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Previous Volume 345:1529-1536 November 22, 2001 Number 21 Next

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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.

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.^{19,22,23,24,25,26,27} 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 1). 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.

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of the Patients.

 
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 2). 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 1A), 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).

View this table: [in this window] [in a new window]   Table 2. Frequency of Exacerbations of Asthma within 3 and 14 Days after Vaccine and Placebo Injections.

 

View larger version (16K): [in this window] [in a new window]   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. The peak flow rate was measured each morning at least six hours after any inhalation of rescue medication. Of the 2032 randomized patients, only those who received, in random order, both injections (vaccine and matching placebo) and who had complete data on the mean daily peak expiratory flow rate (1756 patients) and the use of rescue medication (1858 patients) in the 14 days after each injection were included. There was no significant difference after vaccine injection and placebo injection in the mean daily peak expiratory flow rates (P=0.92) or in the percentage of patients who were using rescue medication (P=0.20 by conditional logistic regression for the vaccine–placebo paired response).33

 
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 3). 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.

View this table: [in this window] [in a new window]   Table 3. Variations in the Frequency of Exacerbations of Asthma during the 14 Days after Vaccine and Placebo Injections in Various 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 4). 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).

View this table: [in this window] [in a new window]   Table 4. Frequency of Secondary Outcomes during the 14 Days after Vaccine and Placebo Injections.

 
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 -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 members of the research group are listed in the Appendix.

Source Information

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.

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{at}im.wustl.edu.

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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.

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