with Chronic Asthma after Immunization with Killed Influenza Virus

Acute respiratory viral infection is a frequent cause of exacerbations of asthma in asthmatic patients. Furthermore, viral infections have been shown to increase bronchial sensitivity to inhaled methacholine, carbachol (carbocholine), and histamine. This change may be due partly to epithelial airway damage which exposes the airway receptors to inhaled irritants. Viral infections may also reduce β-adrenergic responsiveness and so enhance bronchial hyperreactivity.

Although conclusive evidence of benefit has not been presented, it has been recommended that all patients with severe asthma, except for those with hypersensitivity to egg protein, should be immunized annually against influenza. On the other hand, several reports have suggested that asthmatic patients may experience an exacerbation of bronchial symptoms following immunization with killed or live influenza vaccine. The frequency of serious vaccine-related symptoms is not known, nor is it clear whether impairment of clinical status or increase in airway obstruction or both are typical of all patients or only of certain subgroups of subjects.

The present study was undertaken to ascertain possible adverse and protective effects of influenza immunization in a large group of patients with different types of asthma (our website is full of thought-provoking articles about asthma) and with varying clinical pictures and to identify possible risk groups with respect to adverse effects after vaccination. A double-blind randomized study was used.

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Materials and Methods


The patients (n = 328) were recruited in nine centers. The criteria of selection for the trial were moderate to severe disease with daily need of antiasthma medication, an ability to maintain normal daily activities, age above 15 years, ability to make reliable measurements of peak expiratory flow (PEF) and to keep relevant records, no viral infections during the six weeks prior to the influenza vaccination, and stable asthma during the run-in period of two weeks. All of the patients had been nonsmokers for the last two years prior to the study.

Patients were not eligible for the study if they smoked, if they had a history of allergy to egg, were currently receiving immunotherapy or regularly taking β-adrenergic blocking agents or oral corticosteroids at a dosage exceeding the equivalent of 10 mg of prednisolone per day, or if they had some other serious chronic disease such as diabetes, bronchiectasis, chronic bronchitis, emphysema, cancer, or chronic collagen disease.

The patients were considered to be atopic if there was evidence of extrinsic allergy judged by positive cutaneous prick tests in a routine battery. If cutaneous tests were negative, the patients were classified as having intrinsic asthma. Patients with equivocal cutaneous tests were grouped as “not defined” (ND). All patients fulfilled the criteria for bronchial asthma set by the American College of Chest Physicians and the American Thoracic Society. The mean baseline PEF for the whole group in the morning before medication was 361 L/min (SD ± 125) and after medication 421 L/min (SD ± 123).

The clinical characteristics of the patients are given in Table 1. The differences between the groups are not statistically significant The majority (62 percent) had been on daily antiasthmatic medication for less than five years. Eighty-seven percent reported having annually had one or several respiratory infections obviously with viral etiology annually during the preceding years. Thirty-eight percent of the patients reported that their first asthmatic symptoms had occurred in connection with a respiratory infection. The majority of the patients (93 percent) gave a history of exacerbation of asthma in connection with viral respiratory infections. One third of the patients had been immunized with influenza vaccine in 1980 or previously.

Six patients were excluded from the study during the run-in period (as described subsequently) because of acute respiratory infection, lability of asthma, or noncompliance in filling in the follow-up forms. Four patients received the vaccine (two of them placebo and two active vaccine) but discontinued the follow-up during the one-week period after immunization. None of these four patients had any adverse reactions after the injection. Thus, 318 subjects (125 male and 193 female subjects) completed the first three weeks of the study. During the later months, another 27 patients were lost to follow-up.

Informed consent was obtained from all participants. The study was approved by the ethical committees of all participant institutes and hospitals.

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Methods and Design of the Study

The patients kept record of their PEF values, medication, and symptom scores throughout the study. After a run-in period of two weeks, the patients were enrolled in the trial, stratified in three groups by age (15 to 29 years, 30 to 49 years, and 50 years or more) and randomly allocated to placebo or active vaccine. The mean PEF in the morning before medication during the second week of the run-in period was used as the baseline value in the calculations.

Immediately after the run-in period in August 1981, the patients were given a 0.5-ml intramuscular injection of either physiologic saline solution or a commercially available split-type influenza vaccine (Flupar-Vaccin, Orion, Helsinki) containing 3,000 HA units of A/Bangkok/1/79 (H3N2) antigen and 3,000 HA units of B/Singa-pore/222/79 antigen, complemented with a subvirion component, 8 tig of hemagglutinin of A/Brazil/11/78 (H1N1). During the following week the patients recorded PEF three times during the day and, if awake, also during the night. The first recording in the morning was carried out on awakening in the morning and the second recording 15 minutes after the patients usual dose of a bronchodilating aerosol. Hie best of three successive recordings was used in the calculations. Breathlessness, cough, and production of sputum were assessed daily on a scale of zero to three. In addition, fever greater than 37.5°C (99.5°F), sore throat, symptoms of rhinitis, and daily medication were recorded.

After the first three weeks of the study, the patients recorded PEF twice per day (in the morning and in the evening) and continued to record symptoms and daily medication as described previously until the end of April 1982. Medical checkup was carried out once per month.

Specimens of serum for antiviral antibodies were collected prior to (sample 1) and five weeks after (sample 2) immunization (September and November 1981). A third specimen (sample 3) was collected five months later in March 1982. A complete set of specimens of serum was available from 301 subjects, 154 of them in the group receiving vaccine. The specimens of serum were stored at -20°C.

The collections of serum were studied for hemagglutination-inhibiting antibodies against the following influenza viruses: A/Brazil/11/78 (H1N1); A/Finland/1/79 (H1N1); A/Finland/26/81 (H1N1); A/Bangkok/1/79 (H3N2); A/Finland/31/80 (H3N2); A/Finland/34/80 (H3N2); and B/HongKong/5/72. The strains serving as antigens in the tests were selected to represent the viruses of the present vaccine and the antigenic variants epidemic in Finland in the immediate past. The tests for hemagglutination-inhibiting antibodies were conducted according to the principles of Robinson and Dowdle. The samples of serum were pretreated at a dilution of 1:6 for 18 hours at 37°C and subsequently were heated for one hour at 56°C to remove nonspecific inhibitors. Four hemagglutinating virus Units were used as antigen. The influenza B virus antigen was used as untreated and alternatively submitted to treatment with ether.“ The three specimens of serum from each subject were always tested simultaneously. The two-tailed f-test and the x test were used for statistical analysis.

Table 1—Clinical Characteristics for Patients with Asthma Treated with Active Vaccine or with Placebo

Data Activevaccine Placebo
No. of patients 161 157
Female subjects, percent 61.5 60.6
Age, yr
Mean 47 48
Range 20-73 17-73
Mean duration of asthma, yr 9.1 8.9
Atopic subjects, percent 45 40
Intrinsic asthma, percent 45 48
Atopic status not defined, percent 10 12
Chronic or seasonal rhinitis, percent 65 59
Aspirin sensitivity, percent 21 24
Regular use of oral steroids, percent 19 21
Mean duration of antiasthmatic
medication, yr 4.9 5.0