Original Article
The Safety of Inactivated Influenza Vaccine in Adults and Children with Asthma
N Engl J Med 2001; 345:1529-1536November 22, 2001
- Abstract
Background
Influenza causes substantial morbidity in adults and children with asthma, and vaccination can prevent influenza and its complications. However, there is concern that vaccination may cause exacerbations of asthma.
Methods
To investigate the safety of the inactivated trivalent split-virus influenza vaccine in adults and children with asthma, we conducted a multicenter, randomized, double-blind, placebo-controlled, crossover trial in 2032 patients with asthma (age range, 3 to 64 years). The order of injection of vaccine and placebo was assigned randomly, with a mean of 22 days between the injections. Each day during the two weeks after each injection, the patients recorded peak expiratory flow rates, symptoms thought to be related to the injection, use of asthma medications, unscheduled health care visits for asthma, and asthma-related absences from school or work. The primary outcome measure was an exacerbation of asthma in the two weeks after the injections.
Results
The frequency of exacerbations of asthma was similar in the two weeks after the influenza vaccination and after placebo injection (28.8 percent and 27.7 percent, respectively; absolute difference, 1.1 percent; 95 percent confidence interval, –1.4 percent to 3.6 percent). The exacerbation rates were similar in subgroups defined according to age, severity of asthma, and other factors. Among symptoms thought to be associated with the injection, only body aches were more frequent after the vaccine injection than after placebo injection (25.1 percent vs. 20.8 percent, P<0.001).
Conclusions
The inactivated influenza vaccine is safe to administer to adults and children with asthma, including those with severe asthma. Given the morbidity of influenza, all those with asthma should receive the vaccine annually.
Media in This Article
Figure 1
Daily Mean Peak Expiratory Flow Rates (Panel A) and Percentage of Patients Who Used Rescue Medication to Control Asthma (Panel B) during the Two Weeks after Vaccine and Placebo Injections.Table 1
Base-Line Characteristics of the Patients.Article Activity
- Article
Outbreaks of influenza are associated with substantial adverse effects, including time lost from work or school, pneumonia, and hospitalization, especially among people who have chronic diseases such as asthma.1-4 Infection with influenzavirus makes people with asthma more susceptible to bronchoconstriction, exacerbations of asthma, and even prolonged declines in lung function.5 Influenza is a common reason for hospitalization in children with asthma.3,6-8 Immunization is 70 to 90 percent effective in preventing influenza when the strains included in the vaccine match the strains in circulation.9-13 Some reports suggest that vaccination reduces morbidity in patients with asthma, and immunization is widely recommended for all such patients.13-17 However, reviews of the literature have found that there is inconclusive evidence of the safety of the influenza vaccine in patients with asthma.18-21
Currently, fewer than 10 percent of patients with asthma receive the influenza vaccine, as compared with 68 percent of the portion of the general population that is older than 65 years — another group for which annual immunization is recommended.7,17,22 Among the reasons given for the low rates of vaccination are an aversion to injections and fears that the vaccine is not safe.19,22-27 Because of these issues, the American Lung Association Asthma Clinical Research Centers conducted a randomized, controlled trial to evaluate the safety of the influenza vaccine in patients with asthma.
Methods
Participants
Between September 15 and November 30, 2000, a total of 2032 patients were recruited from 19 centers. Eligible patients ranged in age from 3 to 64 years, had physician-diagnosed asthma, had been taking prescribed treatment for asthma within the preceding 12 months, and had stable asthma. Stable asthma was defined by the absence of visits to the emergency department, hospitalization, increased doses of systemic corticosteroids, or urgent visits to a health care provider for asthma in the two weeks before enrollment. All patients or their parents gave written informed consent. Patients were excluded if they were allergic to egg products or thimerosal, were unable to use the peak flowmeter properly (if they were older than five years of age), did not have a telephone, had a history of the Guillain–Barré syndrome, had had an influenza vaccination within the preceding six months, had had a febrile illness (temperature, ≥38.0°C) within 24 hours before enrollment, or had any other condition that in the opinion of the investigator might put a patient at risk or interfere with his or her participation in the study.
Study Design and Treatment
The study design was a randomized, double-blind, crossover trial in which each eligible patient was assigned to receive an injection of influenza vaccine and an injection of placebo in random order (vaccine followed by placebo or placebo followed by vaccine), with four weeks between injections. Two syringes containing either heat-killed trivalent split-virus influenza type A and B vaccine (Fluzone, Aventis-Pasteur) or an identical-appearing placebo saline solution were packaged into consecutively numbered kits and labeled as either the first or second injection by a central pharmacy according to an assignment list prepared by the data-coordinating center. Randomization of the injection order was carried out with use of a permuted-block design with a block size of six; assignments were not stratified according to the enrolling center. The contents of the syringes were not divulged until the trial was completed.
Before randomization, all patients completed a questionnaire that included questions about demographic characteristics; smoking history; age at onset of asthma; hospitalizations; unscheduled health care visits for asthma or courses of oral corticosteroids during the preceding 12 months; current asthma medications; average daily use of albuterol for the relief of symptoms during the 2 weeks before randomization; current symptoms, as assessed by the Asthma Symptom Utility Index28; and history of influenza vaccination, including any adverse reactions. For 14 days after each injection, patients completed a diary recording peak expiratory flow rates in the morning with use of a peak flowmeter (Mini-Wright flowmeter, Ferraris Medical) at least six hours after any inhalation of bronchodilator rescue medication, asthma symptom score,29 use of asthma medications, use of corticosteroids, unscheduled contact with a health care provider (telephone calls or visits) for asthma, absences from school or work due to asthma, and symptoms thought to be associated with the vaccine or placebo injection (reactogenicity).
The Asthma Symptom Utility Index28 is derived from a 10-item questionnaire completed by the patient. Scores range from 0 to 1, with higher scores indicating fewer symptoms. The asthma symptom score is a four-level classification based on the frequency of episodes of asthma, limitations of activities, and interruptions in sleep. Scores range from 0 to 3, with higher scores indicating more symptoms.
The study was approved by the local institutional review boards at each clinical center and at the data-coordinating center. The study was also approved by an independent data and safety monitoring committee, which met once before the trial began, to approve the study protocol, and once during the trial, to review safety data.
Outcome Measures
The primary outcome measure was an exacerbation of asthma within 14 days after an injection, defined as the occurrence of one or more of the following: a decrease of at least 30 percent in the peak expiratory flow rate from the second-highest morning peak expiratory flow rate measured during the study (the “personal best” flow rate), an increase in the daily use of bronchodilator rescue medication (e.g., albuterol) above the average use reported in the two weeks before randomization (four or more puffs of a bronchodilator from a metered-dose inhaler or two or more uses of nebulized albuterol for the relief of symptoms), an increase in the use of systemic corticosteroids for asthma or the addition of systemic corticosteroids to the treatment regimen, or the unscheduled use of health care for the treatment of asthma, including a visit to the emergency department, hospitalization, or a visit or a telephone call to a health care provider.
Other outcome measures included a decrease of at least 20 percent in the peak expiratory flow rate from the personal-best rate during the 14 days after each injection, the average morning peak expiratory flow rate, symptoms thought to be associated with the vaccine or placebo injection (rhinitis, sore throat, cough, headache, body aches, fever, chills, and fatigue), the number of days without symptoms of asthma, the amount of time lost from work or school because of illness, and an increase in the dose of a current medication used for the long-term control of asthma or the addition of such a medication to the treatment regimen.
Statistical Analysis
The study was designed to include 2000 patients in order to provide the statistical power to reject at a level of 95 percent confidence the hypothesis that the rate of exacerbations of asthma in the three days after the injection of influenza vaccine was more than 6 percentage points higher than the rate after the placebo injection, with a one-sided type I error rate of 5 percent. A two-group test of the equivalence of binomial proportions was used,30 and the values were based on published rates of exacerbations of asthma in the three days after vaccine injection and placebo injection of 4.7 percent and 1.2 percent, respectively.2 The sample size was chosen to allow for the possibility of a carryover effect of vaccinations; if a carryover effect was detected, only the data obtained after the first injection would be used. In the absence of a carryover effect, the power of the study exceeded 99 percent. We reduced the possibility of a carryover effect of vaccination during the two-week follow-up measures by using a four-week period between the two injections.
Each outcome measure was analyzed according to the intention-to-treat principle, and the analyses included all patients who received both injections and for whom complete data on outcome measures were available for both follow-up periods. The range of equivalence of the rates of exacerbations of asthma after vaccine injection and after placebo injection was determined from the difference in the rates and in the associated 95 percent exact confidence intervals for the difference in paired binomial proportions.31,32 If the upper bound of the 95 percent confidence interval was less than the prespecified limit of 6 percentage points, the rates during the two periods were considered equivalent. The differences in the rates and 95 percent confidence intervals during the follow-up periods were examined in subgroups of patients defined according to demographic characteristics, the presence or absence of obesity, smoking status, number of symptoms of asthma, medication use, and lung function to determine whether the finding of equivalence was consistent among the subgroups. Conditional logistic-regression analysis was used to test for interactions, in order to determine whether the difference in rates between vaccine injection and placebo injection varied according to subgroups.33 Other asthma-related and vaccine-related measures during the 14-day period after each injection were analyzed with use of McNemar's test for paired binary categorical variables (with the chi-square statistic) and the Wilcoxon signed-rank test for continuous variables.31 Possible carryover effects of the order of the injections were also examined with the use of conditional logistic-regression models. All P values are two-sided. All data analyses were performed with SAS software, version 8.0.34
Results
Of the 2032 patients who were enrolled and assigned to receive vaccine and placebo injections, 2009 (98.9 percent) received both injections, 1952 (96.1 percent) received both injections and completed both 14-day post-injection diaries, and 1865 (91.8 percent) had peak expiratory flow rates measured during both periods (the daily measurement of peak expiratory flow rate was not required in patients who were three to five years old). The mean time between injections was 22 days. A broad cross section of adults and children with asthma was enrolled (Table 1Table 1
Base-Line Characteristics of the Patients.). There were more boys than girls and more women than men enrolled, as would be expected on the basis of the age and sex distribution of asthma in the United States.29,36 The scores on the Asthma Symptom Utility Index and the frequency of symptoms of asthma suggested that, at base line, most patients had mild-to-moderate persistent asthma; however, there was substantial variability.The overall rates of exacerbations of asthma during the 14 days after vaccine injection and the 14 days after placebo injection were equivalent (28.8 percent and 27.7 percent, respectively; absolute difference, 1.1 percent; 95 percent confidence interval, –1.4 percent to 3.6 percent) (Table 2Table 2
Frequency of Exacerbations of Asthma within 3 and 14 Days after Vaccine and Placebo Injections.). The most common types of exacerbation were an increase in the use of rescue medications and a decrease of 30 percent or more in the peak expiratory flow rate from the personal-best value. The daily mean peak expiratory flow rates were similar after vaccine injection and placebo injection (Figure 1AFigure 1Daily Mean Peak Expiratory Flow Rates (Panel A) and Percentage of Patients Who Used Rescue Medication to Control Asthma (Panel B) during the Two Weeks after Vaccine and Placebo Injections.), as were the percentages of patients who were using bronchodilator rescue medication to control their asthma (Figure 1B). When the frequency of exacerbations of asthma within three days after injection was assessed, the patterns were similar after vaccine and placebo injections (Table 2 and Figure 1).The frequency of exacerbations varied considerably among the subgroups that were categorized according to demographic characteristics, smoking status, asthma symptoms before enrollment, and lung function; however, none of the differences in values after vaccine and placebo injections were significant. All 95 percent confidence intervals were consistent with the conclusion that there was no difference in the rates after vaccine injection and placebo injection (Table 3Table 3
Variations in the Frequency of Exacerbations of Asthma during the 14 Days after Vaccine and Placebo Injections in Various Subgroups.). In a few cases the upper bound of the 95 percent confidence interval extended beyond the limit of equivalence of 6 percentage points owing to the small size of some subgroups.There was no significant difference between vaccine injection and placebo injection in other asthma-related outcomes, including the number of symptom-free days, daily symptom score, the percentage of patients with a decrease in the peak expiratory flow rate of at least 20 percent from personal-best values, the rate of new or increased use of medication for the long-term control of asthma, or the percentage of patients who missed one or more days of work or school (Table 4Table 4
Frequency of Secondary Outcomes during the 14 Days after Vaccine and Placebo Injections.). Patients reported body aches more frequently after vaccine injection than after placebo injection (25.1 percent vs. 20.8 percent, P<0.001), but the frequency of other symptoms thought to be associated with treatment was similar (Table 4).Discussion
The main finding of this controlled study is that influenza vaccination does not worsen asthma. This finding should be reassuring to patients and to their physicians, and it provides evidence that the current guidelines for the immunization of patients with asthma are safe.23 We could not identify any subgroup based on the severity of asthma or demographic characteristics in which influenza vaccine increased the rate of exacerbations of asthma over the rate associated with the placebo injection. As expected, there were slightly more symptoms, such as headache, body aches, and chills, in the first 72 hours after the administration of the vaccine than after the administration of placebo.
Our findings fail to confirm the results of an earlier double-blind, placebo-controlled, crossover trial of adults with asthma.21 The previous study was smaller (262 patients), had a shorter period of observation (72 hours), used two types of influenza vaccine (a trivalent split-virus preparation and a surface-antigen preparation), and reported only eight exacerbations of asthma. The length of observation in our study was 14 days, thereby enabling us to detect potentially delayed reactions to the vaccine. We also found no difference in the frequency of asthma symptoms in the first three days after vaccine injection and placebo injection.
Our finding of rates of exacerbations of asthma of 13.2 percent and 28.2 percent within 3 and 14 days after injection, respectively, was higher than expected on the basis of the findings of Nicholson et al.21 The higher rates in our study can be explained by the broader criteria we used. The frequency of exacerbations in our study is consistent with the results of a survey of the general population of patients with asthma in the United States.16,38 In that survey, 41 percent of respondents reported symptoms of asthma frequent enough for them to be classified as having moderate or severe persistent asthma.16,38 This high rate of spontaneous exacerbations, as well as the high rate of symptoms in our study even after placebo injection, may contribute to the oft-held belief that immunization induces symptoms.
A recent retrospective cohort study from the Centers for Disease Control and Prevention evaluated the frequency of exacerbations of asthma in children after influenza vaccination at four large health maintenance organizations.39 The results conflicted, depending on the method used to adjust for the severity of asthma. In a traditional cohort–control analysis, controlling for the use of β-agonists and cromolyn, previous hospitalizations, and visits to the emergency department for asthma, the investigators found a substantially increased risk of an exacerbation of asthma after vaccination across three influenza seasons (adjusted relative risk, 1.4 to 2.2). However, when they compared data before and after vaccination in subjects with at least one exacerbation of asthma, they found a significant reduction in the risk of exacerbations (adjusted relative risk, 0.59 to 0.78). These conflicting results reflect the difficulty in accurately controlling for asthma severity with the use of retrospective measures, given the seasonal variation in the severity of asthma and the selection bias attributable to the selection of vaccine recipients in a nonrandomized study. We found that patients with more symptoms were more likely to have an exacerbation than those with fewer symptoms, but there were no differences in the frequency of exacerbations of asthma after vaccine injection and after placebo injection among patients with more severe asthma. Therefore, we conclude that inactivated influenza vaccine is safe in patients with more severe asthma.
Our study demonstrates the effectiveness of large, simple clinical trials that address an important public health issue. A recent systematic review of the literature evaluating the safety of influenza vaccination in patients with asthma was inconclusive.18 Unlike smaller studies, ours found no significant increase in the risk of an exacerbation of asthma after influenza vaccination in a diverse population of adults and children with asthma. One potential limitation of our study is that the majority of our patients were recruited from the clinic populations of pulmonary and allergy specialists in academic referral centers, so our study sample may represent patients with more severe asthma than in the general population. However, many of our patients had mild-to-moderate asthma, and we found no trends related to the severity of asthma; hence, our findings can be extrapolated to patients with less severe disease. Another potential limitation of our study is that it was conducted during only one influenza season, with just one preparation of vaccine. It is possible that other formulations of influenza vaccine might have different effects. We emphasize that our findings cannot be extrapolated to cold-attenuated live influenza vaccines that may become available in the future.40,41
In summary, we found that in a large, diverse group of adults and children with asthma, influenza vaccination is safe. Since fewer than 10 percent of patients with asthma are vaccinated against influenza, we encourage the promotion of programs that emphasize the importance of this vaccine in patients with asthma.19,27 Strategies such as patient-reminder systems, educational interventions, and reminders to health care providers can help increase compliance with current immunization recommendations.7 Given the substantial effects of influenza in patients with asthma, the efficacy of the inactivated vaccine, and the safety of the vaccine in these patients, health care providers should urge patients with asthma to be immunized and thus reduce the morbidity and mortality associated with influenza in this population.
Supported by grants from the American Lung Associations of Alabama, Central Florida, Colorado, Delaware, Eastern Missouri, Finger Lakes (New York), Georgia, Gulfcoast Florida, Hudson Valley (New York), Illinois, Indiana, Louisiana, Maine, Metropolitan Chicago, Michigan, Mid-Ohio, Minnesota, Nashua–Suffolk (New York), New Hampshire, New York City, North Carolina, Northeast Florida, Ohio, Oklahoma, Pennsylvania, South Florida, Southeast Florida, Texas, Vermont, Western Missouri, Wisconsin, Greater Norfolk County (Massachusetts), Hawaii, Middlesex County (Massachusetts), New York State, Northern Rockies, Queens (New York), Western Massachusetts, and Virginia; Baylor College of Medicine; the Thalheim Family; Duke University; the Ernest N. Morial Asthma, Allergy, and Respiratory Disease Center; the Merck Foundation; and Glaxo–SmithKline.
Drs. Fish and Wise have received honorariums or consulting fees from Aventis, the parent company of Aventis-Pasteur, the manufacturers of Fluzone, the influenza vaccine used in the study. Aventis-Pasteur did not provide any support for the study, and the influenza vaccine used in the study was purchased from Aventis-Pasteur by Asthma Clinical Research Centers.
The Writing Committee (Mario Castro, M.D., M.P.H., Allen Dozor, M.D., James Fish, M.D., Charles Irvin, Ph.D., Steven Scharf, M.D., Ph.D., Mary Ellen Scheipeter, R.N., B.S.N., Janet Holbrook, Ph.D., M.P.H., James Tonascia, Ph.D., and Robert Wise, M.D.) assumes responsibility for the overall content of the manuscript.
Source Information
Address reprint requests to Dr. Castro at Washington University School of Medicine, Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110-1093, or at mcastro@im.wustl.edu.
The members of the research group are listed in the Appendix.
Appendix
The following persons participated in the study: Baylor College of Medicine, Houston: N. Hanania (principal investigator), P. Enright (coprincipal investigator), M. Sockrider (coprincipal investigator), A. Delgado (principal clinic coordinator for adults), R. McConnell (principal clinic coordinator for children), M. Brock; Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla, N.Y.: A. Dozor (principal investigator), N. Amin (coprincipal investigator), M. Heydendael (principal clinic coordinator), J. Boyer, S. Gjonaj, D. Lowenthal, J. Thorpe (principal clinic nurse); Columbia University–New York University Consortium, New York: P. Rothman (principal investigator), J. Reibman (coprincipal investigator), K. Geromanos (principal clinic coordinator at Columbia University), W. Hoerning (principal clinic coordinator at New York University Consortium), R. Mellins (Columbia University), D. Valacer (Cornell University), G. Turino (Columbia University), C. Cassino (New York University and Columbia University), G. Skloot (Mt. Sinai Medical Center), E. Dimango (Columbia University); Duke University Medical Center, Durham, N.C.: L. Williams (principal investigator), J. Sundy (coprincipal investigator), M. Wilson (principal clinic coordinator); Emory University School of Medicine, Atlanta: G. Teague (principal investigator), E. Honig (coprincipal investigator), G. Washington (principal clinic coordinator); Illinois Consortium, Chicago: L. Smith (principal investigator), E. Naureckas (coprincipal investigator), B. Lenhard (principal clinic coordinator), K. Manteuffel, J. Moy, C.S. Olopade, L. Wilkens, S. Reynolds, G. Zagaja; Indiana University, Asthma Clinical Research Center, Indianapolis: W. Martin, II (principal investigator), J. Mastronarde (coprincipal investigator), K. Keller (principal clinic coordinator), J. McMahon, J. Valente; Jefferson Medical College, Philadelphia: J. Fish (principal investigator), S. Peters (coprincipal investigator), D. Lang (coinvestigator), C. Czajka (principal clinic coordinator), N. Axtman; Louisiana State University Health Sciences Center, Ernest N. Morial Asthma, Allergy, and Respiratory Disease Center, New Orleans: D. Thomas (principal investigator), J. Ali (coprincipal investigator), C. Glynn (principal clinic coordinator), E. Fox; National Jewish Medical and Research Center, Denver: S. Wenzel (principal investigator), P. Silkoff (coprincipal investigator), R. Gibbs (principal clinic coordinator), B. Schoen, C. Ruis, D. Wyatt; Nemours Children's Clinic–University of Florida Consortium, Jacksonville: J. Lima (principal investigator), K. Blake (coprincipal investigator), L. Duckworth and C. Moore (principal clinic coordinators), J. Cury, D. Schaeffer, F. Livingston; North Shore–Long Island Jewish Health System, New Hyde Park, N.Y.: S.M. Scharf (principal investigator), A. Fein (coprincipal investigator), P. Logalbo, L. Stepner (principal clinic coordinator), G. Malia (principal coordinator for children), D. Mayer, S. Markovics, A. Mensch; Northern New England Consortium (formerly Vermont Lung Center at the University of Vermont), Colchester, Vt.: C.G. Irvin (principal investigator), D.A. Kaminsky (coprincipal investigator), M. Lynn (principal clinic coordinator), L.A. Baggott, C.S. Bush, M. DiCello, A.E. Filderman, L.J. Filderman, R.K. Fischer, V. Gardiner, E.M. Harrow, M. Li, C. Mackillop, S.A. Mette, L.M.L. Moon, M.A. Poll, D. Schlichting, P.A. Shapero, K.D. Siegel, E. White-Montor; Ohio State University Children's Hospital, Columbus: K. McCoy (principal investigator), J. Jones (coprincipal investigator), M. Johnson (principal clinic coordinator), E. Allen, R. Shell; University of Alabama at Birmingham, Birmingham: W.C. Bailey (principal investigator), L.B. Gerald (coprincipal investigator), R. Lyrene (investigator), G.A. DuBois (investigator), L. Corley III (investigator), S. Erwin (principal clinic coordinator), B. Martin (clinic coordinator); University of Miami, Miami–University of South Florida, Tampa: A. Wanner (principal investigator), R. Lockey (principal investigator), A. Brown (principal clinic coordinator for University of Miami), M. Hernandez (principal clinic coordinator for University of South Florida), A. Diecidue, S. Mohapatra, G. Piedimonte; University of Minnesota, Minneapolis: M.N. Blumenthal (principal investigator), G. Berman (coprincipal investigator) at the Clinical Research Institute, G. Brottman (coprincipal investigator) at Hennepin County Medical Center, J. Parker (coprincipal investigator) at St. Mary's Duluth, R. Sveum (coprincipal investigator) at Park Nicollet Medical Center, S. Leikam (principal clinic coordinator) and C. Quintard (clinic coordinator) at the Clinical Research Institute, J. Bertrand (clinic coordinator) at Hennepin County Medical Center, J. Blankush (clinic coordinator) at St. Mary's Duluth, L. Rillo (clinic coordinator) at Park Nicollet Medical Center; University of Missouri, Kansas City School of Medicine, Kansas City: G. Salzman (principal investigator), D. Pyszczynski (coprincipal investigator), J. Portnoy (coprincipal investigator), P. Dowling (coprincipal investigator), S. Schmitz (clinical trial manager), R. Mangold (clinic coordinator), M. Ricklefs (clinic coordinator), D. Horner (clinic coordinator), S. Flack (clinic coordinator); St. Louis Asthma Clinical Research Center: Washington University, St. Louis University, and Clinical Research Center, St. Louis: M. Castro (principal investigator), M.E. Scheipeter (principal clinic coordinator), B. Becker, E. Fisher, P. Korenblat, R. Slavin, R. Strunk, J. Tillinghast, E. Albers, S. Crocker, S. DeMartino, M. Jenkerson, D. Keaney, L. Robertson, G. Sanders, L. Tegtmeier, D. Turnbow, M. White, and N. Zimmermann (clinic coordinators); Chair's Office, Respiratory Hospital, Winnipeg, Man., Canada: N. Anthonisen (study chair); Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore: R. Wise (center director), J. Holbrook (deputy director), C. Levine (principal coordinator), E. Brown, C. Dawson, M. Donithan, C. Meinert, D. Nowakowski, D. Shade, J. Tonascia, X. Wang; Data and Safety Monitoring Board: L. Hudson (chair), V. Chinchilli, P. Lanken, B. McWilliams, C. Rinaldo, D. Tashkin; Project Office, American Lung Association, New York: R. Vento (project officer), G. Pezza, N. Edelman (scientific consultant); Research Coordinating Committee: D. Schraufnagel (chair), M. Iannuzzi (vice-chair), W. Bailey, J. Brown, W.B. Davis, H. DeLisser, F. McCormack, D. Sheppard, A. Wanner, T. Weaver, N. Nedilsky.
- References
References
1
Barker WH . Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970-78. Am J Public Health 1986;76:761-765
CrossRef | Web of Science | Medline2
Sullivan KM ,Monto AS ,Longini IM Jr . Estimates of the US health impact of influenza. Am J Public Health 1993;83:1712-1716
CrossRef | Web of Science | Medline3
Neuzil KM ,Mellen BG ,Wright PF ,Mitchel EF Jr ,Griffin MR . The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225-231
Full Text | Web of Science | Medline4
Izurieta HS ,Thompson WW ,Kramarz P , et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342:232-239
Full Text | Web of Science | Medline5
Kondo S ,Abe K . The effects of influenza virus infection on FEV1 in asthmatic children: the time-course study. Chest 1991;100:1235-1238
CrossRef | Web of Science | Medline6
Glezen WP ,Greenberg SB ,Atmar RL ,Piedra PA ,Couch RB . Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000;283:499-505
CrossRef | Web of Science | Medline7
Neuzil KM . Influenza vaccine in children with asthma: why no progress? J Pediatr 2000;138:301-303
Web of Science8
Neuzil KM ,Wright P ,Mitchel E ,Griffin M . The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000;137:856-864
CrossRef | Web of Science | Medline9
Bridges C ,Thompson W ,Meltzer M , et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 2000;284:1655-1663
CrossRef | Web of Science | Medline10
Edwards KM ,Dupont WD ,Westrich MK ,Plummer WD Jr ,Palmer PS ,Wright PF . A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 1994;169:68-76
CrossRef | Web of Science | Medline11
Keitel WA ,Cate TR ,Couch RB . Efficacy of sequential annual vaccination with inactivated influenza virus vaccine. Am J Epidemiol 1988;127:353-364
Web of Science | Medline12
Nichol KL ,Lind A ,Margolis KL , et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med 1995;333:889-893
Full Text | Web of Science | Medline13
Sugaya N ,Nerome K ,Ishida M ,Matsumoto M ,Mitamura K ,Nirasawa M . Efficacy of inactivated influenza vaccine in preventing antigenically drifted influenza type A and well-matched type B. JAMA 1994;272:1122-1126
CrossRef | Web of Science | Medline14
Bell TD ,Chai H ,Berlow B ,Daniels G . Immunization with killed influenza virus in children with chronic asthma. Chest 1978;73:140-145
CrossRef | Web of Science | Medline15
Fairchok MP ,Trementozzi DP ,Carter PS ,Regnery HL ,Carter ER . Effect of prednisone on response to influenza virus vaccine in asthmatic children. Arch Pediatr Adolesc Med 1998;152:1191-1195
Web of Science | Medline16
National Asthma Education and Prevention Program. Expert Panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, Md.: National Heart, Lung, and Blood Institute, 1998. (NIH publication no. 98-4051.)
17
National Health Interview Survey: receiving influenza vaccine. Hyattsville, Md.: National Center for Health Statistics, 2000:22-4. (Accessed October 17, 2001, at www.cdc.gov./nchs/about/major/nhis/nhis2.htm.)
18
Cates C, Jefferson T, Bara A. Influenza vaccination in asthma: efficacy and side-effects (Cochrane review): the Cochrane Library. Oxford, England: Update Software, 1999 (Accessed October 17, 2001, at www.update-software.com/cochrane.)
19
Kramarz P ,DeStefano F ,Gargiullo PM , et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Arch Fam Med 2000;9:617-623
CrossRef | Medline20
Stenius-Aarniala B ,Huttunen JK ,Pyhala R , et al. Lack of clinical exacerbations in adults with chronic asthma after immunization with killed influenza virus. Chest 1986;89:786-789
CrossRef | Web of Science | Medline21
Nicholson KG ,Nguyen-Van-Tam JS ,Ahmed AH , et al. Randomised, placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma. Lancet 1998;351:326-331
CrossRef | Web of Science | Medline22
Szilagyi PG ,Rodewald LE ,Savageau J ,Yoos L ,Doane C . Improving influenza vaccination rates in children with asthma: a test of a computerized reminder system and an analysis of factors predicting vaccination compliance. Pediatrics 1992;90:871-875
Web of Science | Medline23
Fox J . Education seen as key in bringing vaccines to adults. ASM News 1996;63:29-3324
Innes A ,Beresford E ,Bedford J . Influenza vaccination in asthma: a primary care experience. Br J Gen Pract 2000;50:27-30
Web of Science | Medline25
Park CL ,Frank AL ,Sullivan M ,Jindal P ,Baxter BD . Influenza vaccination of children during acute asthma exacerbation and concurrent prednisone therapy. Pediatrics 1996;98:196-200
Web of Science | Medline26
Watson JM ,Cordier JF ,Nicholson KG . Does influenza immunisation cause exacerbations of chronic airflow obstruction or asthma? Thorax 1997;52:190-194
CrossRef | Web of Science | Medline27
Williams WW ,Hickson MA ,Kane MA ,Kendal AP ,Spika JS ,Hinman AR . Immunization policies and vaccine coverage among adults: the risk for missed opportunities. Ann Intern Med 1988;108:616-625[Erratum, Ann Intern Med 1988;109:348.]
Web of Science | Medline28
Revicki DA ,Leidy NK ,Brennan-Diemer F ,Sorensen S ,Togias A . Integrating patient preferences into health outcomes assessment: the multiattribute Asthma Symptom Utility Index. Chest 1998;114:998-1007
CrossRef | Web of Science | Medline29
The Childhood Asthma Management Program Research Group
Full Text | Web of Science | Medline30
Elashoff J. NQuery advisor user's guide. Cork, Ireland: Statistical Solutions, 2000.
31
Armitage P, Berry G. Statistical methods in medical research. 2nd ed. London: Blackwell Scientific, 1987.
32
Gardner M, Altman D. Statistics with confidence — confidence intervals and statistical guidelines. London: British Medical Journal, 1989.
33
Hosmer DW Jr, Lemeshow S. Applied logistic regression. 2nd ed. New York: John Wiley, 2000.
34
SAS/STAT user's guide. Cary, N.C.: SAS Institute, 1999.
35
Hankinson JL ,Odencrantz JR ,Fedan KB . Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159:179-187
Web of Science | Medline36
Surveillance for asthma -- United States, 1960-1995. Mor Mortal Wkly Rep CDC Surveill Summ 1998;47:1-27
Medline37
Rosner B ,Prineas R ,Loggie J ,Daniels SR . Percentiles for body mass index in U.S. children 5 to 17 years of age. J Pediatr 1998;132:211-222
CrossRef | Web of Science | Medline38
Asthma in America: executive summary. Research Triangle Park, N.C.: Glaxo Wellcome, 1998.
39
Kramarz P ,Destefano F ,Gargiullo PM , et al. Does influenza vaccination prevent asthma exacerbations in children? J Pediatr 2001;138:306-310
CrossRef | Web of Science | Medline40
Nichol KL ,Mendelman PM ,Mallon KP , et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 1999;282:137-144
CrossRef | Web of Science | Medline41
Belshe RB ,Mendelman PM ,Treanor J , et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 1998;338:1405-1412
Full Text | Web of Science | Medline
- Citing Articles (56)
Citing Articles
1
Rodolfo M. Pascual, Stephen P. Peters. (2011) Asthma. Medical Clinics of North America 95:6, 1115-1124
CrossRef2
Susanna Esposito, Nicola Principi. (2011) Different influenza vaccine formulations and adjuvants for childhood influenza vaccination. Vaccine 29:43, 7535-7541
CrossRef3
Tsutomu Iwata. (2011) Health assurance in school, matter of care in vaccinations and surgical operation for asthmatic children. Nihon Shoni Arerugi Gakkaishi. The Japanese Journal of Pediatric Allergy and Clinical Immunology 25:2, 184-190
CrossRef4
R. Pesek, R. Lockey. (2011) Vaccination of adults with asthma and COPD. Allergy 66:1, 25-31
CrossRef5
P. Loulergue, P.R. Burgel, F. Carrat, B. Fritzell, J.P. Guthmann, C. Locht, U.F. Power, E. Varon, D. Dusser, O. Launay. (2010) Report of the 2nd “French Clinical Vaccinology Meeting Jean-Gerard Guillet”: Immunization and respiratory diseases. Vaccine 28:40, 6551-6555
CrossRef6
Emmanuel B. Walter, Shilpa Rajagopal, Yuwei Zhu, Kathleen M. Neuzil, Mary P. Fairchok, Janet A. Englund. (2010) Trivalent inactivated influenza vaccine (TIV) immunogenicity in children 6 through 23 months of age: Do children of all ages respond equally?. Vaccine 28:27, 4376-4383
CrossRef7
R. Jiménez-García, V. Hernández-Barrera, P. Carrasco-Garrido, A. Lopez Andrés, J. Miguel Diez, Á. Gil Miguel. (2010) Coverage and Predictors of Adherence to Influenza Vaccination among Spanish Children and Adults with Asthma. Infection 38:1, 52-57
CrossRef8
Emmanuel B. Walter, Janet A. Englund, Mark Blatter, Jack Nyberg, Frederick L. Ruben, Michael D. Decker. (2009) Trivalent Inactivated Influenza Virus Vaccine Given to Two-Month-Old Children. The Pediatric Infectious Disease Journal 28:12, 1099-1104
CrossRef9
Peng-jun Lu, Gary L. Euler, David B. Callahan. (2009) Influenza Vaccination Among Adults with Asthma. American Journal of Preventive Medicine 37:2, 109-115
CrossRef10
Melissa Rosenberg, Robert Sparks, Ann McMahon, John Iskander, James D. Campbell, Kathryn M. Edwards. (2009) Serious adverse events rarely reported after trivalent inactivated influenza vaccine (TIV) in children 6–23 months of age. Vaccine 27:32, 4278-4283
CrossRef11
Alvaro Pedroza, José G. Huerta, Maria de la Luz Garcia, Arsheli Rojas, Irma López-Martínez, Martín Penagos, Carlos Franco-Paredes, Christele Deroche, Cesar Mascareñas. (2009) The safety and immunogenicity of influenza vaccine in children with asthma in Mexico. International Journal of Infectious Diseases 13:4, 469-475
CrossRef12
Fanta, Christopher H., . (2009) Asthma. New England Journal of Medicine 360:10, 1002-1014
Full Text13
Edward B. Mougey, Hua Feng, Mario Castro, Charles G. Irvin, John J. Lima. (2009) Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenetics and Genomics 19:2, 129-138
CrossRef14
Mark Anderson, Will Carroll. (2009) Virus vaccines and children with asthma. Current Opinion in Allergy and Clinical Immunology 9:1, 44-49
CrossRef15
Neil C. Thomson. 2009. Other Therapies. , 729-736.
CrossRef16
Menachem Rottem. (2008) Asthma prevalence and exacerbations in children: is there an association with childhood vaccination?. Expert Review of Clinical Immunology 4:6, 687-694
CrossRef17
Catherine WM Ong, Paul Ananth Tambyah. (2008) Update on antivirals and vaccines for seasonal and potential pandemic use. Expert Review of Respiratory Medicine 2:3, 391-402
CrossRef18
Manjusha J. Gaglani, Pedro A. Piedra, Mark Riggs, Gayla Herschler, Charles Fewlass, W Paul Glezen. (2008) Safety of the Intranasal, Trivalent, Live Attenuated Influenza Vaccine (LAIV) in Children With Intermittent Wheezing in an Open-Label Field Trial. The Pediatric Infectious Disease Journal 27:5, 444-452
CrossRef19
Christopher J Cates, Tom Jefferson, Brian H Rowe, Christopher J Cates. 2008. Vaccines for preventing influenza in people with asthma. .
CrossRef20
Sofia Kalaboka, Isabella Annesi-Maesano. (2007) The complex link between immunization against childhood diseases and allergy. Expert Review of Vaccines 6:4, 635-643
CrossRef21
The American Lung Association Asthma Clinical Research Centers. (2007) Randomized Comparison of Strategies for Reducing Treatment in Mild Persistent Asthma. New England Journal of Medicine 356:20, 2027-2039
Full Text22
Pedro Plans-Rubió. (2007) Prevention and control of influenza in persons with chronic obstructive pulmonary disease. International Journal of COPD 2:1, 41-53
CrossRef23
H Cody Meissner. (2007) Influenza vaccines: a pediatric perspective. Current Opinion in Pediatrics 19:1, 58-63
CrossRef24
Hee Jin Cheong. (2007) Safety of Influenza Vaccine. Journal of the Korean Medical Association 50:3, 267
CrossRef25
Maj Meredith L. Moore, Maj Amy L. Parker. (2006) Influenza Vaccine Compliance Among Pediatric Asthma Patients: What Is the Better Method of Notification?. Pediatric Asthma, Allergy & Immunology 19:4, 200-204
CrossRef26
Douglas M. Fleming, Pietro Crovari, Ulrich Wahn, Timo Klemola, Yechiel Schlesinger, Alexangros Langussis, Knut ??ymar, Maria Luz Garcia, Alain Krygier, Herculano Costa, Ulrich Heininger, Jean-Louis Pregaldien, Sheau-Mei Cheng, Jonathan Skinner, Ahmad Razmpour, Melanie Saville, William C. Gruber, Bruce Forrest. (2006) Comparison of the Efficacy and Safety of Live Attenuated Cold-Adapted Influenza Vaccine, Trivalent, With Trivalent Inactivated Influenza Virus Vaccine in Children and Adolescents With Asthma. The Pediatric Infectious Disease Journal 25:10, 860-869
CrossRef27
C M Machado. (2006) Reply to Ikegame et al.. Bone Marrow Transplantation 38:4, 324-325
CrossRef28
Nicola A Hanania, Robert L Atmar, Mario Castro. (2006) Influenza vaccine in patients with asthma. Expert Review of Vaccines 5:1, 111-118
CrossRef29
Susanna Esposito, Paola Marchisio, Samantha Bosis, Lara Lambertini, Laura Claut, Nadia Faelli, Ciro Bianchi, Giorgio L. Colombo, Nicola Principi. (2006) Clinical and economic impact of influenza vaccination on healthy children aged 2–5 years. Vaccine 24:5, 629-635
CrossRef30
H. J. Bueving. (2006) Is influenza vaccination in asthmatic children helpful?. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 36:1, 21-25
CrossRef31
Alan Johnson, Gregory Berg, Edward Fleegler, Marilyn Sauerbrun. (2005) A Matched-Cohort Study of Selected Clinical and Utilization Outcomes for an Asthma Care Support Program. Disease Management 8:3, 144-154
CrossRef32
Usha Sambamoorthi, Patricia A. Findley. (2005) Who are the elderly who never receive influenza immunization?. Preventive Medicine 40:4, 469-478
CrossRef33
Sebastian L. Johnston, Fernando Ferrero, Maria Luz Garcia, Regina Dutkowski. (2005) Oral Oseltamivir Improves Pulmonary Function and Reduces Exacerbation Frequency for Influenza-Infected Children With Asthma. The Pediatric Infectious Disease Journal 24:3, 225-232
CrossRef34
Ana L. MacDowell, Leonard B. Bacharier. (2005) Infectious triggers of asthma. Immunology and Allergy Clinics of North America 25:1, 45-66
CrossRef35
Herman J Bueving, Siep Thomas, Johannes C van der Wouden. (2005) Is influenza vaccination in asthma helpful?. Current Opinion in Allergy and Clinical Immunology 5:1, 65-70
CrossRef36
Shin Watanabe, Yoshiharu Hoshiyama, Satoshi Matsukura, Fumio Kokubu, Masatsugu Kurokawa, Hideki Kuga, Mio Kawaguchi, Yosuke Inoue, Koushi Ieki, Miho Odaka, Shintaro Suzuki, Mie Aoki, Tomoko Akabane, Hiroko Takeuchi, Mitsuru Adachi, Takeshi Kawaguchi. (2005) Prevention of Asthma Exacerbation with Vaccination against Influenza in Winter Season. Allergology International 54:2, 305-309
CrossRef37
Kristin L Nichol. (2005) Influenza Vaccination in the Elderly. Drugs & Aging 22:6, 495-515
CrossRef38
Danuta M. Skowronski, Gordean Bjornson, Entesar Husain, Daniel L. Metzger, David W. Scheifele. (2005) Oculorespiratory Syndrome After Influenza Immunization in Children. The Pediatric Infectious Disease Journal 24:1, 63-69
CrossRef39
John M. Wood, James S. Robertson. (2004) From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza. Nature Reviews Microbiology 2:10, 842-847
CrossRef40
Menachem Rottem, Yehuda Shoenfeld. (2004) Vaccination and allergy. Current Opinion in Otolaryngology & Head and Neck Surgery 12:3, 223-231
CrossRef41
KENNETH M. ZANGWILL, ROBERT B. BELSHE. (2004) Safety and efficacy of trivalent inactivated influenza vaccine in young children: a summary for the new era of routine vaccination. The Pediatric Infectious Disease Journal 23:3, 189-197
CrossRef42
Frederick L. Ruben. (2004) Inactivated Influenza Virus Vaccines in Children. Clinical Infectious Diseases 38:5, 678-688
CrossRef43
Karl G Nicholson, John M Wood, Maria Zambon. (2003) Influenza. The Lancet 362:9397, 1733-1745
CrossRef44
CJ Cates, TO Jefferson, AI Bara, BH Rowe, Christopher Cates. 2003. Vaccines for preventing influenza in people with asthma. .
CrossRef45
Kelly D. Stone. (2003) Atopic diseases of childhood. Current Opinion in Pediatrics 15:5, 495-511
CrossRef46
Danuta M. Skowronski, Barbara Strauss, Gaston De Serres, Diane MacDonald, Stephen A. Marion, Monika Naus, David M. Patrick, Perry Kendall. (2003) Oculo‐respiratory Syndrome: A New Influenza Vaccine–Associated Adverse Event?. Clinical Infectious Diseases 36:6, 705-713
CrossRef47
Christian Herzog, Ian C Metcalfe, Urs B Schaad. (2002) Virosome influenza vaccine in children. Vaccine 20, B24-B28
CrossRef48
AE Tattersfield, AJ Knox, JR Britton, IP Hall. (2002) Asthma. The Lancet 360:9342, 1313-1322
CrossRef49
Eelko Hak, James Nordin, Feifei Wei, John Mullooly, Sung Poblete, Raymond Strikas, Kristin L. Nichol. (2002) Influence of High‐Risk Medical Conditions on the Effectiveness of Influenza Vaccination among Elderly Members of 3 Large Managed‐Care Organizations. Clinical Infectious Diseases 35:4, 370-377
CrossRef50
Bryce Binstadt, Henry Bernstein. (2002) Current Opinion in Pediatrics 14:4, 498-507
CrossRef51
Paul L. Enright. (2002) The diagnosis and management of asthma is much tougher in older patients. Current Opinion in Allergy and Clinical Immunology 2:3, 175-181
CrossRef52
Stephen B. Greenberg. (2002) Respiratory viral infections in adults. Current Opinion in Pulmonary Medicine 8:3, 201-208
CrossRef53
(2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:3, 255-270
CrossRef54
Eelko Hak, Arno W. Hoes, Theo J.M. Verheij. (2002) Influenza Vaccinations. Drugs 62:17, 2413-2420
CrossRef55
&NA;. (2001) No worsening of asthma with influenza virus vaccine. Inpharma Weekly &NA;:1316, 21
CrossRef56
&NA;. (2001) No worsening of asthma with influenza virus vaccine. Reactions Weekly &NA;:880, 5
CrossRef
