The Effect of Smoking Intervention and an Inhaled Bronchodilator on Airways Reactivity in COPD: The...

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DOI: 10.1378/chest.124.2.449 2003;124;449-458 Chest

Altose, Paul L. Enright and Donald P. Tashkin Robert A. Wise, Richard E. Kanner, Paula Lindgren, John E. Connett, Murray D.

Reactivity in COPD: The Lung Health StudyThe Effect of Smoking Intervention and an Inhaled Bronchodilator on Airways

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The Effect of Smoking Intervention andan Inhaled Bronchodilator on AirwaysReactivity in COPD*The Lung Health Study

Robert A. Wise, MD, FCCP; Richard E. Kanner, MD, FCCP;Paula Lindgren, MS; John E. Connett, PhD; Murray D. Altose, MD, FCCP;Paul L. Enright, MD; and Donald P. Tashkin, MD, FCCP; for the Lung HealthStudy Research Group†

Background: The Lung Health Study (LHS), a 5-year, randomized, prospective clinical trial,studied the effects of smoking intervention and therapy with inhaled anticholinergic bronchodi-lators on FEV1 in participants who were 35 to 60 years of age and had mild COPD. Participantswere randomized into the following three groups: usual care; smoking cessation plus inhaledipratropium bromide; and smoking cessation plus placebo inhaler. This report evaluates theeffects of these interventions, demographic characteristics, smoking status, and FEV1 changes onairway responsiveness (AR).Methods and results: Of 5,887 participants, 4,201 underwent methacholine challenge testing bothat study entry and study completion. All groups increased AR during the 5-year period. Theincrease in AR was greatest in continuing smokers and was associated with a greater FEV1decline. An intent-to-treat analysis indicated no significant differences in AR changes among thethree groups.Conclusions: Changes in AR over a 5-year period in the LHS were primarily related to changesin the FEV1. The greater the decline in FEV1, the greater the increase in AR. Smoking cessationhad a small additional benefit in AR beyond its favorable effects on FEV1 changes.

(CHEST 2003; 124:449–458)

Key words: airway hyperresponsiveness; airways reactivity; COPD; ipratropium; methacholine bronchoprovocationchallenge; smoking cessation

Abbreviations: AHR � airway hyperresponsiveness; AR � airway responsiveness; AV5A � initial fifth annual visit;AV5B � final fifth annual visit; LHS � Lung Health Study; LMCR � log of the methacholine responsiveness;SIA � special intervention with ipratropium inhaler; SIP � special intervention with placebo inhaler; UC � usual care

T he Lung Health Study (LHS) was a multicenterclinical trial of the effect of smoking cessation

intervention and ipratropium bromide inhalation onlung function decline in men and women with mildCOPD. Participants underwent methacholine chal-lenge tests to assess airways responsiveness (AR) at

entry1 into the study and at the end of the study 5years later. The primary results of the study showedthat the smoking intervention program increased theproportion of those patients who sustained smokingcessation for the duration of the trial from 5%(control group) to 22% (intervention groups). Sus-

*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 Schoolof Public Health (Ms. Lindgren and Dr. Connett), Minneapolis,MN; Case Western Reserve University (Dr. Altose), Cleveland,OH; University of Arizona (Dr. Enright), Tucson, AZ; andUniversity of California at Los Angeles School of Medicine (Dr.Tashkin), Los Angeles, CA.†See Appendix for a list of participants in the LHS ResearchGroup.This research was supported by contracts NO1-HR46002 andNO1-46014 from the Division of Lung Diseases, National Heart,Lung, and Blood Institute, National Institutes of Health. Thefollowing pharmaceutical companies supplied drugs used in this

study: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield,CT (Atrovent and placebo inhalers); and Marion Merrell DowInc, Kansas City, MO (Nicorette). The Salt Lake City Center hasbeen assisted by the Clinical Research Center, Public HealthResearch grant M01-RR00064 from the National Center forResearch Resources.Manuscript received September 9, 2002; revision accepted No-vember 27, 2002.Reproduction of this article is prohibited without written permis-sion from the American College of Chest Physicians (e-mail:permissions@chestnet.org).Correspondence to: Richard E. Kanner, MD, FCCP, University ofUtah Health Sciences Center, 26 North 1900 East, Salt Lake City,UT 84132; e-mail: kanner@med.utah.edu

www.chestjournal.org CHEST / 124 / 2 / AUGUST, 2003 449

tained smoking cessation had a beneficial effect onthe rate of FEV1 decline. Ipratropium treatmentshowed an additional small but reversible beneficialeffect on the decline in lung function. Continuoussmokers showed nearly twice the annual loss ofFEV1 as sustained quitters over the 5-year period(63 vs 34 mL per year).1,2

Initially, 63% of men and 87% of women showeda � 20% fall in FEV1 with inhalation of � 25 mg/mLmethacholine, indicating airway hyperresponsiveness(AHR). Forty-six percent of the men and 74% ofwomen showed AHR at a methacholine concentra-tion of � 10 mg/mL.3 The significantly higher prev-alence of AHR in women when compared to that ofmen could be accounted for almost entirely byadjusting for the initial FEV1.4 During 5 years offollow-up, persons with greater degrees of AR atstudy entry showed a greater longitudinal decline inFEV1.5

Only a few studies have reported longitudinalmeasures of AR in a large group of patients withCOPD, and none have reported longitudinalchanges in AR. Since the degree of AR is associatedwith the subsequent annual decline in FEV1, this isan important measurement in determining the prog-nosis of a patient with COPD. Since smoking statusis associated with FEV1, it would be anticipated thatthis also might affect AR. The large LHS cohort thatwas closely observed for 5 years allowed us to analyzethe effect of the treatment assignment, demographiccharacteristics, smoking status, and changes in FEV1

on 5-year changes in AR.

Materials and Methods

LHS Design

The study design, spirometric methodology, measurement ofAR, and smoking intervention program all have been reported onin detail.3,6–8 A total of 5,887 cigarette-smoking participants withan FEV1 of � 50% of predicted and � 90% of predicted, and anFEV1/FVC ratio of � 0.70 were enrolled into the study andrandomized into one of the following three groups: usual care(UC); smoking cessation plus a special intervention with anipratropium bromide inhaler (SIA); and smoking cessation plus aspecial intervention with a placebo inhaler (SIP). For safety andethical reasons, methacholine provocation was not performed atthe end of the study in those patients with the followingconditions: (1) FEV1 � 50% of predicted; (2) previous metha-choline provocation during which FEV1 fell to � 25% of pre-dicted; (3) myocardial infarction within 3 months, unstableangina, or congestive heart failure; (4) participant refusal; and(5) lack of a suitable testing environment. A total of 4,201participants had interpretable methacholine challenge tests per-formed 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 atthe AV5B, which was scheduled to occur at least 40 h after thelast dose of study drug. Those patients who were assigned toeither ipratropium or placebo inhalers had their study inhalerscollected at the initial fifth annual visit (AV5A). Due to difficultiesin scheduling visits, 62 participants in the SIA group (4.2%) and69 in the SIP group (4.7%) were tested � 40 h after the AV5A.The mean (� SD) interval between the AV5A and the AV5B was40.6 � 89.9 days. This allowed for the adequate washout ofipratropium and the avoidance of a rebound increase in ARfollowing withdrawal from long-term ipratropium therapy.9

Participants were instructed to avoid theophylline and hista-mine compounds for 24 h, inhaled bronchodilators for 12 h,caffeine for 6 h, and cigarette smoking for 2 h prior to undergoingtesting. Participants inhaled five inspiratory capacity breaths ofincreasing methacholine concentrations using a nebulizer (model626; DeVilbiss; Somerset, PA) and a dosimeter. The nebulizerwas connected to a pressure source at 20 lb per square inch, andthe activation time of the dosimeter was 0.6 s. The concentrationsof methacholine in citrated buffer (pH, 5.03) with 0.4% phenolincluded the following: diluent control; 1 mg/mL methacholine; 5mg/mL methacholine; 10 mg/mL methacholine; and 25 mg/mLmethacholine. After each level of methacholine, spirometry wasperformed. If the FEV1 fell to � 15% from the diluent level, fivebreaths of the next concentration were administered. If the FEV1declined � 15% but � 20% from the diluent value, only threebreaths of the next higher concentration was administered beforerepeating spirometry. If the FEV1 still did not fall by � 20% fromthe diluent level, then the additional two breaths were adminis-tered, and spirometry was again performed. The session wascompleted when either the highest concentration was adminis-tered or there was a � 20% fall in FEV1 compared to the FEV1after the diluent inhalation.

AR was quantified by the 2-point slope of percentage decline inFEV1 from the postdiluent control value vs the methacholineconcentration, with a constant added to the negative of the slopeto compensate for the few positive slopes. The value waslog-transformed for a less skewed distribution. Thus, AR isexpressed 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 ofsalivary cotinine and/or exhaled carbon monoxide levels) wasdefined by the following terms: (1) sustained quitters definedparticipants who were not smoking at any of the annual visits;(2) intermittent quitters defined participants who were notsmoking at some but not all of the annual visits; and (3)continuous smokers defined participants who were smoking at allof the annual visits.

Inhaler Compliance

Participants were defined as having satisfactory adherence atannual visits if they reported taking � 50% of the prescribednumber of inhalations of medication over the preceding12 months. Adherence with the assigned medication was catego-rized as follows: sustained satisfactory adherence was attained ifa participant was adherent with medication use at all five annualvisits; intermittent satisfactory adherence was attained if a partic-ipant was adherent at some but not all of the five annual visits;

450 Clinical Investigations

and not satisfactory adherence indicated a participant was notadherent at any of the five annual visits.

Statistical Analysis

The results are reported either as the mean � SD for descrip-tive statistics, or as the mean � SEM or the 95% confidenceintervals for comparative statistics. Multiple linear regression wasused to determine the effect of specific characteristics, adjustedfor all other characteristics of interest, on the change in AR usinga statistical software package (SAS PROC GLM; SAS Institute;Cary, NC).10,11 Several models were constructed with likelycandidate variables and interaction terms. The model presentedin this report is the most parsimonious model that reasonablyaccounts for the changes in AR in this study group.

Results

Demographics and Temporal Changes in AirwaysReactivity

The clinical and demographic characteristics ofthe 4,201 participants in this study group are shownin Table 1. The reasons for the exclusion of the datafor the remaining 1,686 LHS participants are givenin Table 2. The study sample showed an overallincrease in AR over the 5-year period, irrespective oftreatment assignment, gender, or smoking status(Table 3). The increase in reactivity for the entire

group was small, approximately 0.12 LMCR units.At randomization, 4.1% of the group responded to1 mg/mL methacholine, whereas 8.9% responded tothis level at the AV5B. Cumulatively, 69.1% of theparticipants responded to � 25 mg/mL methacho-line at baseline, which increased to 76.8% at theAV5B (Fig 1). Among the 1,297 individuals who didnot exhibit a � 20% decline in FEV1 in response tomethacholine at baseline, 555 (42.8%) showed apositive response 5 years later. In contrast, amongthe 2,904 people who showed a � 20% response atbaseline, only 233 (8.0%) did not respond to thehighest concentration used 5 years later.

Individual participants tended to retain the samelevel of responsiveness at follow-up as they had atbaseline. The intraperson correlation of participants’baseline responsiveness with values measured 5years later was 0.70. Fewer than 17% of participantschanged AR by two or more concentrations fromtheir initial level, and more individuals had an in-crease than had a decrease in AR.

Effect of Gender, Cigarette Smoking, and FEV1

Changes on AR

Women tended to have higher levels of AR atbaseline and tended to have increases in AR morethan did men, but the gender difference was notstatistically significant (Table 3).

Smoking status had a large effect on change in AR.Continuous smokers had almost twice the increase inAR of intermittent smokers (p � 0.001) and showedmore than a threefold increase in AR compared tosustained quitters (p � 0.001) [Table 3]. The change

Table 1—Clinical and Demographic Characteristics atBaseline (n � 4,201)*

Characteristic Value

Mean age at baseline, yr 48.1 � 6.78Female gender 36.8Physician-confirmed asthma 2.6Chronic bronchitis† 20.9FEV1, % predicted 76.2 � 8.8FEV1/FVC ratio, % 63.7 � 5.5Cigarettes smoked per day 30.8 � 12.8Non-white race 3.9LMCR 0.422 � 0.362Wheeze (highest reported level)

None 23.9With colds 18.5Apart from colds 27.2Most days, nights 30.4

Shortness of breath (highest reported level)None 59.8Hurrying uphill 28.9Walking with peers 5.8Walking at own pace 1.9Walking 100 yards 2.9Dressing/undressing 0.6

Hay fever 19.1Dust or fume exposure 47.6

*Values given as mean � SD or percentage of total, unless otherwiseindicated.

†Defined as chronic productive cough on most days for at least 3consecutive months for 2 consecutive years.

Table 2—Reasons for Exclusion From Analysis

Reason No. SIA SIP UC

Unanalyzable baselinetest

196 67 74 55

Responded to diluent atbaseline

39 15 15 9

Died in interval 147 52 44 51No 5-year spirometry 311 94 108 109FEV1 � 50% of

predicted315 94 95 126

Refused test 174 52 49 73Angina or congestive

heart failure33 13 9 11

Lowest FEV1 at baseline� 25% predicted

5 3 0 2

Diluent responders atAV5B

8 2 3 3

Incomplete test at AV5B 60 23 14 23Other* 398 124 141 133Total 1,686 539 552 595

*Indicates hospitalized, other serious illness, whereabouts unknown,or moved from area.

in FEV1 was inversely correlated with changes inAR. Decreases in the FEV1 were associated withincreases in AR, and an increase in FEV1 correlatedwith a decrease or with less of an increase in thismeasurement (Fig 2).

FEV1 at the time of the methacholine provocationtest accounts for some of the variance in AR, andcigarette smoking status is associated with changes in

FEV1. Therefore, we performed a multiple linearregression analysis to determine the contributions ofseveral candidate variables to changes in AR whenadjusted for the others (Table 4). This analysisshowed that there were significant independent andinteractive effects of both smoking status and changein FEV1, but that a considerable degree of thesmoking status effect could be accounted for by the

Figure 1. The cumulative percentage of the study population responding with a � 20% fall in FEV1is shown for each of the sequential methacholine concentrations that were administered. The shift ofthe cumulative distribution upward and to the left indicates that there was an overall increase inresponsiveness to methacholine during the study interval.

Table 3—Reactivity at Baseline and Year 5 Reactivity Change*

Group No.

Baseline Reactivity Year 5 Reactivity5 Year Change in

Reactivity

p Value† p Value‡Mean SD Mean SD Mean SD

All 4,201 0.422 0.362 0.543 0.408 0.121 0.303 � 0.001Gender

Women 1,545 0.571 0.351 0.695 0.397 0.125 0.318 � 0.001 0.547Men 2,656 0.335 0.340 0.454 0.388 0.119 0.294 � 0.001

Smoking statusContinuous smoker 2,177 0.404 0.341 0.569 0.390 0.166 0.286 � 0.001Intermittent smoker 1,209 0.449 0.386 0.540 0.424 0.091 0.307 � 0.001 � 0.001Sustained quitter 815 0.430 0.377 0.477 0.424 0.047 0.321 � 0.001

Treatment groupSIA 1,422 0.437 0.369 0.565 0.415 0.128 0.317 � 0.001SIP 1,410 0.417 0.354 0.518 0.403 0.100 0.301 � 0.001 0.006UC 1,369 0.411 0.362 0.546 0.405 0.135 0.289 � 0.001

*Values are given as the log transformation of the slope change in percent baseline FEV1 per mg/mL methacholine. More positive values indicategreater reactivity.

†For t test comparisons of the mean change in reactivity from baseline to year 5.‡For analysis of variance comparisons of the mean change in reactivity within each group (ie, men vs women).

changes in FEV1 (Fig 2). An analysis of subgroups byquintile of change in FEV1 showed that continuoussmokers and sustained quitters with the greatestdeclines in FEV1 had similar increases in AR. On theother hand, for patients in those groups with theleast decline in lung function, there was a greaterincrease in AR among continuing smokers thanamong sustained quitters (p � 0.0001).

Another significant predictor of the change in ARwas the age of the participants. Older participantsshowed relatively more of an increase in AR evenafter adjustment for change in FEV1, treatment group,gender, and smoking status (Table 4). There is somecollinearity between the variables in that change inFEV1, with the change in LMCR and final smokingstatus all correlated. The treatment group also wascorrelated with the final smoking status.

Contribution of Drug Treatment Assignment toChanges in Airways Reactivity

Intent-to-treat comparisons showed that the small-est increase in AR occurred in the SIP group, andthat the largest increase occurred in the UC group.After adjustment for other factors, including smok-ing status and change in FEV1, there was a tendencyfor the individuals assigned to the SIA treatmentgroup to show greater increases in AR than those inthe UC group. To determine whether this may havebeen related to the drug, we subdivided the SIA andthe SIP treatment groups into strata based on self-reported adherence to the drug treatment. Thisanalysis demonstrated that the participants who weremost adherent to treatment with the placebo had theleast increment in AR, whereas those who were in

Table 4—Multivariate Analysis of Change inAirways Reactivity*

Variable Effect Size† p Value

Male vs female gender � 0.011 0.24Treatment group

SIA vs UC 0.028 0.02SIP vs UC 0.001 0.94

Smoking statusCS vs SQ 0.088 0.0002IS vs SQ 0.055 0.0001

Age at baseline (per 10 yr) 0.045 0.0001Change in FEV1 over 5 yr, L � 0.399 0.0001Change in FEV1 � smoking status

CS vs SQ 0.103 0.031IS vs SQ 0.178 0.0006

Intercept � 0.226 0.0001

*CS � continuous smoker; IS � intermittent smoker; SQ � sustainedquitter.

†A negative value means that there was less of an increase in AR.

Figure 2. The mean change in AR (ie, �LMCR) is plotted against the change in FEV1 over the 5-yearinterval. Separate plots are made for each smoking category. The continuous-smoking group is shiftedto the left, indicating a greater decline in FEV1 compared to the group of sustained quitters. Thecontinuous-smoking group is shifted upward, indicating a tendency for a greater increase in AR for agiven decline in FEV1. The effect of changes in FEV1, however, has greater influence on changes inAR than does smoking status.

the lowest placebo adherence group had the greatestincrement in AR. In comparison, the SIA group didnot show a clear relationship of adherence to in-creases in responsiveness. Those in the highest andlowest strata of adherence showed the largest incre-ments (Fig 3). When persons in the strata withconsistently high adherence were compared, thosewho were using ipratropium had more of an increasein AR than those who were using placebo(p � 0.0062 [SIA vs SIP groups for participants withsustained satisfactory adherence]). These analysesare subject to confounding by smoking behavior andinhaler usage as well as by the misclassification oftrue medication usage, due, in part, to deceptiveexcessive actuations of the inhaler (dumping).12

Those participants with the best adherence to theirinhaler usage were also those who were able to stopsmoking for the 5-year period. Since stopping smok-ing results in a more favorable change in FEV1 andsince FEV1 is negatively correlated with changes inAR, then those participants with better inhaler ad-herence would be expected to have less of anincrease in AR, or even a decrease.

Further analysis confirmed the results of theprevious report9 that the apparent increase in theprogression of AR in the SIA group could be ac-counted for by a transient increase in AR in peoplewho recently had stopped using their ipratropiuminhaler after actively using the inhaler during thestudy period (ie, a rebound effect). Those partici-

pants who had their AV5B visit � 40 h after stoppingtheir inhaler usage did not have an increase in ARthat was independent of changes in FEV1 andsmoking status.

Discussion

The main finding of this study was that there wasan overall tendency for AR to increase over a 5-yearperiod in this group of long-term smokers withmild-to-moderate COPD. This increase in AR oc-curred in persons in all the analyzed subgroupsexcept for those who quit smoking and subsequentlyimproved their pulmonary function. Increasing ARwas more pronounced in women, continuous smok-ers, and those participants with the largest declinesin FEV1. The unifying theme of our analyses was thatfactors associated with greater declines in FEV1 arealso associated with greater increases in AR. In tryingto separate the effects of smoking status fromchanges in FEV1 by linear regression and subgroupanalysis, we noted a small benefit from smokingcessation on the change in AR that was not ac-counted for by the beneficial effect on the decline inFEV1. We could detect no benefit associated withthe random assignment to ipratropium inhalation.Thus, in COPD patients, cross-sectional analysisdemonstrates that AR is inversely correlated with

Figure 3. The mean change in AR (ie, �LMCR) is plotted for each category of self-reportedmedication adherence in the smoking intervention groups. Error bars indicate the SEM for eachsubgroup.

FEV1, and longitudinal data analysis demonstratesthat further declines in FEV1 result in a furtherincrease in AR.

Longitudinal Changes in Airways Reactivity

Cross-sectional general population studies of mid-dle-aged adults have demonstrated an increase inmethacholine and histamine responsiveness with ad-vancing age.13–15 Where it has been analyzed,16

however, much of the age-related change in metha-choline reactivity can be statistically accounted for bythe associated reduction in FEV1. In this studypopulation, we did not observe a cross-sectionaleffect of age on the prevalence of AR, althoughbaseline levels of lung function were important.3 Thereason for this discrepancy may be that the LHSstudy population encompassed a relatively narrowage range (ie, 35 to 60 years of age), all participantsbeing cigarette smokers with airway obstruction, andthus had an initial high prevalence of AR in all agecategories. This study group clearly does not repre-sent a general population sample.

Bronchoprovocation challenge is a reproducibletest over a period of time within two to threedoubling concentrations.17 There is seasonal varia-tion in the repeatability of the results, especially inthose persons with atopy.18 We tried to control forthese variables in our analyses. Whenever possible,we tried to perform the study at the same time of dayas the original study and within a 3-month window ofthe month and day of the baseline test. Also, thelarge number of participants in this study shouldhelp to control for these confounding variables.

We are unaware of previous studies of longitudinalchanges in AR in persons with COPD. The Norma-tive Aging Study19 examined a 3-year follow-up ofmethacholine challenges in 435 people who hadbeen selected from an initially healthy populationsample. Little change in methacholine responsive-ness was noted in this group of healthy individuals,who demonstrated a mean normal decline in FEV1of 31 mL per year. In contrast, the persons in ourstudy sample, who were selected for abnormal lungfunction, exhibited accelerated mean declines of 52to 56 mL per year in the three study groups after thefirst annual visit. A Dutch random population study20

of 2,216 persons showed a tendency for AR toincrease over study intervals of � 18 years. It is likelythat the latter study had greater sensitivity than didthe Normative Aging Study because of the largerpopulation and the longer interval in which age-related declines in lung function were observed. Thepresent study of people with mild-to-moderateCOPD shows that older individuals have greater

increments in AR even after adjusting for changes inFEV1, smoking status, and other explanatory vari-ables (Table 4).

The association between AR and FEV1 might bedue to airway geometry in which resistance is in-versely related to the fourth power of the radius ofthe airway. Thus, the smaller the radius, the greaterthe resistance. A change in radius from 3 to 2 mmwill have a greater effect in increasing resistancethan will a change from 10 to 9 mm. Anotherpossible explanation may be that smaller airwayshave less of an internal surface area and less volumethan large airways. Thus, the same dose of inhaledmethacholine will be more concentrated when itreaches receptors in the walls of smaller airways.This also may be the reason that women have moreAHR than their male counterparts.4

Cigarette Smoking and Airways Reactivity

Although the cigarette-smoking intervention inthe LHS showed a significant benefit with respect todecline in lung function, the intention-to-treat anal-ysis did not find a significant benefit of the treatmentassignment itself for changes in AR. It is possible thatthis discrepancy reflects greater intraperson variabil-ity in measures of AR compared to FEV1, althoughthe large number of participants should control forthis as random changes in one direction should bebalanced by random changes in others in the oppo-site direction. A second possibility is that personswith the lowest levels of lung function (ie, � 50% ofpredicted) at the end of the 5-year follow-up periodwere more likely to be in the UC group rather thanin either the SIA or SIP groups and, thus, wereexcluded for safety reasons from the final broncho-provocation study. Also, more UC participants re-fused the methacholine challenge at the AV5B (Ta-ble 2). Thus, more participants from the UC group inwhom the FEV1 was the lowest at the AV5B wereexcluded from the present analysis than were thosefrom the intervention groups. This could bias theresults against finding a beneficial treatment effecton AR (ie, a “survivor effect”). A third possibleexplanation is that the progression of AR is a consti-tutional characteristic that is linked to the decline inFEV1 (ie, the “Dutch Hypothesis”) but that smokingcessation or drug intervention may abate the declinein FEV1 without affecting the progression of AR.Finally, the intention-to-treat analysis may not havehad sufficient statistical power to detect changesbetween the groups since by the AV5B the differ-ence in the number of current smokers among thegroups had narrowed. In the SIA and SIP groups,only 22% were sustained quitters, and at each annualvisit � 60% of those participants in the two inter-

vention groups were smoking. In the UC group, thenumber of current smokers steadily declined, withalmost 22% reporting abstinence at the AV5A.

The effect of cigarette smoking status on AR issomewhat controversial. Some general populationstudies14,15,21,22 have shown that cigarette smokershave greater AR, whereas others23 have found thisonly in atopic individuals. A previous study24 ofsmokers with chronic cough has not shown an im-provement in AR following 6 months of smokingcessation despite improvement in cough. The Nor-mative Aging Study19 found that smokers who quitduring a 3-year follow-up interval tended to have adecline in AR, but the results were of borderlinestatistical significance.

In the present study, we attempted to separateairway mechanical effects and smoking behaviorusing multiple regression models (Table 4) andsubgroup analyses (Fig 2). These analyses showedthat most of the effect of smoking status on AR couldbe attributed to the attendant changes in FEV1 thatare associated with smoking status. There was, how-ever, an interaction between smoking status andchange in pulmonary function such that continuingand intermittent smokers who demonstrated littlechange in lung function had greater increments inAR than sustained quitters with similar changes intheir FEV1 (Fig 2). Therefore, we think that there isa direct effect of cigarette smoking on the progres-sion of AR, possibly due to inflammatory or neuro-genic mechanisms, that is separable from the effecton lung geometry, although the effect is small.

Potential Limitations of the Study

It is possible that there was some unrecognizeddrift in our technique for methacholine testing overtime, despite rigorous efforts to standardize ourprocedures. These procedures included centralizedcompounding of the methacholine solutions by areference pharmacy, centralized calibration and dis-tribution of the nebulizers and dosimeters, andrigorously standardized spirometric procedures.7Concerns about the stability of methods are inherentin any longitudinal study design. Our confidence thatthe study group demonstrated a progression of AR issupported by similar cross-sectional findings in gen-eral population samples. Moreover, while concernsabout the stability of the testing methods would limitthe strength of our conclusions about the overallprogression of AR in the population, secular changesshould not bias the analysis of differences betweensubgroups of participants who were subjected to thesame testing procedures. Another potential limita-tion of the study presented here is that those indi-viduals with the lowest levels of lung function who

died, who developed interval heart diseases, who hadsevere reactions at initial testing, or who refusedsubsequent testing were excluded from retesting.Since all of these criteria would tend to excludeindividuals with the lowest lung function and theworst general health status, it is likely that our resultswould be biased toward showing less progression ofAR. Because of the possibility that there was infor-mative censoring of the responsiveness data, wemust be somewhat guarded in interpreting the effectof the treatment assignment. Overall, however, wethink that it is reasonable to conclude that factorsthat slow the decline in FEV1 will also slow theprogression of AR.

Summary and Conclusions

In summary, we have found that a cohort ofvolunteers with mild-to-moderate COPD who en-rolled in a clinical trial of smoking cessation andinhaled anticholinergic bronchodilator therapy showedcontinuing increases in AR. This progression wasgreater mainly in those who had the greatest decline inFEV1 but also occurred in older individuals and con-tinuing smokers.

Appendix: List of Participants in the LHSResearch Group

The principal investigators and senior staff of the clinical andcoordinating centers, the National Heart, Lung, and BloodInstitute, members of the Safety and Data Monitoring Board, andthe Morbidity and Mortality Review Board are as follows.

Case Western Reserve University, Cleveland, OH

M.D. Altose, MD (Principal Investigator); A.F. Connors, MD(Co-Principal Investigator); S. Redline, MD (Co-Principal Inves-tigator); 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-PrincipalInvestigator).

Mayo Clinic, Rochester, MN

P.D. Scanlon, MD (Principal Investigator); L.J. Davis, PhD(Co-Principal Investigator); R.D. Hurt, MD (Co-Principal Inves-tigator); 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 QualityControl 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 Pul-monary Function Coordinator).

University of Alabama at Birmingham, AL

W.C. Bailey, MD (Principal Investigator and Associate Chief ofStaff for Education, Department of Veterans Affairs MedicalCenter, Birmingham, AL); C.M. Brooks, EdD (Co-PrincipalInvestigator); J.J. Dolce, PhD; D.M. Higgins; M.A. Johnson; andB.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-PrincipalInvestigator); 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; andI.P. Zuniga.

University of Manitoba, Winnipeg, MB, Canada

N.R. Anthonisen, MD (Principal Investigator, Steering Com-mittee 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. Dur-kin; P.L. Enright, MD (former Principal Investigator, MayoClinic); 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 (formermember); 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. ofEpidemiology 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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DOI: 10.1378/chest.124.2.449 2003;124;449-458 Chest

Altose, Paul L. Enright and Donald P. Tashkin Robert A. Wise, Richard E. Kanner, Paula Lindgren, John E. Connett, Murray D.

Reactivity in COPD: The Lung Health StudyThe Effect of Smoking Intervention and an Inhaled Bronchodilator on Airways

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