l
J
Frequency of Adverse Reactions after Influenza Vaccination KARENL. MARGOLIS,M.D.Minneapolis, MinnesotaGREGORYA. POLAND,M.D.Rochester, Minnesota KRISTIN L. NICHOL,M.D.,M.P.H., DAVIDS. MACPHERSON,M.D.,JEFFREYD. MEYER,M.D.Minneapolis, Minnesota JANEE. KORN,M.D.,M.P.H.Worcester, Massachusetts RICHARDP. LOFGREN,M.D., M.P.H. Minneapolis, Minnesota
PURPOSE: A l t h o u g h c o n c e r n about side effects constitutes a major deterrent to patient compliance with recommendations for influenza vaccination, there is a paucity of data about the frequency of adverse reactions to n e w e r trivalent vaccines. Our aim w a s to determine the frequency of adverse reactions to influenT~ vaccine in older, chronically ill persons, m a n y of w h o m are at high risk for influenza-related morbidity. PATIENTS AND METHODS: We conducted a telephone survey of 40% of the patients w h o w e r e vaccinated at a walk-in flu shot clinic. The subjects w e r e randomly assigned to two groups. To determine postvaccine symptom rates, Group I w a s interviewed seven days after vaccination. Group II w a s interviewed 21 days after vaccination in order to control for baseline symptom rates. Both groups w e r e queried about fever, disability, and flu-like illness in the w e e k preceding the interview. RESULTS: Of 816 patients selected, 650 (79.6%) completed the interview. The m e a n age of the subjects w a s 63, and more than two thirds w e r e at risk for influenza-related morbidity. The frequencies of self-reported fever (5.3% versus 5.1%, p = 0.91) and disability (10.4% versus 9.3%, p = 0.65) w e r e similar in the t w o groups. However, a significantly higher proportion of Group I subjects reported a flu-like illness compared to the Group II subjects (14.2% versus 8.7%, p = 0.03). Although Group I subjects w e r e more likely to report flu-like illness within t w o days of vaccination compared to a similar time interval for Group II subjects, there w a s no corresponding clustering of disability after vaccination. CONCLUSION: We conclude that the overall frequency of symptoms in both groups w a s low; however, the absolute risk of a flu-like illness w a s 5.5 % higher during the first w e e k following influenza vaccination w h e n compared with the third w e e k after the injection. These symptoms did not result in a decreased ability to perform usual daily activities.
From the Department of Medicine, Section of General Medicine (KLN, DSM, RPL), Minneapolis Veterans Administration Medical Center and the University of Minnesota, Minneapolis, Minnesota, the Department of Medicine (KLM) and Department of Emergency Medicine (JDM), Hennepin County Medical Center, Minneapolis, Minnesota, Mayo Clinic (GAP), Rochester, Minnesota, and the Department of Medicine (JEK), University of Massachusetts Medical Center, Worchester, Massachusetts. This work was presented in part at the 11th Annual Meeting of the Society of General Internal Medicine, Arlington, Virginia, April 26, ]988, and was published in abstract form (Clin Res 1988; 36: 745A). Requests for reprints should be addressed to Karen L. Margolis, M.D., Department of Medicine, Hennepin County Medical Center, 70] Park Avenue, Minneapolis, Minnesota 55415. Manuscript submitted May 1, ]989, and accepted in revised form September 7, 1989.
is a serious illness that causes substantial morbidity and mortality, particularly in the elderly Iandnfluenza chronically ill [1,2]. Despite strong recommendations by the United States Public Health Service and others, fewer than one third of those at high risk are vaccinated in any given year in the United States [35]. Concern about adverse consequences of treatment is often cited as a cause of patient noncompliance with medical recommendations [6]. It is therefore not surprising that studies in the elderly have shown that fear of side effects is a major deterrent to influenza vaccination [7-10]. Until the late 1960s, local and systemic adverse reactions to influenza vaccines were common and at times severe [11]. With the introduction of new purification techniques, a considerable reduction in the frequency and severity of reactions was noted [11,12]. In large-scale clinical trials of purified influenza vaccines conducted in 1976 [13] and 1978 [14], the rates of systemic reaction were low, perhaps not exceeding that found in placebo recipients. Most of the subjects in these studies, however, were young, healthy volunteers. Only a small percentage were elderly or chronically ill. An important question, then, remains unanswered: what is the frequency of adverse reactions to influenza vaccine in older, chronically ill persons at highest risk for influenza-related morbidity? To answer this question, we surveyed vaccine recipients who attended a walk-in flu shot clinic. PATIENTS AND METHODS
The Minneapolis Veterans Affairs Medical Center is a University of Minnesota-affiliated teaching hospital that provides care to more than 31,000 outpatients. As part of an institution-wide influenza vaccination program conducted during the fall of 1987, a walk-in flu shot clinic was held for two weeks in November. An October mailing to all outpatients included information about influenza, risk factors for complications, and the dates, time, and location of the walk-in clinic. More than 2,200 patients received a 0.5-mL deltoid intramuscular injection of split-antigen (subvirion) trivalent influenza vaccine (A/Taiwan/1/86 [H1N1], A/Leningrad/360/86 [H3N2], and B/Ann Arbor/i/86) at the clinic. From walk-in clinic records, 816 subjects were selected according to the terminal digit of their social security number and were randomly assigned to two groups. Group I was interviewed seven days after vaccination and Group II was interviewed 21 days after vaccination. It was assumed that any vaccine-related adverse effects would occur within the first seven days and would have subsided by the 14th day, and that the two sets of interviews would therefore measure postvaccine and background symptom rates, respectively. January 1990 The American Journal of Medicine Volume88
27
REACTIONSTO INFLUENZAVACCINE/ MARGOLISET AL TABLE I Reasons for Excluding Subjects from the Study
Number randomly assigned Number interviewed (%) Number excluded (%) No telephone Not reached Deafness Dementia Refused
GroupI
GroupII
422 338 (80.1) 84 (19.9) 19 57 2 4 2
394 312 (79.2) 82 (20.8) 31 49 0 0 2
TABLE II Characteristics of Study Subjects
Number of subjects Percent male Age (mean 4- SD) Percent over age 65 Percent with history of Heart disease Lung disease Diabetes Other serious illness Percent with any risk factor*
GroupI
GroupII
p Value
338 83.2 63.6 4- 10.4 45.8
312 81.7 63.0 4- 10.3 40.4
-0.68 0.46 O.18
19.9 8.9 12.5 18.8 69.1
21.5 9.2 12.3 20.2 66.9
0.70 0.97 0.97 0.71 0.61
* High-risk conditions predisposing to influenza morbidity include age greater than 65, cardiopulmonary disease, diabetes mellitus, and a number of other serious medical conditions [1]. TABLE III Symptoms Experienced during Previous Seven Days by Group I and Group II Subjects Groupl Number of subjects Number reporting fever (%) Number reporting any disability days (%) Number reporting flu-like illness (%) Days per flu-like illness (mean 4- SD) Number reporting arm soreness (%)
338
Groupll pValue
312
18(5.3) 16(5.1) 35(10.4) 29(9.3) 48 (14.2) 27 (8.7) 2.7=1=2.1 3.64-2.7 66 (19.5) --
-0.91 0.65 0.03 0,09 --
Demographic information and self-reported data on risk factors for influenza morbidity were obtained from each subject at the time of vaccination. The validity of patient self-report of these risk factors has been established for this population (Nichol KL, unpublished observations). Data on symptoms were collected by trained interviewers using a closed-ended telephone questionnaire according to a specified protocol. Up to three attempts were made to contact each person, including one telephone call after 5 P.M. The subjects were not informed of the purpose of the interview. Both the Group I and Group II subjects were told that they would be asked three questions regarding their health in the previous week. First, they were asked whether they had had a fever. No documentation was required. Second, to identify any disability they had experienced, subjects were asked if they had stayed in bed longer than usual or had curtailed their usual activities because of illness. Third, they were asked whether they had had a "flu-like illness," defined for them as an illness characterized by "muscle 28
January1990 The American Journal of Medicine Volume88
aches, tiredness, and a general sick feeling." This definition was used both because of the common colloquial use of the term "flu" to describe a nonspecific viral syndrome and because these symptoms, along with the fever, are described as potential side effects of influenza vaccination [1]. If the subjects answered yes to any of the three questions, the onset and duration of the symptoms were determined. In addition, those who answered yes to the flu-like illness question were asked in lay terms whether the episode had included myalgias, fatigue, malaise, headache, coryza, cough, anorexia, diarrhea, or constipation. At the end of the interview, the Group I subjects were reminded of their vaccination and were asked whether they had experienced arm soreness or disability resulting from the injection. The two-tailed Student's t-test was used to assess the significance of differences in continuous variables between the two groups. Categorical data were analyzed using the chi-square test. Subjects who were not reached or who could not be interviewed were excluded from the analysis. RESULTS
Of 816 persons selected for the study, 422 were randomly assigned to Group I and 394 to Group II. Interviews were completed for 80% of Group I and 79% of Group II subjects (p = 0.75). The reasons for excluding potential subjects are shown in T a b l e I. Subject characteristics are given in T a b l e II. Most of the study subjects were older men who reported at least one risk factor for influenza complications. The two groups were similar with respect to mean age, sex, proportion over age 65, and reported risk factors for influenza morbidity. Interview results are given in T a b l e III. No significant differences were found between Group I and Group II in the proportion of subjects reporting fever or disability. However, a significantly higher proportion of Group I subjects reported a flu-like illness (14.2% versus 8.7%, p = 0.03). Flu-like illness in Group I subjects tended to be of shorter duration (2.7 versus 3.6 days, p = 0.09) and more often occurred in the first two days of the interview week (Figure 1; 31% versus 17%, p = 0.02). There was no corresponding difference between the two groups with respect to the timing of any disability (Figure 1; 22% versus 19%, p = 0.58). Specific flu-like symptoms experienced by the subjects did not differ significantly between the two groups (chi-square for heterogeneity = 2.32, p = 0.97). Myalgias, fatigue, or malaise, or any combination of the three were the most common symptoms, and were present in 50% to 80% of the subjects who reported a flu-like illness. Headache, coryza, or cough were present in 40% to 50% of the flu-like illness episodes. Gastrointestinal complaints such as anorexia, diarrhea, or constipation were present in only 10% to 40~ of the episodes. Arm soreness at the injection site lasting for more than one hour was reported by 66 (19.5%) of Group ] subjects (Table III). Ten of these subjects reduced their use of the arm for one or more days. COMMENTS
This study documents that ambulatory adults whc are given influenza vaccine report an increased frequency of flu-like illness in the week after vaccination~
REACTIONS TO INFLUENZA VACCINE / MARGOLIS ET AL 140' 120' 100'
Figure 1. Timing of flu-like illness and
disability days. The total number of days of flu-like illness and disability reported by Group I and Group 41 subjects is shown. The shaded area within each bar represents the number of "flu" days and disability days that occurred in the first two days of the interview week. The proportion of total "flu" days and disability days that occurred in the first two days is noted within each column (e.g., 40 of 128 total "flu" days occurred in the first two days of the interview week for Group I subjects, 40 of 128 = 31%).
i
I
80,
[ ] Total for Interview Week
I
60 Z
•
Total for lstTwo Days of Interview Week
40, 17%
I
22%
m Group I
Group II
"Flu" days
when compared with the one-week period beginning 14 days after vaccination. They do not, however, report any increase in fever or disability. Large clinical trials of purified influenza vaccine, performed in 1976 in response to the threat of a "swine flu" pandemic, found that most of the vaccines tested were "difficult to distinguish from a saline placebo when fever or other systemic symptoms were scored" [13]. Roughly 40% of the placebo recipients experienced some systemic symptoms, compared with 30% to 60% of those who received various vaccines. In 1978, a second group of trials using vaccines of more uniform potency again demonstrated no significant difference in the rate and severity of systemic reaction between subjects who received vaccine and those who received placebo [14]. The pooled rate of systemic reaction was 33% in the vaccinees, versus 25% for placebo recipients (p = 0.07). However, the usefulness of these studies to clinicians is limited, since only about 10% of the subjects were elderly or chronically ill. In addition, the subjects were divided into many different vaccine testing groups, and consequently the studies lacked sufficient power to distinguish small but potentially clinically important differences in reactogenicity between vaccine and placebo. Since 1978, several trials have established the safety of administering influenza vaccine to asthmatic persons [15-18], but the ambulatory elderly population has been inadequately studied. The present study addresses some of the weaknesses of earlier studies. The subjects were representative of vaccine recipients in a community setting, with more than two thirds falling into high-risk groups. Furthermore, the sample size was adequate to have an 80% probability of detecting a 6% increase above the background rate of flu-like illness. Given the nonconcurrent comparison group design of this study, several potential biases deserve comment. First, vaccine side effects could have persisted to the third week, resulting in a false elevation of the background rate. However, this would only diminish the magnitude of any differences observed. Second, although there were no documented cases of influenza in Minnesota until well after our data were collected [19], other viral illness could have been active during the data-collection period for Group I. However, this would not explain the clustering of flu-like illness that was observed within two days of vaccination. Third,
Group [
Group II
Disability days
our results could have been biased if persons in Group I who experienced side effects were selectively not reached because they had been hospitalized. A computerized search of the hospital's database for excluded subjects revealed four admissions in Group I and five in Group II during the two interview periods; none of these admissions, however, was related to illness that could be attributed to vaccination. Finally, we were unable to distinguish whether the increased reporting of flu-like illness was secondary to true vaccine-mediated adverse reactions or simply to heightened somatic awareness following vaccination. It is a common lay belief that a person can actually "get the flu from a flu shot" [7]. The public's wary attitude toward influenza vaccine probably arose because of the reactogenicity of early vaccines, but after two decades, current purified vaccines are still regarded with suspicion. At the height of the 1976 "swine flu" vaccination program, even before the reports of the occurrence of Guillain-Barr~ syndrome, 34% of those polled stated that they were afraid of the vaccine [20]. Subsequent vaccines have not been associated with neurologic sequelae [1]; however, studies in Seattle veterans have shown that concern about this and other side effects remains high [10]. Although this fear of side effects deters many from vaccination and may lead to heightened awareness of symptoms among others who choose to be vaccinated, it is important to note that vaccine recommendation by a health care provider is extremely influential in overcoming such negative attitudes [9,10].
CONCLUSION Although the overall frequency of symptoms in both groups was low, the absolute risk of a flu-like illness in ambulatory adults attending a walk-in clinic was 5.5% higher during the first week following influenza vaccination when compared with the third week after the injection. These symptoms did not result in a decreased ability to perform usual daily activities and were of short duration. This information may help to reduce concerns that health professionals and vaccine recipients have about side effects of influenza vaccination.
ACKNOWLEDGMENT We would like to thank Stephen Margolis, Ph.D., for his assistance with the data analysis.
January 1990 The American Journal of Medicine Volume 88
29
REACTIONS TO INFLUENZA VACCINE / MARGOLISET AL
REFERENCES 1. Recommendationsof the Immunization Practices Advisory Committee (ACIP): Prevention and control of influenza. MMWR1988; 37: 361-364, 369-373. 2. Barker WH, MulloolyJP: Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980; 112: 798-811. 3. Centers for DiseaseControl: United States Immunization Survey, ]97]-1978. Government Printing Office, 1978. 4. Fedson DS: Influenza prevention and control: past practices and future prospects. Am J Med 1987; 82 (suppl 6A): 42~47. 5. Centers for Disease Control: Influenza vaccination levels in selected states-Behavioral Risk Factor Surveillance System, 1987. MMWR 1989; 38: 124, 129133. 6. ErakerSA, Kirscht JP, Becker MH: Understandingand improving patient compliance. Ann Intern Med 1984; 100: 258-268. 7. Carter W8, Beach LR, lnui TS, Kirscht JP, ProdzinskiJC: Developingand testing a decision model for predicting influenzavaccination compliance. Health Serv Res ]986; 20: 897-932. 8. Nicholson KG, Wiselka MJ, May A: Influenzavaccination in the elderly: perceptions and policies of general practitioners and outcome of the 1985-86 immunization programme in Trent, UK. Vaccine ]987; 5: 302-306. 9. Buchner DM, Carter WB, Inui TS: The relationshipof attitude changesto compliance with influenza vaccination. Med Care ]985; 23: 771-779. 10. Centers for Disease Control: Adult immunization: knowledge, attitudes and practices--DeKalb and Fulton Counties, Georgia, 1988. MMWR 1988; 37: 657664.
30
January1990 The American Journal of Medicine Volume88
11. Ruben FL, Jackson GG: A new subunit influenza vaccine: accel~tability comparedwith standard vaccinesand effect of dose on antigenicity. J Infect Dis i§72; 125: 656-664. 12: Mostow SR, Schoenbaum SC, Dowdle WR: Studies with inactiva:ted influenza vaccine purified by zonal centrifugation. I. Adverse reactions and serok~gical responses. Bull WHO 1969; 41: 525-53& 13. Parkman PD, Galasso GJ, Top FH, Noble GR: Summary of clinical trials of influenza vaccines. J Infect Dis 1976; 134: 100-107. 14. LaMontagne JR, Noble GR, Quinnan GV, et al: Summary Of clinical trials of inactivated influenza vaecine--1978, Rev Infect Dis 1983; 5: 723736. 15. Campbell BG, Edwards RL: Safety of influenza vaccinations in adults with asthma,. Med J Aust 1984; 140: 773-775. 16. Kava T, Laitinen LA: Effects of killed and live attenuated influenza vaccine on symptoms and specific airway conductance in asthmatic and healthy subjects. Allergy 1985; 40: 42-47. 17. Stenius-Aarniala B, Huttunen JK, Pyhala R, et al: Lack of exacerbations in adults with chronic asthma after immunization with killed influenza virus. Chest 1986; 89: 786-789. 18. Albazzaz MK, Harvey JE, Grilli EA, Caul EO, Roome AP: Subunit influenza vaccine in adults with asthma: effect on clinical state, airway reactivity, and antibody response. Br Med J 1987; 294: 1196-1197. 19. Minnesota Department of Health Disease Control Newsletter 1988; 14: 5-6. 20. Fedson DS: Influenza: the continuing need and justification for immunization. Primary Care 1977; 4: 761-779.
J
Frequency of Adverse Reactions after Influenza Vaccination KARENL. MARGOLIS,M.D.Minneapolis, MinnesotaGREGORYA. POLAND,M.D.Rochester, Minnesota KRISTIN L. NICHOL,M.D.,M.P.H., DAVIDS. MACPHERSON,M.D.,JEFFREYD. MEYER,M.D.Minneapolis, Minnesota JANEE. KORN,M.D.,M.P.H.Worcester, Massachusetts RICHARDP. LOFGREN,M.D., M.P.H. Minneapolis, Minnesota
PURPOSE: A l t h o u g h c o n c e r n about side effects constitutes a major deterrent to patient compliance with recommendations for influenza vaccination, there is a paucity of data about the frequency of adverse reactions to n e w e r trivalent vaccines. Our aim w a s to determine the frequency of adverse reactions to influenT~ vaccine in older, chronically ill persons, m a n y of w h o m are at high risk for influenza-related morbidity. PATIENTS AND METHODS: We conducted a telephone survey of 40% of the patients w h o w e r e vaccinated at a walk-in flu shot clinic. The subjects w e r e randomly assigned to two groups. To determine postvaccine symptom rates, Group I w a s interviewed seven days after vaccination. Group II w a s interviewed 21 days after vaccination in order to control for baseline symptom rates. Both groups w e r e queried about fever, disability, and flu-like illness in the w e e k preceding the interview. RESULTS: Of 816 patients selected, 650 (79.6%) completed the interview. The m e a n age of the subjects w a s 63, and more than two thirds w e r e at risk for influenza-related morbidity. The frequencies of self-reported fever (5.3% versus 5.1%, p = 0.91) and disability (10.4% versus 9.3%, p = 0.65) w e r e similar in the t w o groups. However, a significantly higher proportion of Group I subjects reported a flu-like illness compared to the Group II subjects (14.2% versus 8.7%, p = 0.03). Although Group I subjects w e r e more likely to report flu-like illness within t w o days of vaccination compared to a similar time interval for Group II subjects, there w a s no corresponding clustering of disability after vaccination. CONCLUSION: We conclude that the overall frequency of symptoms in both groups w a s low; however, the absolute risk of a flu-like illness w a s 5.5 % higher during the first w e e k following influenza vaccination w h e n compared with the third w e e k after the injection. These symptoms did not result in a decreased ability to perform usual daily activities.
From the Department of Medicine, Section of General Medicine (KLN, DSM, RPL), Minneapolis Veterans Administration Medical Center and the University of Minnesota, Minneapolis, Minnesota, the Department of Medicine (KLM) and Department of Emergency Medicine (JDM), Hennepin County Medical Center, Minneapolis, Minnesota, Mayo Clinic (GAP), Rochester, Minnesota, and the Department of Medicine (JEK), University of Massachusetts Medical Center, Worchester, Massachusetts. This work was presented in part at the 11th Annual Meeting of the Society of General Internal Medicine, Arlington, Virginia, April 26, ]988, and was published in abstract form (Clin Res 1988; 36: 745A). Requests for reprints should be addressed to Karen L. Margolis, M.D., Department of Medicine, Hennepin County Medical Center, 70] Park Avenue, Minneapolis, Minnesota 55415. Manuscript submitted May 1, ]989, and accepted in revised form September 7, 1989.
is a serious illness that causes substantial morbidity and mortality, particularly in the elderly Iandnfluenza chronically ill [1,2]. Despite strong recommendations by the United States Public Health Service and others, fewer than one third of those at high risk are vaccinated in any given year in the United States [35]. Concern about adverse consequences of treatment is often cited as a cause of patient noncompliance with medical recommendations [6]. It is therefore not surprising that studies in the elderly have shown that fear of side effects is a major deterrent to influenza vaccination [7-10]. Until the late 1960s, local and systemic adverse reactions to influenza vaccines were common and at times severe [11]. With the introduction of new purification techniques, a considerable reduction in the frequency and severity of reactions was noted [11,12]. In large-scale clinical trials of purified influenza vaccines conducted in 1976 [13] and 1978 [14], the rates of systemic reaction were low, perhaps not exceeding that found in placebo recipients. Most of the subjects in these studies, however, were young, healthy volunteers. Only a small percentage were elderly or chronically ill. An important question, then, remains unanswered: what is the frequency of adverse reactions to influenza vaccine in older, chronically ill persons at highest risk for influenza-related morbidity? To answer this question, we surveyed vaccine recipients who attended a walk-in flu shot clinic. PATIENTS AND METHODS
The Minneapolis Veterans Affairs Medical Center is a University of Minnesota-affiliated teaching hospital that provides care to more than 31,000 outpatients. As part of an institution-wide influenza vaccination program conducted during the fall of 1987, a walk-in flu shot clinic was held for two weeks in November. An October mailing to all outpatients included information about influenza, risk factors for complications, and the dates, time, and location of the walk-in clinic. More than 2,200 patients received a 0.5-mL deltoid intramuscular injection of split-antigen (subvirion) trivalent influenza vaccine (A/Taiwan/1/86 [H1N1], A/Leningrad/360/86 [H3N2], and B/Ann Arbor/i/86) at the clinic. From walk-in clinic records, 816 subjects were selected according to the terminal digit of their social security number and were randomly assigned to two groups. Group I was interviewed seven days after vaccination and Group II was interviewed 21 days after vaccination. It was assumed that any vaccine-related adverse effects would occur within the first seven days and would have subsided by the 14th day, and that the two sets of interviews would therefore measure postvaccine and background symptom rates, respectively. January 1990 The American Journal of Medicine Volume88
27
REACTIONSTO INFLUENZAVACCINE/ MARGOLISET AL TABLE I Reasons for Excluding Subjects from the Study
Number randomly assigned Number interviewed (%) Number excluded (%) No telephone Not reached Deafness Dementia Refused
GroupI
GroupII
422 338 (80.1) 84 (19.9) 19 57 2 4 2
394 312 (79.2) 82 (20.8) 31 49 0 0 2
TABLE II Characteristics of Study Subjects
Number of subjects Percent male Age (mean 4- SD) Percent over age 65 Percent with history of Heart disease Lung disease Diabetes Other serious illness Percent with any risk factor*
GroupI
GroupII
p Value
338 83.2 63.6 4- 10.4 45.8
312 81.7 63.0 4- 10.3 40.4
-0.68 0.46 O.18
19.9 8.9 12.5 18.8 69.1
21.5 9.2 12.3 20.2 66.9
0.70 0.97 0.97 0.71 0.61
* High-risk conditions predisposing to influenza morbidity include age greater than 65, cardiopulmonary disease, diabetes mellitus, and a number of other serious medical conditions [1]. TABLE III Symptoms Experienced during Previous Seven Days by Group I and Group II Subjects Groupl Number of subjects Number reporting fever (%) Number reporting any disability days (%) Number reporting flu-like illness (%) Days per flu-like illness (mean 4- SD) Number reporting arm soreness (%)
338
Groupll pValue
312
18(5.3) 16(5.1) 35(10.4) 29(9.3) 48 (14.2) 27 (8.7) 2.7=1=2.1 3.64-2.7 66 (19.5) --
-0.91 0.65 0.03 0,09 --
Demographic information and self-reported data on risk factors for influenza morbidity were obtained from each subject at the time of vaccination. The validity of patient self-report of these risk factors has been established for this population (Nichol KL, unpublished observations). Data on symptoms were collected by trained interviewers using a closed-ended telephone questionnaire according to a specified protocol. Up to three attempts were made to contact each person, including one telephone call after 5 P.M. The subjects were not informed of the purpose of the interview. Both the Group I and Group II subjects were told that they would be asked three questions regarding their health in the previous week. First, they were asked whether they had had a fever. No documentation was required. Second, to identify any disability they had experienced, subjects were asked if they had stayed in bed longer than usual or had curtailed their usual activities because of illness. Third, they were asked whether they had had a "flu-like illness," defined for them as an illness characterized by "muscle 28
January1990 The American Journal of Medicine Volume88
aches, tiredness, and a general sick feeling." This definition was used both because of the common colloquial use of the term "flu" to describe a nonspecific viral syndrome and because these symptoms, along with the fever, are described as potential side effects of influenza vaccination [1]. If the subjects answered yes to any of the three questions, the onset and duration of the symptoms were determined. In addition, those who answered yes to the flu-like illness question were asked in lay terms whether the episode had included myalgias, fatigue, malaise, headache, coryza, cough, anorexia, diarrhea, or constipation. At the end of the interview, the Group I subjects were reminded of their vaccination and were asked whether they had experienced arm soreness or disability resulting from the injection. The two-tailed Student's t-test was used to assess the significance of differences in continuous variables between the two groups. Categorical data were analyzed using the chi-square test. Subjects who were not reached or who could not be interviewed were excluded from the analysis. RESULTS
Of 816 persons selected for the study, 422 were randomly assigned to Group I and 394 to Group II. Interviews were completed for 80% of Group I and 79% of Group II subjects (p = 0.75). The reasons for excluding potential subjects are shown in T a b l e I. Subject characteristics are given in T a b l e II. Most of the study subjects were older men who reported at least one risk factor for influenza complications. The two groups were similar with respect to mean age, sex, proportion over age 65, and reported risk factors for influenza morbidity. Interview results are given in T a b l e III. No significant differences were found between Group I and Group II in the proportion of subjects reporting fever or disability. However, a significantly higher proportion of Group I subjects reported a flu-like illness (14.2% versus 8.7%, p = 0.03). Flu-like illness in Group I subjects tended to be of shorter duration (2.7 versus 3.6 days, p = 0.09) and more often occurred in the first two days of the interview week (Figure 1; 31% versus 17%, p = 0.02). There was no corresponding difference between the two groups with respect to the timing of any disability (Figure 1; 22% versus 19%, p = 0.58). Specific flu-like symptoms experienced by the subjects did not differ significantly between the two groups (chi-square for heterogeneity = 2.32, p = 0.97). Myalgias, fatigue, or malaise, or any combination of the three were the most common symptoms, and were present in 50% to 80% of the subjects who reported a flu-like illness. Headache, coryza, or cough were present in 40% to 50% of the flu-like illness episodes. Gastrointestinal complaints such as anorexia, diarrhea, or constipation were present in only 10% to 40~ of the episodes. Arm soreness at the injection site lasting for more than one hour was reported by 66 (19.5%) of Group ] subjects (Table III). Ten of these subjects reduced their use of the arm for one or more days. COMMENTS
This study documents that ambulatory adults whc are given influenza vaccine report an increased frequency of flu-like illness in the week after vaccination~
REACTIONS TO INFLUENZA VACCINE / MARGOLIS ET AL 140' 120' 100'
Figure 1. Timing of flu-like illness and
disability days. The total number of days of flu-like illness and disability reported by Group I and Group 41 subjects is shown. The shaded area within each bar represents the number of "flu" days and disability days that occurred in the first two days of the interview week. The proportion of total "flu" days and disability days that occurred in the first two days is noted within each column (e.g., 40 of 128 total "flu" days occurred in the first two days of the interview week for Group I subjects, 40 of 128 = 31%).
i
I
80,
[ ] Total for Interview Week
I
60 Z
•
Total for lstTwo Days of Interview Week
40, 17%
I
22%
m Group I
Group II
"Flu" days
when compared with the one-week period beginning 14 days after vaccination. They do not, however, report any increase in fever or disability. Large clinical trials of purified influenza vaccine, performed in 1976 in response to the threat of a "swine flu" pandemic, found that most of the vaccines tested were "difficult to distinguish from a saline placebo when fever or other systemic symptoms were scored" [13]. Roughly 40% of the placebo recipients experienced some systemic symptoms, compared with 30% to 60% of those who received various vaccines. In 1978, a second group of trials using vaccines of more uniform potency again demonstrated no significant difference in the rate and severity of systemic reaction between subjects who received vaccine and those who received placebo [14]. The pooled rate of systemic reaction was 33% in the vaccinees, versus 25% for placebo recipients (p = 0.07). However, the usefulness of these studies to clinicians is limited, since only about 10% of the subjects were elderly or chronically ill. In addition, the subjects were divided into many different vaccine testing groups, and consequently the studies lacked sufficient power to distinguish small but potentially clinically important differences in reactogenicity between vaccine and placebo. Since 1978, several trials have established the safety of administering influenza vaccine to asthmatic persons [15-18], but the ambulatory elderly population has been inadequately studied. The present study addresses some of the weaknesses of earlier studies. The subjects were representative of vaccine recipients in a community setting, with more than two thirds falling into high-risk groups. Furthermore, the sample size was adequate to have an 80% probability of detecting a 6% increase above the background rate of flu-like illness. Given the nonconcurrent comparison group design of this study, several potential biases deserve comment. First, vaccine side effects could have persisted to the third week, resulting in a false elevation of the background rate. However, this would only diminish the magnitude of any differences observed. Second, although there were no documented cases of influenza in Minnesota until well after our data were collected [19], other viral illness could have been active during the data-collection period for Group I. However, this would not explain the clustering of flu-like illness that was observed within two days of vaccination. Third,
Group [
Group II
Disability days
our results could have been biased if persons in Group I who experienced side effects were selectively not reached because they had been hospitalized. A computerized search of the hospital's database for excluded subjects revealed four admissions in Group I and five in Group II during the two interview periods; none of these admissions, however, was related to illness that could be attributed to vaccination. Finally, we were unable to distinguish whether the increased reporting of flu-like illness was secondary to true vaccine-mediated adverse reactions or simply to heightened somatic awareness following vaccination. It is a common lay belief that a person can actually "get the flu from a flu shot" [7]. The public's wary attitude toward influenza vaccine probably arose because of the reactogenicity of early vaccines, but after two decades, current purified vaccines are still regarded with suspicion. At the height of the 1976 "swine flu" vaccination program, even before the reports of the occurrence of Guillain-Barr~ syndrome, 34% of those polled stated that they were afraid of the vaccine [20]. Subsequent vaccines have not been associated with neurologic sequelae [1]; however, studies in Seattle veterans have shown that concern about this and other side effects remains high [10]. Although this fear of side effects deters many from vaccination and may lead to heightened awareness of symptoms among others who choose to be vaccinated, it is important to note that vaccine recommendation by a health care provider is extremely influential in overcoming such negative attitudes [9,10].
CONCLUSION Although the overall frequency of symptoms in both groups was low, the absolute risk of a flu-like illness in ambulatory adults attending a walk-in clinic was 5.5% higher during the first week following influenza vaccination when compared with the third week after the injection. These symptoms did not result in a decreased ability to perform usual daily activities and were of short duration. This information may help to reduce concerns that health professionals and vaccine recipients have about side effects of influenza vaccination.
ACKNOWLEDGMENT We would like to thank Stephen Margolis, Ph.D., for his assistance with the data analysis.
January 1990 The American Journal of Medicine Volume 88
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REACTIONS TO INFLUENZA VACCINE / MARGOLISET AL
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11. Ruben FL, Jackson GG: A new subunit influenza vaccine: accel~tability comparedwith standard vaccinesand effect of dose on antigenicity. J Infect Dis i§72; 125: 656-664. 12: Mostow SR, Schoenbaum SC, Dowdle WR: Studies with inactiva:ted influenza vaccine purified by zonal centrifugation. I. Adverse reactions and serok~gical responses. Bull WHO 1969; 41: 525-53& 13. Parkman PD, Galasso GJ, Top FH, Noble GR: Summary of clinical trials of influenza vaccines. J Infect Dis 1976; 134: 100-107. 14. LaMontagne JR, Noble GR, Quinnan GV, et al: Summary Of clinical trials of inactivated influenza vaecine--1978, Rev Infect Dis 1983; 5: 723736. 15. Campbell BG, Edwards RL: Safety of influenza vaccinations in adults with asthma,. Med J Aust 1984; 140: 773-775. 16. Kava T, Laitinen LA: Effects of killed and live attenuated influenza vaccine on symptoms and specific airway conductance in asthmatic and healthy subjects. Allergy 1985; 40: 42-47. 17. Stenius-Aarniala B, Huttunen JK, Pyhala R, et al: Lack of exacerbations in adults with chronic asthma after immunization with killed influenza virus. Chest 1986; 89: 786-789. 18. Albazzaz MK, Harvey JE, Grilli EA, Caul EO, Roome AP: Subunit influenza vaccine in adults with asthma: effect on clinical state, airway reactivity, and antibody response. Br Med J 1987; 294: 1196-1197. 19. Minnesota Department of Health Disease Control Newsletter 1988; 14: 5-6. 20. Fedson DS: Influenza: the continuing need and justification for immunization. Primary Care 1977; 4: 761-779.
