Hyperresponsiveness as a Determinant of the Outcome in Chronic Obstructive Pulmonary Disease 1 - 3 DIRKJE S. POSTMA, JOHAN B. WEMPE, TINEKE E. J. RENKEMA, THOMAS W. VAN DER MARK, and GERARD H. KOETER

Introduction Airway hyperresponsiveness is a characteristic feature in allergic patients with sudden attacks of reversible airflow obstruction: asthma. It presents itself in the patient with cough, dyspnea, and/or wheezingon exposure to cold air, chemical compounds, smoke, cooking smells, etc. Complaints of acute episodes of cough and/or dyspnea also commonly occur at intervals in patients with persistent, and never fully reversible, airflow obstruction (chronic obstructive pulmonary disease, COPD). In a laboratory setup such complaints are generally recognized by patients with COPD when a bronchoconstricting response is induced by methacholine and/or histamine, for example (1). The importance of increased airway responsiveness in asthma is illustrated by the observation that the severity of the responsiveness is related to the need for medication to suppress asthma symptoms (2). Some cross-sectional studies show that the severityof airway hyperresponsiveness also is related to the severity of current asthma symptoms (3-5). The relationship becomes, however,less close when serial measurements are performed and individual levels of hyperresponsiveness are related to concurrent asthma severity (6). Knowledge on the clinical significance of hyperresponsiveness in COPD is scarcer. It seems to be associated with, and may itself be, an important risk factor that can predict the insidious and progressive loss of pulmonary function, which may ultimately lead to COPo. In this report, we discuss the importance of airwayhyperresponsiveness in the outcome of COPD and current pharmacologic possibilitiesto modulate hyperresponsiveness. Relation of Airway Hyperresponsiveness with Outcome of Disease in COPD It is accepted that survival in patients with COPD is generally shorter than in age- and sex-matched healthy subjects. FEV, is the best predictor with respect to survival: the lower the FEV" the worse is survival (7, 8). Age is the second most important predictor, increasing age of course being associated with an increasing risk of mortality. Next to these two important variables, smoking, reversibility of airflow obstruction, and level of airway responsiveness are influencing the outcome of disease (9-15). . Another way of expressing outcome of disease is looking at the rate of decline of FEV, over time. A rapid change in FEV, indicates rapid disease progression, ultimately leading to mortality. In a healthy population, the 1458

SUMMARY A better outcome of patients with chronic obstructive pulmonary disease (COPO) appears to be determined by higher FEV1, smoking cessation, lower airway hyperresponslveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for Institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponslveness in patients with COPO. But there are large gaps In our understanding of the effects of bronchodilator and antIInflammatory drugs on airway hyperresponslveness. After acute administration, sympathomimetlcs cause a larger reduction of airway hyperresponslveness than do ant/chollnergics, both In asthma and In COPO. What happens after longer periods of treatment Is not yet clear In COPO, whereas in asthmathere may occur a deterioration of airway responsiveness. Corticosteroids appear to have a beneficial effect on lung function and the severity of airway hyperresponslveness in asthma. In COPO, however, no definite conclusion can be drawn as to the beneficial effect of corticosteroids, but short·term effects are not promising. The available dats from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way, also, a subgroup of patients with COPO who Improve with corticosteroids and/or bronchodllators may be found. It seems advisable to Include both subjective (I.e., quality of life, complaints, symptoms) and objective (I.e•• hospitalization, survival, FEV" PEFR, PC,., and reversibility) data as Investigational tools for outcome analysis. AM REV RESPIR DIS 1991; 143:1458-1462

FEV, decreases 20 to 30 mllyr. In patients with COPD this is accelerated to 40 to 80 mllyr (individual values have even been presented as high as 200 mllyr [16]). Factors associated with a more rapid fall in FEV, over time are level of FEV" smoking, degree of reversibility of airflow obstruction, and level of airway hyperresponsiveness. Patients with a low FEV, are shown to exhibit a slow decline in lung function (12). This is most likely accounted for by a survivor effect; only when decreasesin FEV, weresmall did patients survive long enough to generate data to calculate the decline in FEV,. Smoking is shown to be negatively associated with decline in FEV, , smokers being reported to have a twofold higher fall in FEV, per year than exsmokers (16). Even in severely affected patients it seems worthwhile to quit smoking, as survival is better in quitters, as shown after 6 yr of follow-up (17). Independent of FEV" reversibilityof FEV, has been shown to be significantly related to decline in FEV, (9, 12-18). But results are conflicting: is reversibilitya good (12-17) or a bad (9, 18) sign? In the IPPB-study group (12) and in our group, patients were systematically treated with bronchodilators, in contrast to other studies. When patients receiving regular therapy demonstrate a higher degree of reversibilityto be related to a favorable course in FEV" and in untreated patients this association is found to be the opposite, thissuggests an influence oftreatment on prognosis. Regular bronchodilating therapy may in-· fluence rate of decline of FEV I and course of COPD, a hypothesis that is now being

tested in the United States and in The Netherlands. Barter and Campbell (9) were the first to note that a higher degree of hyperresponsiveness was related to a poorer outcome of disease in COPD. We observed, in a retrospective study (16) in 81 patients with COPD and a follow-up of 20 yr, also that a higher degree of airway hyperresponsiveness was correlated with a steeper fall in FEV,. With a PC,o histamine ~ 2 mg/ml, the mean (± SD) fall in FEV, was 127 ± 59 mIlyr, with a PC,o histamine> 4 mg/ml, a mean fall of47 ± 22 mllyr occurred. That hyperresponsiveness seems to exacerbate both the development of airflow obstruction and progressiveloss of lung function in patients with COPD, especially in smokers, may have important implicationsfor management. It is theoretically possible that diminishment of airway responsivenessin patients with asthma and COPD may not only decrease the actual complaints of sudden attacks of airflow obstruction but may also beneficially influence the outcome of the disease.

I From the Department of Pulmonology, University Hospital, Groningen, Groningen, The Netherlands. z Supported in part by The Netherlands Asthma Foundation. 3 Correspondence and requests for reprints should be addressed to Dirkje S. Postma, Department of Pulmonology, UniversityHospital Groningen, Oostersingel 59, 9713 E2 Groningen, The Netherlands.

1459

HYPERRESPONSIVENESS AS A DETERMINANT OF THE OUTCOME IN COPD

Acute Effect of Bronchodilators on Hyperresponsiveness Asthma Several studies have looked at the effect of drugs on airway hyperresponsiveness in asthmatic patients, using different doses, timing, and routes of administration. Most studies have looked at a change in airway hyperresponsiveness in the first fewhours after inhalation of a single dose of the drug. Inhaled sympathomimetics in therapeutic doses give acute dose-dependent protection against airway hyperresponsiveness to provoking stimuli. The effect of anticholinergics is variable. When the protective effects of sympathomimetics and anticholinergics are compared in the same asthmatic patient, the change in airway hyperresponsiveness for a given degree of bronchodilation seems to be more pronounced after the sympathomimetic than after the anticholinergic drug (19-22). The increase in the provocative dose (PD) or provocative concentration (PC) that causes a given response, usually a 200/0 fall in FEV, (PD,oFEV.. PC,oFEV,), ranges from 1.1 to 3.8 doubling doses (DD) for sympathomimetics. The increases have been larger when sympathomimetics have been given by inhalation than when given orally. The protective effect of anticholinergics ranges from 0.5 to 1.5 DD. The magnitude of the change in airway hyperresponsiveness after sympathomimetics appears to be dose related. Britton and coworkers (22) investigated six asthmatic patients after four doses of salbutamol (5, 30, 200, and 1,000J.1g) and four doses of ipratropium bromide (lb; 5, 30, 200, and 1,000 J.1g) on separate days. There was a clear doserelated reduction in airway hyperresponsiveness after salbutamol in parallel with the increase in FEV, (maximal change, 0.7 L), improvement being 0.3, 1.1, 1.5, and 3.0 DD, respectively, for the four doses. This doserelated effect could not be observed after the inhalation of lb. When doses of salbutamol (S) and Ib that were equipotent in terms of bronchodilatation were compared, S produced a much greater increase in PD, suggesting that bronchodilation had little effect on airwayresponsiveness in this patient group.

COPD There are only a few studies on the protection of bronchodilators in patients with COPD. One study showedthat despite irreversibility of airflow obstruction, airway responsiveness improved after an inhaled sympathomimetic (23). Inhaled Ib had, however, no effect (24). Another study investigated the effect of a sympathomimetic and anticholinergic drug in both patients with asthma and those with COPD (25). It compared the merits of 2 mg of the anticholinergic drug oxyfenonium bromide with that of 0.08 mg of the sympathomimetic drug fenoterol, both givenintramuscularly. In asthmatics fenoterol had a twofold better protection against histamine than did oxyfenonium. The same effect was observed after inhalation of SO,. In the group with COPD, how-

TABLE 1 CLINICAL CHARACTERISTICS OF TWO STUDY GROUPS

Number Used for analysis. n Age, yr Sex Smoking status FEV" % pred PC•• histamine, mglml

Asthma

COPD

12 10 28.8 (2.41)* 2 F, 8 M 8 N, 2 E 67.6 (2.25) 0.37

12 9 61.2 (1.22) 2 F, 7 M 1 N, 3 E, 5 S

59.4 (3.51) 0.55

• Geometric mean shown in parentheses.

ever, the anticholinergic had a threefold better effect against histamine than the sympathomimetic. As in asthmatics, the effect on SO,-provocation was the same; these effects could not simply be explained by effects on FEV.. as postbronchodilator FEV, values were comparable for both drugs. Thus, the sympathomimetic drug provided the greatest protective effect in asthmatics and the anticholinergic in patients with COPD. As the protective effects were tested with intramuscularly applied bronchodilators, results are, however, not comparable with inhaled drugs.

.

chodilator allowsthe followingdoses to reach more peripheralbronchi. Differencesin results as compared with other studies may thus result from differences in application and dosing of the bronchodilators. As the doseresponse curves were indicative for a plateau in FEV, levels, our results suggest that the dominant role for the cholinergic pathway in airflow obstruction in COPD has to be reconsidered. Salbutamol provided also a stronger protection against histamine than did Ib, reduction in PC,o being 3.9 and 2.7 DD for S, and 1.1 and 1.0DD for Ib in patients with asthma or COPD, respectively.The beneficial effect of S was greater in the asthmatic group than in the COPD group, even more so when the overallincrease in %FEV, of S wastaken into account. It is accepted that a positive correlation exists between PC,o values and FEV, values below a level in %FEV, of 70. One would, therefore, expect a bigger change in PC,o histamine when %FEV, changes from 57to 72% (COPD) than when it changesfrom 68 to 93% (asthma). The difference in protection of Ib betweenthe two groups is negligible, as the differenceis only 0.2DD and within the measurement error.

Comparison oj Asthma and COPD In a recent study, we measured changes in PC,o histamine in 10 patients with asthma and in nine patients with COPD (table 1). PC,o was measured after nebulized salbutamol and ipratropium bromide in doubling doses until a plateau in FEV, was reached, concentrations of S being 0.94, 1.88, 3.75,7.50, and 15.00mg and concentrations orIb being 0.19,0.35, 0.75,1.50, and 3.00mg. The change in PC,o after bronchodilation was compared with that after nebulized saline (placebo, P) in a double-blind, randomized order. On the third concentration of bronchodilator, no patient showed an improvement of more than 5% in FEV, when FEV, Long.:rerm Effects of Bronchodilators valueswerecompared with those after the secon Hyperresponsiveness ond concentration. Salbutamol produced a Asthma higher bronchodilator effect than did Ib in both study groups. Postbronchodilator FEV, Only a few studies have looked at the change percent predicted (%FEV,) levels for asthin hyperresponsiveness after sympathomimatic patients were 67, 82, and 94% for P, .metics when given daily for several weeks in Ib, and S,respectively. In patients with COPD, asthmatics (33-35). As modulation of airway %FEV, values were 57,68, and 72 for P, IB, hyperresponsiveness has only been measured and S, respectively. when the bronchodilator effect had disapIt has been well established that Sand Ib peared, from 6 h to 4 wk after the dose, comare both potent bronchodilators. Youngasthparison with single-dose studies are not justimatics seemto respond better to sympathomi- fied. Although resultsshow a disadvantageous metics (26-28), whereas patients with COPD effect on hyperresponsiveness, interpretation show an equal or even better response to an- is hampered by the design of the studies. It ticholinergic drugs (26, 27, 29-31), at least concerns single treatment studies where corwhen single doses of anticholinergics and ticosteroids are withdrawn from the patients. sympathomimetics were given. Our study This generally results in a deteriorating clinishows that S has a stronger bronchodilator cal state of the patients. It may thus well be effect than Ib in both individuals with asthma that the small decrease in PC,o values after and COPD patients. In contrast to other the sympathomimetic period is only the restudies, however, we used doubling doses of sult of prolonged withdrawal of corticostebronchodilators until the maximal attaina- roids and not of the introduction of sympathble bronchodilation was reached. Cumulative omimetics. Studies with a (third crossover) dose-response studies are known to show a placebo period, although time-consuming greater airway response than noncumulative and hampered by a high dropout rate, are and single-dose studies (32). This probably therefore necessary. One study, however, resultsfrom the fact that the first dose ofbron- showed that an increase inairway responsive-

POSTMA, WEMPE, RENKEMA, VAN DER MARK, AND KO~TER

1460 bud = budesonid1i! beel 0; biodomethCS 63070; FEV!OJo VC, 48070; PC zo histamine, 8.8 with 30-s inhalation method) and 129 with severe airflow obstruction (mean OJoFEV1> 25070; FEV 10/0 VC, 270/0, PCzo histamine. 4.0 mg/ml with 30-s inhalation method). Orally administered prednisone in a dosage of at least 10mg/day was associated with a halt in annual decline in lung function. It took, however, between 6 months and 2 yr before the effects of corticosteroids on FEV I could be observed.

Initial conflicts in the 1950s and 1960s on the benefit of orally administered prednisolone in COPD may have largely resulted from the fact that studies on case series, observational cohort studies, or nonrandomized studies were presented. A few studies exist with a good study design (43-52). When response to therapy after 7 to 14 days is defined as an increase in FEV 1 of at least 20070, these studies show some responders, ranging from 7 to 430/0 of the mostly rather small study groups. Analysis of the available presented data in the literature suggests that a response may occur irrespective of baseline FEV! (53), and occurs over a wide scale of FEV 1 values. It is as yet not clear whether patients with higher sputum and/or blood eosinophil numbers, or perhaps neutrophils, or a higher reversibility after inhaling five sympathomimetics are better responders with regard to lung function. We have recently assessed the effects of 4 days of prednisolone given orally in 57 patients with COPD and clinical symptoms suggesting emphysema (52). Twenty-five smokers and 32 ex-smokers were investigated. Mean OJoFEV 1 (smokers, 61.5; ex-smokers, 62.4070) and geometric mean PC 10 histamine (smokers, 4.72; ex-smokers, 5.69 mg/mi with the 30-s inhalation method) were not significantly different between smokers and ex-smokers receiving placebo. OJoFEV1 did not change significantly (smokers, 59.6; ex-smokers, 61.4070) with placebo. PC zo histamine with prednisolone was, however, significantly lower in smokers (geometric mean, 3.78 mg/ml) than in ex-smokers (geometric mean, 6.52 mg/rnl). Thus, short-term, orally administered corticosteroids may even worsen hyperresponsiveness in clinically stable, smoking patients with COPD. This deleterious effect might hypothetically result from continuation of the smoke stimulus, whereas the antiinflammatory corticosteroid dampens the defense. Results on inhaled corticosteroids, with regard to lung function and hyperresponsiveness, in non-prednisolone-treated patients with COPD are even scarcer. But they support the above-mentioned negative effects of orally administered corticosteroids in smokers with COPD. Auffarth and coworkers (54) recently investigated 24 nonallergic patients WIth COPD (mean age, 57yr; mean OJoFEV h 53070; range, 32 to 74070; geometric mean PC1 0 histamine, 1.07 mg/ml). After 8 wk of treat-

Comparison of Asthma and COPD

Conclusions A better outcome of patients with COPD appears to be determined by higher FEV 1, smok-

HYPERRESPONSIVENESS AS A DETERMINANT OF THE OUTCOME IN COPO

ing cessation, lower airway hyperresponsiveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponsiveness in patients with COPD. But there are large gaps in our understanding of the effects of bronchodilator and antiinflammatory drugs on airway hyperresponsiveness. After acute administration, sympathomimetics cause a larger reduction of airway hyperresponsiveness than do anticholinergics, both in asthma and in COPD. What happens after longer periods oftreatment is, however, as yet not clear in COPD. Corticosteroids appear to have a beneficial effect on the clinical symptoms, lung function, and the severity of airway hyperresponsiveness in asthma, although improvement in PC,o values is rather small even after several weeks of follow-up. In COPD, however, no definite conclusion can be drawn as to the profitable effect of corticosteroids on airway hyperresponsiveness, but short-term effects are not promising. The available data from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way also, a subgroup of patients with COPD who improve with corticosteroids and/or bronchodilators may be found. It seems advisable to include both subjective (i.e.,quality of life, complaints, symptoms) and objective (i.e., hospitalization, survival, FEV1, PEFR, PC,o, and reversibility) data as investigational tools for outcome analysis.

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1462 47. Mitchell DM, Gildeh P, Rehahn M, Dimond AH, Collins JV. Effects of prednisolone in chronic airflow limitation. Lancet 1984; ii:193-5. 48. O'Reilly JF, Shaylor JM, Fromings KM, Harrison BDW. The use of the 12minute walking test in assessing the effect of oral steroid therapy in patients with chronic airways obstruction. Br J Dis Chest 1982; 76:374-82. 49. Shim C, StoverDE, WilliamsMH Jr. Response to corticosteroids in chronic bronchitis. J Allergy Clin Immunol 1978; 62:363-7. 50. Strain DS, KinasewitzGT, Franco DP, George RB. Effect of steroid therapy on exercise performance in patients with irreversiblechronic obstructive pulmonary disease. Chest 1985; 88:718-21. 51. Stokes TC, O'Reilly JF, Shaylor JM, Harrison BOW. Assessment of steroid responsiveness in patients with chronic airflow obstruction. Lancet 1982; ii:345-8. 52. Renkema TEJ, Postma DS, Sluiter HJ. Modulation of airway hyperreactivity by prednisolone in patients with emphysema (abstract). Am Rev Respir Dis 1988; 137(4, part 2:242). 53. Postma DS, Renkema TEJ, Koeter GH. Effects of corticosteroids in "chronic bronchitis" and "chronic obstructive airway disease." Agents Actions. 1990; 30(Suppl.):41-57. 54. Auffarth B, Postma DS, de Monchy JGR, Van der Mark ThW, Boorsma M, Keeter GH. Effects of inhaled budesonide on spirometry, reversibility, airway responsiveness, and cough threshold in smokers with COPD. Thorax 1991 (In Press). 55. Pride NB, Taylor RG, Lim TK, Joyce H, Watson A. Bronchial hyperresponsiveness as a risk factor for progressive airflow obstruction in smokers. Bull Eur Physiopathol Respir 1987; 23:369-75. 56. Engel T, Heinig JH, Konar A, Madsen 0, Weeke ER. Airway reactivity at smokers with chronic bronchitis; a double blind placebo controlled study of inhaled budesonide. J Allergy Clin Immunol 1986; 77:153. 57. Postma DS, Peters I, Steenhuis EJ, Sluiter HJ. Moderately severechronic airflow obstruction. Can corticosteroids slow down progression? Eur Respir J 1988; 1:22-6. 58. Postma DS, Steenhuis EJ, Vander WeeleLTh Sluiter HJ. Severe chronic airflow obstruction--':

Can corticosteroids slow down progression? Eur J Respir Dis 1985; 67:56-64.

Dr. Anderson: Prednisone and aerosol steroids may not have different actions, but they will have different time courses.

Dr. Pride: Have you had the opportunity to follow changes in bronchial hyperresponsiveness before and after stopping smoking? We know that stopping smoking is an extremely effective antiinflammatory treatment in COPD, but what its effect is on lung function decline takes a long time to become obvious. Dr. Postma: From our data it appears that it will take at least 6 yr before survival has improved after smoking cessation. We have no data on PC 20 values at follow-up. It may well be that the reason that our group of smokers shows a decrease (though not significant) in PC 20 after corticosteroids, whereas ex-smokers improve, is caused by the continuation of the irritating effect of smoke while the defense is diminished by antiinflammatory drug treatment.

Dr. O'Byrne: Could there be an association betweenthe outcome and airwayhyperresponsiveness in patients with COPD because the patients with more severe disease have more airflow obstruction and therefore are more hyperresponsive rather than that more airway hyperresponsiveness causes more severe COPD? Dr. Postma: Firstly: A lower level of FEV 1 is related to worse survival but to less decline in FEV 1. This largely results from a survivor effect. Secondly:The severityof airwayhyperresponsiveness in COPD is negatively associated with the level of airway obstruction. When we analyzed our group of 81nonatopic patients with COPD, we found, however,that a lower PC 20 histamine at the beginning of the study was related to a faster decline of ~EV1 after a 20-yr follow-up period, irrespective of the initial FEV 1 value. This may be due to the fact that the range of FEV 1 of the patients in this study was small. Our observations have to be repeated in larger groups of patients with COPD.

Dr. Woolcock: Eventually we will need to know if inhaled corticosteroids have a longterm effect on FEV 1 in COPD. Thus, good trials are needed. In such trials it may be important to ensure that the drug reaches the small airways, and this may require the use of a nebulized form of the drug. In addition, it will be necessary to look at the effects over long periods of time. Dr. Postma: I fully agree. Our two studies on prednisone in patients with COPD show that we need a long observation time, as the effects wereonly apparent after 6 to 24 months.

Dr. Pare: Would you care to speculate on how long-term therapy with a beta-adrenergic or anticholinergic agent could affect the natural history in patients with COPD? Dr. Postma: Bronchodilators havetwo effects: (1) bronchodilation, which is smaller in patients with COPD than in asthmatics, and (2) protection against irritating stimuli in patients with COPD. We have shown that the acute protective effect against histamine in patients with COPD who are maximally bronchodilated with salbutamol is better than that after ipratropium bromide.

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