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

Lack of Clinical Exacerbations in Adults with Chronic Asthma after Immunization with Killed Influenza Virus* Brita Stenius-Aamiala, M.D., F.C.C.P.;]ussi K. Huttunen, M.D.; Beijo Pyhala, Ph.D.; Tan Haahtela, M.D.; Pirjo Jokela, M.D.; Aitno ]ukkara, M.D.; nmo Karakorpi, M.D.; Matti Kataja, Ph.D.; 7l.wmo Kava, M.D.; Paula Kuusisto, M.D.; Aarne Lahdensuo, M.D., F.C.C.P.; Leena Mansury, M.D.; Markus Niemisto, M.D.; Antti Taivainen, M.D.; Seppo Vaara, M.D.; and Erkki Vestennen, M.D. 1be effects of immunization with killed inftuenza virus vaccine were assessed by comparison with placebo in a double-blind study of 318 adult patients with chronic asthma. 1be patients were randomly allocated to active vaccine and placebo. No difference was observed in peak expiratory ftow rate or in clinical symptoms of bronchial obstruction between the groups receiving active vaccine and placebo during the 6rst week after immunization. 1be datawere analyzed separately for age, sex, duration of the disease, hypersensitivity to aspirin (acetylsalicylic acid~ atopic status, patients with a history of attacks of asthma induced by viral infections, patients with a diurnal variation of baseline peak expiratory ftow of !O percent or more, and

patients receiving continuous oral steroid medication, but none of these factors seemed to predict any short-term adverse effects of vaccination. Follow-up for eight months after the vaccination revealed no differences in asthmatic symptoms between the patients treated with active vaccine and those receiving placebo. The antiviral antibody response to vaccination was normal. The possible protection provided by the vaccination against exacerbation of asthma induced by inftuenza could not be evaluated, since the inftuenza epidemic expected during the season failed to occur in Finland. It is concluded that immmunization with killed inftuenza vaccine is safe and is not associated with any significant side effects in adult patients with chronic asthma.

A.cute respiratory viral infection is a frequent cause of l'1exacerbations of asthma in asthmatic patients. 1.2 Furthermore, viral infections have been shown to increase bronchial sensitivity to inhaled methacholine, carbachol (carbocholine), and histamine. u This change may be due partly to epithelial airway damage which exposes the airway receptors to inhaled irritants. 3 Viral infections may also reduce Ji-adrenergic responsiveness and so enhance bronchial hyperreactivity. e.7 Although conclusive evidence of benefit has not been presented, it has been recommended that all patients with severe asthma, except fur those with hypersensitivity to egg protein, should be immunized annually against inftuenm. 8 On the other hand, several reports have suggested that asthmatic patients may experience an exacerbation of bronchial symptoms fullowing immunimtion with killed or live influenm vaccine. ""13 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 influenm immunimtion in a large group of patients with different types of 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.

*From the ~ent of Pulmonary Medicine, Helsinki Universit)' Central Hospital, the National Institute of Public Health, Helsinki, and the Departments of Pulmonary Diseases of the Universities ofTurku, ICuopio, and 'Dunpere, and the Hospitals of Meltola, Pliijit-Hlme, nuru, Ounasrinne, and Kinkomaa, Fin-

land.

Supported by a grant from the Finnish Academy. Manuscript receiWd September 30; revision accepted November

215.

718

Patients

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 ifthey smoked, if they had a history of allergy to egg, were currently receiving immunotherapy or regularly taking ~-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. wThe mean baseline PEF for the whole group in the morning before medication was 361 Umin (SD± 125) and after medication 421 Umin (SD± 123). The clinical characteristics of the patients are given in 'Iable 1. The dlfl'erences between the groups are not statistically significanl The Lack ol Cllnlcal ex-1JalkM 11 In Chlonlc Asthma (Stenlus-Aamlllhl et II)

18ble I-Clinical Characteriatica for Patients fDith Althma n.ated fDith Acta Vaccine or with Placebo Data No. of patients Female subjects, percent Age, yr Mean Range Mean duration of asthma, yr Atopic subjects, percent Intrinsic asthma, percent Atopic status not defined, percent Chronic or seasonal rhinitis, percent Aspirin sensitivity, percent Regular use of oral steroids, percent Mean duration of antiasthmatic medication, yr

Active vaccine

Placebo

161 61.5

157 60.6

47 20-73 9.1 45 45 10 65 21 19

48 17-73 8.9

4.9

5.0

40

48 12 59 24 21

majority (62 percent) had been on daily antiasthmatic medication fur 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 influenm 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 ofasthma, or noncompliance in filling in the rollowup rorms. Four patients received the vaccine (two of them placebo and two active vaccine) but discontinued the fullow-up during the one-week period after immuni7.ation. None of these rour 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 rollow-up. Infurmed consent was obtained from all participants. The study was approved by the ethical committees of all participant institutes and hospitals.

Methods and Delign of the Study The patients kept record of their PEF vitlues, 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 berore medication during the second week ofthe runin 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 influem.a vaccine (Flupal'-Vaccin, Orion, Helsinki) containing 3,000 HA units of A/Bangkok/1!79 (H3N2) antigen and 3,000 HA units of B/Singapore/222179 antigen, complemented with a subvirion component, 811-g ofhemagglutinin of A/Brazil/llf18 (HINl). During the rollowing 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. The best of three successive recordings was used in the calculations. Breathlessness, cough, and production of sputum were assessed daily on a scale ofzero to three. In addition, fever greater than 37.S°C (99.S"F), sore throat, symptoms of rhinitis, and daily medication

were recorded. After the first three weeks ofthe 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 fur antiviral antibodies were collected prior to (sample 1) and five weeks after (sample 2) immuni7.ation (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 fur hemagglutinationinhibiting antibodies against the fullowing influenza viruses: A/Brazil/W78 (HlNl); A/Finland/1179 (HlNl); A/Finland/26/81 (HlNl); A/Bangkok/1!79 (H3N2); A/Finland/31180 (H3N2); A/Finland/34180 (H3N2); and B/HongKong/5172. 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 fur hemagglutination-inhibiting antibodies were conducted according to the principles of Robinson and Dowdle. 15 The sampies of serum were pretreated at a dilution of 1:6 fur 18 hours at + 37"C and subsequently were heated fur one hour at + 56°C to remove nonspecific inhibitors. Four hemagglutinating virus Units were used as antigen. The influenm B virus antigen was used as untreated and alternatively submitted to treatment with ether. 11 The three specimens of serum from each subject were always tested simultaneously. The two-tailed t-test and the 'It test were used fur statistical analysis.

REsui.:rs

No differences were observed between groups receiving active vaccine and placebo in the mean PEF in the morning, noon, or evening during the first seven days after vaccination (Fig 1). Symptom scores for dyspnea, cough, and production of sputum and also the need for medication were similar in the two groups. Age, sex, duration of the disease, hypersensitivity to aspirin, atopic status, history of attacks of asthma induced by viral infections, diurnal variation of baseline PEF of 20 percent or more, or continuous oral steroid medication did not predict exacerbations fol-

PE FR,

% of baseline

110

100 90

80

,. 0

I

I

I

i

I

1 2 3 4 5 Days after vaccination

FIGURE 1. Eft'ect of immuni7.ation with killed influem.a virus on PEF in morning befure medication in all subjects. Values are expressed as percentage of mean PEF in morning befure medication during second week of run-in period. Daahed Unea indicate active vaccine (n = 161); soUd Unea indicate placebo (n = 157). Verlical ban indicate mean :t SD. Differences between groups are not statistically significant. CHEST I 89 I 8 I JUNE, 1888

7ff1

Table 2-Valuea/or PEF in Morning before Thratment in Some Patient Subgroupa during the First 1 Days After lntramUBCUlar lnjedionl of Influenza Vaccine or Placebo Day* 'Ii'eatment

Group Aspirin intolerance Atopic asthma Intrinsic asthma Asthma during viral infectionst Oral steroid medication

Active Placebo Active Placebo Active Placebo Active Placebo Active Placebo

No. of Subjects

24 28 69

59 69 79

113 119 27

33

2

1 106±20 104±20 102±8 102±15 105±21 101±14 105±17 102±14 106±14 103±20

4

3

567

99±13 98±16 98±17 95±16 103±17 93±19 90±16 98±15 93±17 97±15 99±12 98±13 99±13 99±14 101±13 101±11 99±12 100±13 98±16 100±15 99±13 98±15 97±18 99±19 101±20 99±17 101±17 103±15 99±25 98±16 98±16 96±17 97±13 100±13 99±14 99±14 101± 18 99±17 102± 17 102± 15 99±21 99±16 97±15 99±12 99±15 98±15 96±17 98±16 100±21 97±17 96±21 100±19 94±20 103±16 93±21 92±18 92±22 97±22 92±19 96±15

*Expressed as percent of mean during week preceding vaccination (mean± SD). tPatients with history of exacerbations of asthma during viral infections.

matic subjects in a placebo-controlled study. In contrast to our observations, several earlier reports have suggested that asthmatic patients may experience an exacerbation of bronchial symptoms following immunization with killed influenza vaccine. Bell et al8 fuund an increase in the need fur medication during the first 48 hours after vaccination in children with severe chronic asthma. In the study by DeJongste et al, 10 immunization with inactivated influenza vaccine caused a significant fall in the forced expiratory volume in one second but no change in bronchial responsiveness to histamine in six of nine asthmatic children. Other investigatorsu.12 have observed increased obstruction or impairment in clinical symptoms after immunization in adult patients with asthma or chronic bronchitis. In one study, 13 immunization with inactivated vaccine increased sensitivity to methacholine but did not cause spontaneous obstruction in asthmatic adults. Banks et al18 found a correlation between the antibody response and bronchial reactivity to histamine following vaccination with killed influenza virus but no increase in symptoms after vaccination. The reasons for the discrepancy between these reports can be explained in several ways. First, it is

lowing vaccination (Tuble 2). The antibody response to vaccination was good (Tuble 3), not only in subjects seropositive in the phase befure vaccination, but also in seronegative subjects, a part of whom may have been unprimed. During the fullow-up period, the incidence of influenza was very low in Finland. Serologic evidence of infection (more than fuurfold increase in antibody titer in sample 3, as compared to sample 2) was demonstrated only once (an influenza B infection in the placebo group). There· was no difference between the groups in the severity of asthma as evaluated by daily measurements of PEF, symptom scores, changes in daily medication, courses of oral corticosteroids, or hospitalization because of asthma during the eight-month follow-up period between September 1981 and April 1982. DiscuSSION Our results demonstrate that immunization with killed influenza virus vaccine does not impair the clinical status in adult patients with chronic asthma. Absence of adverse effects was documented by several independent indicators. Our study is in keeping with the results of Campbell and Edwards, 17 who found no adverse effects of influenza immunization in 28 asth-

Table 3-E.lfect of Vaccination on Hemagglutination-Inhibiting Antibodies• A/Bangkok/l/79(H3N2) Group Seropositive subjectst Serum befure vaccination (sample 1) Serum after vaccination (sample 2) Subjects showing C!:4-fuld increase in titer in sample 2 as compared with sample 3 Subjects seropositive in sample 1 Subjects seronegative in sample 1 Subjects showing protective titer of C!:48 in sample 2

A/Brazil/ll/78(H1Nl)

B/HongKong/5172

Vaccine

Placebo

Vaccine

Placebo

Vaccine

Placebo

58 95

65 67

40 95

50 50

79 100

79 79

74 77

0 0

61 84

0 0

54

100

0 3

79

27

77

22

97

48

*Vaccine group (n = 154); and placebo group (n = 147). Tuble data are percents of group. t Antibody in titer of C!:l2.

788

Lack of Clinical Ex-1>allol is In Chronic Asthma (Slenlus-Aamlala et al)

possible that clinically significant impairment of bronchial symptoms is seen only in patients with particularly severe or labile asthma. No support for such an explanation was found in our study, but it should be borne in mind that medication was carefully adjusted in all of the patients during the run-in period. This factor, together with better compliance with treatment because of regular recording of PEF and clinical symptoms, may have improved bronchial stability and diminished the sensitivity of the patients to any adverse effects of vaccination. Secondly, it is possible that bronchial obstruction after immunization is restricted to some relatively small group of patients. Our analysis did not identify any group of patients with exceptional responsiveness to vaccination; however, it should be emphasized that in contrast to many previous studies, we ·used a rigidly placebo-controlled double-blind study. The greater frequency of symptoms after immunization seen in other studies may represent a placebo response to the procedure in the study. No direct conclusions about the protective effect of the vaccination can be made, because during the season of 1981 to 1982, the epidemic of influenza did not occur as expected in Finland. The epidemic activity, mainly due to influenza B viruses, increased exceptionally late in spring (unpublished observations of the National Influenza Centre, National Public Health Institute, Helsinki), ie, after the end of the study. According to the seroepidemiologic follow-up survey, which was started in the winter of1971to197219 and has been continued every epidemic season since then, the frequency of serologic infection in 1981 to 1982 for influenza A and B viruses was 3 percent (9/291). This was the lowest value recorded since the beginning of the survey. Thus, the efficacy of the vaccination could be estimated only by means of antibody response. A significant rise in the number of individuals with a protective antibody titer of 48 or more19 was seen for all three antigens which represented the viruses of the vaccine. In conclusion, immunization with killed influenza vaccine does not induce clinical exacerbations in adult patients with chronic asthma. With the exception of subjects with possible or manifest allergy to egg protein, asthmatic adults can safely be immunized with killed influenza virus. Other studies have previously shown that vaccination against influenza is effective in the prevention of acute episodes of chronic bronchitis. llll Thus, it is likely that patients in whom respiratory infections provoke exacerbations of asthma will benefit from immunization against influenza.

ACKNOWLEDGMENTS: We than!c ~_aija Heiskala, M.D., for her help and all our ournurses for their skillful assistance throughout the study. REFERENCES 1 Roldaan AC, Masural N. Viral respiratory infections in asthmatic

children staying in a mountain resort. Eur J Respir Dis 1982;

63:140-50

2 Minor TE, Dick EC, Baker Jw. Ouellette JJ, Cohen M, Reed CE. Rhinovirus and influenza type A infections as precipitants of asthma. Am Rev Respir Dis 1976; 113:149-53 3 Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA. Mechanisms ofbronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131-39 4 Little Jw. Hall WH, Douglas RG, Mudholkar GS, Speers DM, Patel K. Airway hyperreactivity and peripheral airway dysfunction in influenza A infection. Am Rev Respir Dis 1978; 118:295-303 . 5 Parker CD, Bilbo RE, Reed CE. Methacholine aerosol as a test for bronchial asthma. Arch Intern Med 1965; 115:452-58 6 Busse WW. Decreased granulocyte response to isoproterenol in asthma during upper respiratory tract infections. Am Rev Respir Dis 1977; 115:783-91 7 Busse WW, Cooper W, Warshauer DM, Dick EC, Wallow IHL, Albrecht R. Impairment of isoproterenol, H 1 histamine, and prostaglandin El: response of human granulocytes after incubation in vitro with live influenza vaccines. Am Rev Respir Dis 1979; 119:561-69 8 Recommendation of the Public Health Service Advisory Committee on immunization practices: influenza vaccine. Morbidity Mortality Weekly Rep 1979; 28:231-37 9 Bell TD, Chai H, Berlow B, Daniels G. Immunization with killed influenza virus in children with chronic asthma. Chest 1978; 73:140-45 10 DeJongste JC, Degenhart HJ, Neijens HJ, Duiverman EJ, Raatgeep HC, Kerrebijn KF. Bronchial responsiveness and leucocyte reactivity after influenza vaccine in asthmatic patients. Eur J Respir Dis 1984; 65:196-200 11 Anand SC, Itkin IH, Kind LS. Effect of influenza vaccine on metacholine (Mecholyl) sensitivity in patients with asthma of known and unknown origin. J Allergy 1968; 42:187-92 12 Knowles G, Tuylor P, Turnel'-Warwick M. A comparison of antibody responses to admune inactivated influenza vaccine in serum and respiratory secretions of healthy non-smokers, healthy cigarette-smokers and patients with chronic bronchitis. Br J Dis Chest 1981; 75:283-90 13 Ouellette JJ. Reed CE. Increased response of asthmatic subjects to metacholine after influenza vaccine. J Allergy 1965; 36:558-63 14 American College of Chest Physicians and American Thoracic Society. Pulmonary terms and symbols: A report of the ACCPATS Joint Committee on Pulmonary Nomenclature. Chest 1975; 67:583-93 15 Robinson RQ, Dowdle WR. Influenza viruses. In: Lennette EH, Schmidt HJ, eds. Diagnostic procedures for viral and rickettsial infections. New York: American Public Health Association, 1969:426-27 16 Pyhlilii R, Kleemola M, Visakorpi R. The HI test modified by ether treatment in the sero-epidemiological surveillance of influenza B. J Hygiene 1985; 94:341-48 17 Campbell BG, Edwards RL. Safety of influenza vaccination in adults with asthma. Med J Aust 1984; 140:773-75 18 Banks J, Bevan C, Fennerty A, Ebden P, Walters EH, Smith A. Association between rise in antibodies and increase in airway sensitivity after intramuscular injection of killed influenza virus in asthmatic patients. Eur J Respir Dis 1985; 66:268-72 19 Pyhlilii R, Aho K. Serum HI antibody and protection against influenza: a follow-up survey at community level of three epidemics caused by dift'erent H3N2-variants. Int J Epidemiol 1975; 4:127-29 20 Gross PA, Barry DW, D'Esopo N. Influenza immunization in chronic bronchitis: local and systemic immune response. Am Rev Respir Dis 1976; 114:30.5-13 CHEST I 89 I 6 I JUNE, 1966

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