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* From the Johns Hopkins University School of Medicine (Dr. Wise), Baltimore, MD; University of Utah School of Medicine (Dr. Kanner), Salt Lake City, UT; University of Minnesota School of Public Health (Ms. Lindgren and Dr. Connett), Minneapolis, MN; Case Western Reserve University (Dr. Altose), Cleveland, OH; University of Arizona (Dr. Enright), Tucson, AZ; and University of California at Los Angeles School of Medicine (Dr. Tashkin), Los Angeles, CA.
See Appendix for a list of participants in the LHS Research Group.
Correspondence to: Richard E. Kanner, MD, FCCP, University of Utah Health Sciences Center, 26 North 1900 East, Salt Lake City, UT 84132; e-mail: kanner{at}med.utah.edu
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Abstract |
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Methods and results: Of 5,887 participants, 4,201 underwent methacholine challenge testing both at study entry and study completion. All groups increased AR during the 5-year period. The increase in AR was greatest in continuing smokers and was associated with a greater FEV1 decline. An intent-to-treat analysis indicated no significant differences in AR changes among the three groups.
Conclusions: Changes in AR over a 5-year period in the LHS were primarily related to changes in the FEV1. The greater the decline in FEV1, the greater the increase in AR. Smoking cessation had a small additional benefit in AR beyond its favorable effects on FEV1 changes.
Key Words: airway hyperresponsiveness • airways reactivity • COPD • ipratropium • methacholine bronchoprovocation challenge • smoking cessation
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionSummary and ConclusionsAppendixReferences |
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Initially, 63% of men and 87% of women showed a 
20% fall in FEV1 with inhalation of 
25 mg/mL methacholine, indicating airway hyperresponsiveness (AHR). Forty-six percent of the men and 74% of women showed AHR at a methacholine concentration of 10 mg/mL.3
The significantly higher prevalence of AHR in women when compared to that of men could be accounted for almost entirely by adjusting for the initial FEV1.4
During 5 years of follow-up, persons with greater degrees of AR at study entry showed a greater longitudinal decline in FEV1.5
Only a few studies have reported longitudinal measures of AR in a large group of patients with COPD, and none have reported longitudinal changes in AR. Since the degree of AR is associated with the subsequent annual decline in FEV1, this is an important measurement in determining the prognosis of a patient with COPD. Since smoking status is associated with FEV1, it would be anticipated that this also might affect AR. The large LHS cohort that was closely observed for 5 years allowed us to analyze the effect of the treatment assignment, demographic characteristics, smoking status, and changes in FEV1 on 5-year changes in AR.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionSummary and ConclusionsAppendixReferences |
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50% of predicted and < 90% of predicted, and an FEV1/FVC ratio of < 0.70 were enrolled into the study and randomized into one of the following three groups: usual care (UC); smoking cessation plus a special intervention with an ipratropium bromide inhaler (SIA); and smoking cessation plus a special intervention with a placebo inhaler (SIP). For safety and ethical reasons, methacholine provocation was not performed at the end of the study in those patients with the following conditions: (1) FEV1 < 50% of predicted; (2) previous methacholine provocation during which FEV1 fell to < 25% of predicted; (3) myocardial infarction within 3 months, unstable angina, or congestive heart failure; (4) participant refusal; and (5) lack of a suitable testing environment. A total of 4,201 participants had interpretable methacholine challenge tests performed at both baseline and at the final fifth annual visit (AV5B). Data from this group are analyzed in the present report.
Bronchial Provocation Procedure
The follow-up methacholine inhalation test was performed at the AV5B, which was scheduled to occur at least 40 h after the last dose of study drug. Those patients who were assigned to either ipratropium or placebo inhalers had their study inhalers collected at the initial fifth annual visit (AV5A). Due to difficulties in scheduling visits, 62 participants in the SIA group (4.2%) and 69 in the SIP group (4.7%) were tested < 40 h after the AV5A. The mean (± SD) interval between the AV5A and the AV5B was 40.6 ± 89.9 days. This allowed for the adequate washout of ipratropium and the avoidance of a rebound increase in AR following withdrawal from long-term ipratropium therapy.9
Participants were instructed to avoid theophylline and histamine compounds for 24 h, inhaled bronchodilators for 12 h, caffeine for 6 h, and cigarette smoking for 2 h prior to undergoing testing. Participants inhaled five inspiratory capacity breaths of increasing methacholine concentrations using a nebulizer (model 626; DeVilbiss; Somerset, PA) and a dosimeter. The nebulizer was connected to a pressure source at 20 lb per square inch, and the activation time of the dosimeter was 0.6 s. The concentrations of methacholine in citrated buffer (pH, 5.03) with 0.4% phenol included the following: diluent control; 1 mg/mL methacholine; 5 mg/mL methacholine; 10 mg/mL methacholine; and 25 mg/mL methacholine. After each level of methacholine, spirometry was performed. If the FEV1 fell to < 15% from the diluent level, five breaths of the next concentration were administered. If the FEV1 declined > 15% but < 20% from the diluent value, only three breaths of the next higher concentration was administered before repeating spirometry. If the FEV1 still did not fall by 20% from the diluent level, then the additional two breaths were administered, and spirometry was again performed. The session was completed when either the highest concentration was administered or there was a 20% fall in FEV1 compared to the FEV1 after the diluent inhalation.
AR was quantified by the 2-point slope of percentage decline in FEV1 from the postdiluent control value vs the methacholine concentration, with a constant added to the negative of the slope to compensate for the few positive slopes. The value was log-transformed for a less skewed distribution. Thus, AR is expressed as the log of the methacholine responsiveness (LMCR). The higher the number, the greater the AR (LMCR = log10 [0.681 - the 2-point slope]).5
Smoking Status
Smoking status (biochemically verified by measurements of salivary cotinine and/or exhaled carbon monoxide levels) was defined by the following terms: (1) sustained quitters defined participants who were not smoking at any of the annual visits; (2) intermittent quitters defined participants who were not smoking at some but not all of the annual visits; and (3) continuous smokers defined participants who were smoking at all of the annual visits.
Inhaler Compliance
Participants were defined as having satisfactory adherence at annual visits if they reported taking 50% of the prescribed number of inhalations of medication over the preceding 12 months. Adherence with the assigned medication was categorized as follows: sustained satisfactory adherence was attained if a participant was adherent with medication use at all five annual visits; intermittent satisfactory adherence was attained if a participant was adherent at some but not all of the five annual visits; and not satisfactory adherence indicated a participant was not adherent at any of the five annual visits.
Statistical Analysis
The results are reported either as the mean ± SD for descriptive statistics, or as the mean ± SEM or the 95% confidence intervals for comparative statistics. Multiple linear regression was used to determine the effect of specific characteristics, adjusted for all other characteristics of interest, on the change in AR using a statistical software package (SAS PROC GLM; SAS Institute; Cary, NC).10
11
Several models were constructed with likely candidate variables and interaction terms. The model presented in this report is the most parsimonious model that reasonably accounts for the changes in AR in this study group.
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Results |
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25 mg/mL methacholine at baseline, which increased to 76.8% at the AV5B (Fig 1
). Among the 1,297 individuals who did not exhibit a 20% decline in FEV1 in response to methacholine at baseline, 555 (42.8%) showed a positive response 5 years later. In contrast, among the 2,904 people who showed a 20% response at baseline, only 233 (8.0%) did not respond to the highest concentration used 5 years later.
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Effect of Gender, Cigarette Smoking, and FEV1 Changes on AR
Women tended to have higher levels of AR at baseline and tended to have increases in AR more than did men, but the gender difference was not statistically significant (Table 3)
.
Smoking status had a large effect on change in AR. Continuous smokers had almost twice the increase in AR of intermittent smokers (p < 0.001) and showed more than a threefold increase in AR compared to sustained quitters (p < 0.001) [Table 3 ]. The change in FEV1 was inversely correlated with changes in AR. Decreases in the FEV1 were associated with increases in AR, and an increase in FEV1 correlated with a decrease or with less of an increase in this measurement (Fig 2 ).
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Contribution of Drug Treatment Assignment to Changes in Airways Reactivity
Intent-to-treat comparisons showed that the smallest increase in AR occurred in the SIP group, and that the largest increase occurred in the UC group. After adjustment for other factors, including smoking status and change in FEV1, there was a tendency for the individuals assigned to the SIA treatment group to show greater increases in AR than those in the UC group. To determine whether this may have been related to the drug, we subdivided the SIA and the SIP treatment groups into strata based on self-reported adherence to the drug treatment. This analysis demonstrated that the participants who were most adherent to treatment with the placebo had the least increment in AR, whereas those who were in the lowest placebo adherence group had the greatest increment in AR. In comparison, the SIA group did not show a clear relationship of adherence to increases in responsiveness. Those in the highest and lowest strata of adherence showed the largest increments (Fig 3
). When persons in the strata with consistently high adherence were compared, those who were using ipratropium had more of an increase in AR than those who were using placebo (p = 0.0062 [SIA vs SIP groups for participants with sustained satisfactory adherence]). These analyses are subject to confounding by smoking behavior and inhaler usage as well as by the misclassification of true medication usage, due, in part, to deceptive excessive actuations of the inhaler (dumping).12
Those participants with the best adherence to their inhaler usage were also those who were able to stop smoking for the 5-year period. Since stopping smoking results in a more favorable change in FEV1 and since FEV1 is negatively correlated with changes in AR, then those participants with better inhaler adherence would be expected to have less of an increase in AR, or even a decrease.
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Discussion |
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Longitudinal Changes in Airways Reactivity
Cross-sectional general population studies of middle-aged adults have demonstrated an increase in methacholine and histamine responsiveness with advancing age.13
14
15
Where it has been analyzed,16
however, much of the age-related change in methacholine reactivity can be statistically accounted for by the associated reduction in FEV1. In this study population, we did not observe a cross-sectional effect of age on the prevalence of AR, although baseline levels of lung function were important.3
The reason for this discrepancy may be that the LHS study population encompassed a relatively narrow age range (ie, 35 to 60 years of age), all participants being cigarette smokers with airway obstruction, and thus had an initial high prevalence of AR in all age categories. This study group clearly does not represent a general population sample.
Bronchoprovocation challenge is a reproducible test over a period of time within two to three doubling concentrations.17 There is seasonal variation in the repeatability of the results, especially in those persons with atopy.18 We tried to control for these variables in our analyses. Whenever possible, we tried to perform the study at the same time of day as the original study and within a 3-month window of the month and day of the baseline test. Also, the large number of participants in this study should help to control for these confounding variables.
We are unaware of previous studies of longitudinal changes in AR in persons with COPD. The Normative Aging Study19
examined a 3-year follow-up of methacholine challenges in 435 people who had been selected from an initially healthy population sample. Little change in methacholine responsiveness was noted in this group of healthy individuals, who demonstrated a mean normal decline in FEV1 of 31 mL per year. In contrast, the persons in our study sample, who were selected for abnormal lung function, exhibited accelerated mean declines of 52 to 56 mL per year in the three study groups after the first annual visit. A Dutch random population study20
of 2,216 persons showed a tendency for AR to increase over study intervals of 18 years. It is likely that the latter study had greater sensitivity than did the Normative Aging Study because of the larger population and the longer interval in which age-related declines in lung function were observed. The present study of people with mild-to-moderate COPD shows that older individuals have greater increments in AR even after adjusting for changes in FEV1, smoking status, and other explanatory variables (Table 4)
.
The association between AR and FEV1 might be due to airway geometry in which resistance is inversely related to the fourth power of the radius of the airway. Thus, the smaller the radius, the greater the resistance. A change in radius from 3 to 2 mm will have a greater effect in increasing resistance than will a change from 10 to 9 mm. Another possible explanation may be that smaller airways have less of an internal surface area and less volume than large airways. Thus, the same dose of inhaled methacholine will be more concentrated when it reaches receptors in the walls of smaller airways. This also may be the reason that women have more AHR than their male counterparts.4
Cigarette Smoking and Airways Reactivity
Although the cigarette-smoking intervention in the LHS showed a significant benefit with respect to decline in lung function, the intention-to-treat analysis did not find a significant benefit of the treatment assignment itself for changes in AR. It is possible that this discrepancy reflects greater intraperson variability in measures of AR compared to FEV1, although the large number of participants should control for this as random changes in one direction should be balanced by random changes in others in the opposite direction. A second possibility is that persons with the lowest levels of lung function (ie, < 50% of predicted) at the end of the 5-year follow-up period were more likely to be in the UC group rather than in either the SIA or SIP groups and, thus, were excluded for safety reasons from the final bronchoprovocation study. Also, more UC participants refused the methacholine challenge at the AV5B (Table 2)
. Thus, more participants from the UC group in whom the FEV1 was the lowest at the AV5B were excluded from the present analysis than were those from the intervention groups. This could bias the results against finding a beneficial treatment effect on AR (ie, a "survivor effect"). A third possible explanation is that the progression of AR is a constitutional characteristic that is linked to the decline in FEV1 (ie, the "Dutch Hypothesis") but that smoking cessation or drug intervention may abate the decline in FEV1 without affecting the progression of AR. Finally, the intention-to-treat analysis may not have had sufficient statistical power to detect changes between the groups since by the AV5B the difference in the number of current smokers among the groups had narrowed. In the SIA and SIP groups, only 22% were sustained quitters, and at each annual visit > 60% of those participants in the two intervention groups were smoking. In the UC group, the number of current smokers steadily declined, with almost 22% reporting abstinence at the AV5A.
The effect of cigarette smoking status on AR is somewhat controversial. Some general population studies14 15 21 22 have shown that cigarette smokers have greater AR, whereas others23 have found this only in atopic individuals. A previous study24 of smokers with chronic cough has not shown an improvement in AR following 6 months of smoking cessation despite improvement in cough. The Normative Aging Study19 found that smokers who quit during a 3-year follow-up interval tended to have a decline in AR, but the results were of borderline statistical significance.
In the present study, we attempted to separate airway mechanical effects and smoking behavior using multiple regression models (Table 4) and subgroup analyses (Fig 2) . These analyses showed that most of the effect of smoking status on AR could be attributed to the attendant changes in FEV1 that are associated with smoking status. There was, however, an interaction between smoking status and change in pulmonary function such that continuing and intermittent smokers who demonstrated little change in lung function had greater increments in AR than sustained quitters with similar changes in their FEV1 (Fig 2) . Therefore, we think that there is a direct effect of cigarette smoking on the progression of AR, possibly due to inflammatory or neurogenic mechanisms, that is separable from the effect on lung geometry, although the effect is small.
Potential Limitations of the Study
It is possible that there was some unrecognized drift in our technique for methacholine testing over time, despite rigorous efforts to standardize our procedures. These procedures included centralized compounding of the methacholine solutions by a reference pharmacy, centralized calibration and distribution of the nebulizers and dosimeters, and rigorously standardized spirometric procedures.7
Concerns about the stability of methods are inherent in any longitudinal study design. Our confidence that the study group demonstrated a progression of AR is supported by similar cross-sectional findings in general population samples. Moreover, while concerns about the stability of the testing methods would limit the strength of our conclusions about the overall progression of AR in the population, secular changes should not bias the analysis of differences between subgroups of participants who were subjected to the same testing procedures. Another potential limitation of the study presented here is that those individuals with the lowest levels of lung function who died, who developed interval heart diseases, who had severe reactions at initial testing, or who refused subsequent testing were excluded from retesting. Since all of these criteria would tend to exclude individuals with the lowest lung function and the worst general health status, it is likely that our results would be biased toward showing less progression of AR. Because of the possibility that there was informative censoring of the responsiveness data, we must be somewhat guarded in interpreting the effect of the treatment assignment. Overall, however, we think that it is reasonable to conclude that factors that slow the decline in FEV1 will also slow the progression of AR.
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Summary and Conclusions |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionSummary and ConclusionsAppendixReferences |
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Appendix |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionSummary and ConclusionsAppendixReferences |
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Case Western Reserve University, Cleveland, OH M.D. Altose, MD (Principal Investigator); A.F. Connors, MD (Co-Principal Investigator); S. Redline, MD (Co-Principal Investigator); C.D. Deitz, PhD; and R.F. Rakos, PhD.
Henry Ford Hospital, Detroit, MI W.A. Conway, Jr., MD (Principal Investigator); A. DeHorn, PhD (Co-Principal Investigator); J.C. Ward, MD (former Co-Principal Investigator); C.S. Hoppe-Ryan, CSW; R.L. Jentons, MA; J.A. Reddick, RN; and C. Sawicki, RN, MPH.
Johns Hopkins University School of Medicine, Baltimore, MD R.A. Wise, MD (Principal Investigator); S. Permutt, MD (Co-Principal Investigator); and C.S. Rand, PhD (Co-Principal Investigator).
Mayo Clinic, Rochester, MN P.D. Scanlon, MD (Principal Investigator); L.J. Davis, PhD (Co-Principal Investigator); R.D. Hurt, MD (Co-Principal Investigator); R.D. Miller, MD (Co-Principal Investigator); D.E. Williams, MD (Co-Principal Investigator); G.M. Caron; G.G. Lauger, MS; and S.M. Toogood (Pulmonary Function Quality Control Manager).
Oregon Health Sciences University, Portland, OR A.S. Buist, MD (Principal Investigator); W.M. Bjornson, MPH (Co-Principal Investigator); and L.R. Johnson, PhD (LHS Pulmonary Function Coordinator).
University of Alabama at Birmingham, AL W.C. Bailey, MD (Principal Investigator and Associate Chief of Staff for Education, Department of Veterans Affairs Medical Center, Birmingham, AL); C.M. Brooks, EdD (Co-Principal Investigator); J.J. Dolce, PhD; D.M. Higgins; M.A. Johnson; and B.A. Martin.
University of California, Los Angeles, CA D.P. Tashkin, MD (Principal Investigator); A.H. Coulson, PhD (Co-Principal Investigator); H. Gong, MD (former Co-Principal Investigator); P.I. Harber, MD (Co-Principal Investigator); V.C. Li, PhD, MPH (Co-Principal Investigator); M. Roth, MD (Co-Principal Investigator); M.A. Nides, PhD; M.S. Simmons; and I.P. Zuniga.
University of Manitoba, Winnipeg, MB, Canada N.R. Anthonisen, MD (Principal Investigator, Steering Committee Chair); J. Manfreda, MD (Co-Principal Investigator); R.P. Murray, PhD (Co-Principal Investigator); S.C. Rempel-Rossum, BS; and J.M. Stoyko.
University of Minnesota Coordinating Center, Minneapolis, MN J.E. Connett, PhD (Principal Investigator); M.O. Kjelsberg, PhD (Co-Principal Investigator); M.K. Cowles, PhD; D.A. Durkin; P.L. Enright, MD (former Principal Investigator, Mayo Clinic); K.J. Kurnow, MS; W.W. Lee, MS; P.G. Lindgren, MS; S. Mongin, MS; P. O’Hara, PhD, (LHS Intervention Coordinator); H.T. Voelker, BS; and L. Waller, PhD.
University of Pittsburgh, Pittsburgh, PA G.R. Owens, MD (Principal Investigator); R.M. Rogers, MD (Co-Principal Investigator); J.J. Johnston, PhD; F.P. Pope, MSW; and F.M. Vitale, MA.
University of Utah, Salt Lake City, UT R.E. Kanner, MD (Principal Investigator); M.A. Rigdon, PhD (Co-Principal Investigator); K.C. Benton, BA; and P.M. Grant, BS.
Safety and Data Monitoring Board M. Becklake, MD; B. Burrows, MD; P. Cleary, PhD; P. Kimbel, MD (Chairperson; deceased October 27, 1990); L. Nett, RN, RRT (former member); J.K. Ockene, PhD; R.M. Senior, MD (Chairperson); G.L. Snider, MD; W. Spitzer, MD (former member); and O.D. Williams, PhD.
National Heart, Lung and Blood Institute Staff, Bethesda, MD S.S. Hurd, PhD (Director, Division of Lung Diseases); J.P. Kiley, PhD (Project Officer); and M.C. Wu, PhD (Div. of Epidemiology and Clinical Applications).
Mortality and Morbidity Review Board S.M. Ayres, MD; R.E. Hyatt, MD; and B.A. Mason, MD.
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Footnotes |
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This research was supported by contracts NO1-HR46002 and NO1-46014 from the Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health. The following pharmaceutical companies supplied drugs used in this study: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (Atrovent and placebo inhalers); and Marion Merrell Dow Inc, Kansas City, MO (Nicorette). The Salt Lake City Center has been assisted by the Clinical Research Center, Public Health Research grant M01-RR00064 from the National Center for Research Resources.
Received for publication September 9, 2002. Accepted for publication November 27, 2002.
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LMCR) is plotted against the change in FEV1 over the 5-year interval. Separate plots are made for each smoking category. The continuous-smoking group is shifted to the left, indicating a greater decline in FEV1 compared to the group of sustained quitters. The continuous-smoking group is shifted upward, indicating a tendency for a greater increase in AR for a given decline in FEV1. The effect of changes in FEV1, however, has greater influence on changes in AR than does smoking status.