Background Although the prevalence of asthma and morbidity relatedto asthma are increasing, little is known about the naturalhistory of lung function in adults with this disease.
Methods We used data from a longitudinal epidemiologic studyof the general population in a Danish city, the Copenhagen CityHeart Study, to analyze changes over time in the forced expiratoryvolume in one second (FEV1) in adults with self-reported asthmaand adults without asthma. The study was conducted between 1976and 1994; for each patient, three measurements of lung functionwere obtained over a 15-year period. The final data set consistedof measurements from 17,506 subjects (8136 men and 9370 women),of whom 1095 had asthma.
Results Among subjects who participated in all three evaluations,the unadjusted decline in FEV1 among subjects with asthma was38 ml per year, as compared with 22 ml per year in those withoutasthma. The decline in FEV1 normalized for height (FEV1 dividedby the square of the height in meters) was greater among thesubjects with asthma than among those without the disease (P<0.001).Among both men and women, and among both smokers and nonsmokers,subjects with asthma had greater declines in FEV1 over timethan those without asthma (P<0.001). At the age of 60 years,a 175-cm-tall nonsmoking man without asthma had an average FEV1of 3.05 liters, as compared with 1.99 liters for a man of similarage and height who smoked and had asthma.
Conclusions In a sample of the general population, people whoidentified themselves as having asthma had substantially greaterdeclines in FEV1 over time than those who did not.
Although asthma is a very common condition with increasing prevalence,its natural history has not been well described.1 Recent studiesof patients with asthma selected from the general populationhave shown increased mortality in subjects with reduced ventilatoryfunction and have thus underlined the importance of preservationof normal lung function.2,3,4 Although a few previous studieshave reported the development of persistent airway obstructionin some patients with asthma, the data are limited.5,6 A fewstudies have focused on the decline of lung function in adultswith asthma, but the results are conflicting with regard bothto the magnitude of the effect of asthma and to the effect ofsmoking on lung function and decline in lung function.7,8,9,10,11
We analyzed changes in forced expiratory volume in one second(FEV1) among subjects with self-reported asthma and those withoutasthma in the general population. The analyses are based onthe 15-year follow-up of the participants in the CopenhagenCity Heart Study, an ongoing epidemiologic study of people wholive in the city of Copenhagen, Denmark.
Methods
Study Population
The subjects participated in the Copenhagen City Heart Study,a prospective epidemiologic study initiated in 1976. Detailsof the selection procedure, a description of the eligible nonparticipantsand the complete examination program, and information on thesubjects have been presented elsewhere.12,13,14 We previouslyreported that mortality among the subjects with asthma in thiscohort was approximately 1.6 times as high as that among thesubjects without asthma.3 Data from the first five years offollow-up also showed a trend toward a greater decline in FEV1among subjects with asthma.11 We now analyze data on FEV1 valuesfrom the 15-year follow-up evaluation of each patient.
The study sample, consisting of 19,698 persons, was selectedin January 1976 from a population of approximately 90,000 residentsof Copenhagen who were 20 years of age or older and who werelisted in the Copenhagen Population Register. The first examinationround lasted 25 months, from February 27, 1976, to March 31,1978. A total of 14,223 subjects were examined, 74 percent ofthose who were invited and were still alive. The response rateswere highest among subjects between 40 and 70 years of age (68to 80 percent) and lowest among subjects 80 years old or older(28 to 41 percent).
At the end of the first examination, we planned to visit a randomsample of 223 subjects selected from among the nonparticipantsin order to determine whether they differed significantly fromthe participants. However, only 67 of these people (30 percent)could be contacted, despite several attempts. The prevalenceof asthma and chronic mucus hypersecretion among the nonparticipantswho were visited in their homes was slightly higher than amongthe participants. Between 1981 and 1983, the whole populationsample (both participants and nonparticipants), together witha new sample of 500 subjects 20 to 25 years of age, was invitedto undergo a second examination. A total of 12,698 of the 18,089subjects who were still alive were examined (response rate,70 percent). Finally, a third examination of the cohort, togetherwith an additional sample of 3000 subjects 20 to 39 years ofage, was performed between 1991 and 1994. A total of 10,127subjects participated in this examination (response rate, 61percent). After subjects with insufficient data for the analysesof FEV1 were excluded, the final data base consisted of 17,506subjects (8136 men and 9370 women) who were examined at leastonce during the study (Table 1). The study was approved by theethics committee for the city of Copenhagen, and all participantsprovided oral informed consent.
Table 1. Number of Examinations Undergone by the 17,506 Study Subjects.
Procedures
In the first and second examinations of the survey, FEV1 andforced vital capacity (FVC) were measured with an electronicspirometer (model N 403, Monaghan, Littleton, Colo.), whichwas calibrated daily with a 1-liter syringe and weekly againsta water-sealed Godard spirometer. In the third round of examinations,a dry wedge spirometer (Vitalograph, Maidenhead, United Kingdom),which was calibrated weekly with a 1-liter syringe, was used.Unfortunately, at the time of the third survey, the electronicspirometer used in the two previous examinations was no longerfunctioning, precluding a direct comparison between the resultsobtained with the two spirometers. After at least one trialblow, three values were obtained. As a criterion for correctperformance of the procedure, at least two measurements of FEV1and FVC differing by less than 5 percent had to be produced.The highest FEV1 was used in the analyses. Data on FEV1 arereported both as absolute values and as percentages of predictedvalues.11
A self-administered questionnaire concerning symptoms, somaticdiseases, socioeconomic status, smoking status, and drinkinghabits was completed by participants and reviewed by one ofthe investigators. Chronic hypersecretion of mucus was definedas bringing up phlegm during at least three months per yearfor at least two consecutive years. The subjects described themselvesas current smokers, as exsmokers, or as having never smoked.Exsmokers and those who had never smoked were classified asnonsmokers.
The subjects were categorized in terms of the presence or absenceof asthma. Like other epidemiologic studies, our study reliedon the subjects' perception of whether they had the disease.15,16Thus, the presence of asthma was defined by an affirmative responseto the question, "Do you have asthma?"
Statistical Analysis
After adjustment for height, we compared the mean FEV1 and themean decline in FEV1 with age within subgroups of subjects classifiedaccording to the presence or absence of asthma, smoking status,and the presence or absence of chronic hypersecretion of mucus.Separate comparisons were performed for men and women. The subgroupswere generated in the following way. Subjects who reported havingasthma during at least one examination were considered to havehad asthma throughout the 15-year observation period. This conclusionis consistent with previous observations that the lung functionof people in whom asthma develops is often reduced before thedisease becomes clinically apparent, probably reflecting thesubclinical course of the disease. It is also in line with theview of asthma as a disease that seldom disappears in adultsand that, even in remission, may result in reduced lung function.1,11,17Since chronic hypersecretion of mucus, like self-reported asthma,tended to be reported repeatedly by the same subjects throughoutthe examinations ("tracking"), subjects who reported havingchronic mucus hypersecretion at least once during the observationperiod were classified as having had hypersecretion during thewhole study period. On the other hand, because changes in smokinghabits influence the decline in FEV1 within a short time, andour analyses were mainly longitudinal and thus focused on changesin FEV1, we decided to relate lung-function measurements tosmoking status at the time of examination.18 The height-adjustedvalues for FEV1 (the FEV1 divided by the square of the heightin meters) and declines in FEV1 in different subgroups of subjectswere compared with use of both the Wilcoxon test and nonparametricanalysis of variance. All reported P values are based on two-sidedtests of significance.
Results
Table 2 shows the age, smoking status, presence or absence ofmucus hypersecretion, and results of spirometric tests of lungfunction among participants with and without asthma at the initialexamination. Participants with asthma had significantly lowerFEV1 values than those without asthma at the initial examinationand at subsequent examinations. During the follow-up period,the prevalence of asthma increased from 2.3 percent at the firstexamination to 3.3 percent at the second and to 6.3 percentat the third. Thus, 364 subjects who did not report having asthmaat either their first or their second examination did so ata later examination. In contrast, 79 subjects who reported havingasthma at either their first or their second examination didnot report having asthma at a later examination.
Table 2. Characteristics of the Subjects According to the Presence or Absence of Asthma at the First Examination in 1976–1978.
Among subjects who participated in all three surveys, the averagedecline in FEV1 was 22 ml per year in those without asthma and38 ml per year in those with asthma. Table 3 shows the observeddecline in FEV1 in subjects who participated in at least twoexaminations, according to sex, age, smoking status, and thepresence or absence of asthma. In most subgroups, subjects withasthma and smokers had a greater decline in FEV1 than thosewithout asthma and nonsmokers, respectively. Adjustment forheight did not change these findings.
Table 3. Annual Change in FEV1 in Subjects Who Participated in at Least Two Examinations.
Figure 1 shows changes with age in height-adjusted FEV1 accordingto sex, smoking status, and the presence or absence of asthma.The data are for 9370 women and 8136 men with at least one measurementof lung function. For both sexes, the levels of FEV1 were higherand the declines in FEV1 were less steep among subjects withoutasthma than among those with asthma. The average differencebetween subjects with asthma and those without asthma increasedwith age. The difference in the average value for FEV1 betweenthe two most extreme groups, nonsmokers without asthma and smokerswith asthma, was substantial. At 60 years of age, a 175-cm-tallnonsmoking man had an average FEV1 of 3.05 liters, as comparedwith 1.99 liters for a man of similar age and height who smokedand had asthma. The curves relating FEV1 to age were comparedbetween subjects with and without asthma. Among both men andwomen and among both smokers and nonsmokers, the curves differedsignificantly between subjects with asthma and those withoutasthma (P<0.001).
Figure 1. Changes with Age in the Height-Adjusted Forced Expiratory Volume in One Second (FEV1) According to Sex, Smoking Status, and the Presence or Absence of Asthma.
Values are means ±SE, based on 5-year age groups (bars are shown for each 10 years). The numbers of measurements in the various subgroups are shown in parentheses. The curves in each panel differ significantly from each other (P<0.001), indicating that among both men and women and among both smokers and nonsmokers, subjects with asthma had a significantly greater decline in FEV1 than those without asthma.
To evaluate the effect of mucus hypersecretion, we performedadditional analyses of data on subjects with asthma. Figure 2shows changes with age in height-adjusted FEV1 according tosex, smoking status, and the presence or absence of chronicmucus hypersecretion among subjects with asthma. There were1187 measurements of FEV1 for women and 944 measurements formen. In both sexes, the presence of mucus hypersecretion andsmoking was associated with a significantly greater declinein FEV1; smokers with asthma had the lowest values (P<0.01).
Figure 2. Changes with Age in the Height-Adjusted Forced Expiratory Volume in One Second (FEV1) According to Sex, Smoking Status, and the Presence or Absence of Chronic Mucus Hypersecretion among Subjects with Asthma.
Values are means ±SE, based on 5-year age groups (bars are shown for each 10 years). The numbers of measurements in the various subgroups are shown in parentheses. The curves in each panel differ significantly from each other (P<0.01), indicating that among both men and women with asthma and among both smokers and nonsmokers with asthma, subjects with chronic mucus hypersecretion had a significantly greater decline in FEV1 than those without chronic mucus hypersecretion.
Discussion
In this large, community-based study, people who identifiedthemselves as having asthma had substantially greater declinesin FEV1 over time than those who did not. Stratification accordingto smoking status showed that smoking significantly acceleratedthe decline in lung function in both subjects with asthma andthose without asthma. In addition, chronic mucus hypersecretionwas a significant marker of a greater decline in FEV1 in peoplewith asthma, regardless of their smoking status. This observationsuggests that the response to this rather simple and old-fashionedquestion regarding sputum production still has important clinicalimplications. Our findings are in keeping with previous resultsfrom this cohort, which showed increased mortality among peoplewho reported themselves as having asthma; this increase wasmediated mainly through the reduced level of ventilatory function.3
The greater decline in FEV1 among subjects with asthma was apparentfrom both the raw data on the subgroup of subjects who participatedin at least two examinations (Table 3) and from our analysisof FEV1 in all subjects (Figure 1). A conclusion drawn solelyon the basis of the decline in lung function among those whounderwent several examinations may be subject to bias, sincethe decline in FEV1 in this survivor population is likely tohave been less steep than that in the whole sample.
In order to account for the longitudinal nature of the dataand for the correlation of repeated measurements in individualsubjects, we also performed a more detailed analysis, in whichwe modeled FEV1 using a specific method for covariate-dependentrandom effects.19 A nonlinear mixed-effects model with asthma,age, and smoking status as covariates was developed to incorporateFEV1 measurements from all subjects who underwent at least oneexamination.20 Since the results of these analyses were consistentwith those of our simpler analyses, only the results of thesimpler analyses are presented.
Our findings suggest that every effort should be made to keepthe lung function of people with asthma at the highest achievablelevel. Although not smoking is clearly desirable, even peoplewith asthma who did not smoke had, on average, a significantlygreater decline in FEV1 than other nonsmokers in our study.A study of early and continuous treatment of mild asthma withinhaled steroids for up to three years found beneficial effects,not only in terms of symptoms of asthma but also in terms oflung function.21,22 However, there is at present no definiteevidence that long-term treatment with any asthma medicationcan prevent the decline in lung function. Unfortunately, sinceour only detailed information on medications used comes fromthe last examination, between 1991 and 1994, we were unableto evaluate prospectively the effect of treatment on the declinein FEV1.
The results of previous studies of the decline in FEV1 in peoplewith asthma are generally consistent with our findings, butthere are exceptions. In the study by Fletcher and coworkers,23the mean unadjusted decline in FEV1 was 22 ml per year greaterin men with asthma than in men without asthma, a value similarto the 16 ml per year found in our study. In the studies ofPeat and coworkers and in our report of the five-year follow-up,a similar pattern was observed, but the results were not alwaysstatistically significant.8,11 These studies and earlier Danishstudies of patients in chest clinics used less sophisticatedstatistical models, mainly simple linear regression models.9,10However, in the Tucson lung study,7 declines in FEV1 of lessthan 5 ml per year were observed in adults with asthma. Clinicalreports based on small numbers of patients with long-standingasthma have shown that persistent airway obstruction developedin many such patients, but it is not known whether this is anexception or a common finding in asthma.5,6,24 In a recent reportof 25-year follow-up data on adults from a Dutch asthma clinic,more than 75 percent of the patients had FEV1 values below 90percent of the predicted values at the final examination.25Our findings and most previous reports are thus in line withthe perception that asthma is a chronic inflammatory diseasein which ongoing tissue injury and repair may result in irreversiblefibrotic changes in the airways.26,27 In addition, since bronchialhyperreactivity is considered a central feature of asthma, ourobservation of an increased decline in FEV1 with age among peoplewith asthma is also conceptually in line with the hypothesisthat increased airway responsiveness is a risk factor for anaccelerated decline in lung function.28,29
The finding that chronic mucus hypersecretion was a significantmarker of an accelerated decline in FEV1 is also in accordancewith our previous findings of changes in lung function in subjectswithout asthma during the first five years of our survey.30Mucus hypersecretion is quite prevalent in people with asthmaand could be regarded as an indicator of poor control of asthmaand severe disease.31,32 Although we are unaware of pathoanatomicalstudies linking airway inflammation in asthma with sputum production,such correlations have been reported in patients with chronicbronchitis.33
The most important potential bias in our study concerns theclassification of asthma.3 The use of a patient's report ofthe diagnosis invariably leads to some degree of misclassification,because the condition will remain undiagnosed in some subjectswith mild asthma, whereas some subjects with chronic obstructivepulmonary disease will probably report that they have asthma.However, since the prevalence of self-reported asthma in ourcohort was only around 6 percent and showed no increase withage, we do not think that many subjects who reported havingasthma in fact had smoking-induced chronic obstructive pulmonarydisease. Finally, because asthma had a consistent negative influenceon the FEV1, regardless of smoking status, misclassificationof asthma and chronic obstructive pulmonary disease is unlikelyto have biased our results severely.
In conclusion, we found that adults with self-reported asthmahad a greater decline in FEV1 over time than those without asthmaand that smoking adversely influenced this course. Special effortsshould be made to motivate people with asthma not to smoke,and long-term studies should evaluate treatments to postponethe accelerated decline of lung function that occurs in peoplewith asthma.
Supported by grants from the National Union against Lung Diseases,the Danish Heart Foundation, the Danish Ministry of Culture,the Danish Ministry of Health, the Velux Foundation, and theDanish Medical Research Council.
Source Information
From the Copenhagen City Heart Study, Epidemiologic Research Unit, Bispebjerg University Hospital (P.L., J.P., J.V., P.S., G.J.); the Department of Respiratory Medicine 129, Hvidovre Hospital and University of Copenhagen (P.L., J.V.); and the Department of Biostatistics, University of Copenhagen (J.P.) — all in Copenhagen, Denmark.
Address reprint requests to Dr. Lange at the Department of Respiratory Medicine 129, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
References
Burrows B. Airways obstructive diseases: pathogenetic mechanisms and natural histories of the disorders. Med Clin North Am 1990;74:547-559.
Silverstein MD, Reed CE, O'Connell EJ, Melton LJ III, O'Fallon WM, Yunginger JW. Long-term survival of a cohort of community residents with asthma. N Engl J Med 1994;331:1537-1541. [Free Full Text]
Lange P, Ulrik CS, Vestbo J. Mortality in adults with self-reported asthma. Lancet 1996;347:1285-1289. [Medline]
Huovinen E, Kaprio J, Vesterinen E, Koskenvuo M. Mortality of adults with asthma: a prospective cohort study. Thorax 1997;52:49-54. [Free Full Text]
Finucane KE, Greville HW, Brown PJE. Irreversible airflow obstruction: evolution in asthma. Med J Aust 1985;142:602-604. [Medline]
Connolly CK, Chan NS, Prescott RJ. The relationship between age and duration of asthma and the presence of persistent obstruction in asthma. Postgrad Med J 1988;64:422-425. [Abstract]
Burrows B, Bloom JW, Traver GA, Cline MG. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med 1987;317:1309-1314. [Abstract]
Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987;70:171-179. [Medline]
Almind M, Viskum K, Evald T, Dirksen A, Kok-Jensen A. A seven-year follow-up study of 343 adults with bronchial asthma. Dan Med Bull 1992;39:561-565. [Medline]
Ulrik CS, Backer V, Dirksen A. Mortality and decline in lung function in 213 adults with bronchial asthma: a ten-year follow up. J Asthma 1992;29:29-38. [Medline]
Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med 1994;150:629-634. [Abstract]
Jensen G. Epidemiology of chest pain and angina pectoris. Acta Med Scand Suppl 1984;602:1-120.
Appleyard M, ed. The Copenhagen City Heart Study: Østerbroundersøgelsen: a book of tables with data from the first examination (1976-78) and a five year follow-up (1981-83). Scand J Soc Med Suppl 1989;41:1-160. [Medline]
Lange P, Groth S, Mortensen J, et al. Pulmonary function is influenced by heavy alcohol consumption. Am Rev Respir Dis 1988;137:1119-1123. [Medline]
Torén K, Brisman J, Järvholm B. Asthma and asthma-like symptoms in adults assessed by questionnaires. Chest 1993;104:600-608. [Free Full Text]
Enarson DA, Vedal S, Schulzer M, Dybuncio A, Chan-Yeung M. Asthma, asthmalike symptoms, chronic bronchitis, and degree of bronchial hyperresponsiveness in epidemiologic surveys. Am Rev Respir Dis 1987;136:613-617. [Medline]
Boulet L-P, Turcotte H, Brochu A. Persistence of airway obstruction and hyperresponsiveness in subjects with asthma remission. Chest 1994;105:1024-1031. [Free Full Text]
Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA 1994;272:1497-1505. [Abstract]
Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982;38:963-974. [CrossRef][Medline]
Vonesh EF, Carter RL. Mixed-effects nonlinear regression for unbalanced repeated measures. Biometrics 1992;48:1-17. [CrossRef][Medline]
Haahtela T, Järvinen M, Kava T, et al. Comparison of a 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-392. [Abstract]
Haahtela T, Järvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-705. [Free Full Text]
Fletcher C, Peto R, Tinker C, Speizer FE. The natural history of chronic bronchitis and emphysema: an eight-year study of early chronic obstructive lung disease in working men in London. Oxford, England: Oxford University Press, 1976.
Backman KS, Greenberger PA, Patterson R. Airways obstruction in patients with long-term asthma consistent with `irreversible asthma.' Chest 1997;112:1234-1240. [Free Full Text]
Panhuysen CIM, Vonk JM, Köeter GH, et al. Adult patients may outgrow their asthma: a 25-year follow-up study. Am J Respir Crit Care Med 1997;155:1267-1272. [Erratum, J Respir Crit Care Med 1997;156:674.] [Abstract]
Wilson JW, Li X, Pain MCF. The lack of distensibility of asthmatic airways. Am Rev Respir Dis 1993;148:806-809. [Medline]
Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989;1:520-524. [CrossRef][Medline]
Sluiter HJ, Köeter GH, de Monchy JGR, Postma DS, de Vries K, Orie NGM. The Dutch hypothesis (chronic non-specific lung disease) revisited. Eur Respir J 1991;4:479-489. [Abstract]
Rijcken B, Weiss ST. Longitudinal analyses of airway responsiveness and pulmonary function decline. Am J Respir Crit Care Med 1996;154:S246-S249.
Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Am J Respir Crit Care Med 1996;153:1530-1535. [Abstract]
Openshaw PJM, Turner-Warwick M. Observations on sputum production in patients with variable airflow obstruction: implications for the diagnosis of asthma and chronic bronchitis. Respir Med 1989;83:25-31. [Medline]
Connolly CK, Murthy KN, Alcock SM, Prescott RJ. Sputum and pulmonary function in asthma. Chest 1997;112:994-999. [Free Full Text]
Mullen JBM, Wright JL, Wiggs BR, Paré PD, Hogg JC. Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function. Thorax 1987;42:843-848. [Abstract]
Celli, B. R., Thomas, N. E., Anderson, J. A., Ferguson, G. T., Jenkins, C. R., Jones, P. W., Vestbo, J., Knobil, K., Yates, J. C., Calverley, P. M. A.
(2008). Effect of Pharmacotherapy on Rate of Decline of Lung Function in Chronic Obstructive Pulmonary Disease: Results from the TORCH Study. Am. J. Respir. Crit. Care Med.
178: 332-338
[Abstract][Full Text]
van Veen, I. H., ten Brinke, A., Sterk, P. J., Sont, J. K., Gauw, S. A., Rabe, K. F., Bel, E. H.
(2008). Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma. Eur Respir J
32: 344-349
[Abstract][Full Text]
Benfield, T., Lange, P., Vestbo, J.
(2008). COPD Stage and Risk of Hospitalization for Infectious Disease. Chest
134: 46-53
[Abstract][Full Text]
Braganza, G., Chaudhuri, R., Thomson, N. C.
(2008). Review: Treating patients with respiratory disease who smoke. Therapeutic Advances in Respiratory Disease
2: 95-107
[Abstract]
Suglia, S. F., Wright, R. O., Schwartz, J., Wright, R. J.
(2008). Association Between Lung Function and Cognition Among Children in a Prospective Birth Cohort Study. Psychosom. Med.
70: 356-362
[Abstract][Full Text]
Suglia, S. F., Ryan, L., Laden, F., Dockery, D. W., Wright, R. J.
(2008). Violence Exposure, A Chronic Psychosocial Stressor, and Childhood Lung Function. Psychosom. Med.
70: 160-169
[Abstract][Full Text]
Feghali-Bostwick, C. A., Gadgil, A. S., Otterbein, L. E., Pilewski, J. M., Stoner, M. W., Csizmadia, E., Zhang, Y., Sciurba, F. C., Duncan, S. R.
(2008). Autoantibodies in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med.
177: 156-163
[Abstract][Full Text]
Guenegou, A., Boczkowski, J., Aubier, M., Neukirch, F., Leynaert, B.
(2008). Interaction between a Heme Oxygenase-1 Gene Promoter Polymorphism and Serum -Carotene Levels on 8-Year Lung Function Decline in a General Population: The European Community Respiratory Health Survey (France). Am J Epidemiol
167: 139-144
[Abstract][Full Text]
Lee, J. H., Haselkorn, T., Borish, L., Rasouliyan, L., Chipps, B. E., Wenzel, S. E.
(2007). Risk Factors Associated With Persistent Airflow Limitation in Severe or Difficult-to-Treat Asthma: Insights From the TENOR Study. Chest
132: 1882-1889
[Abstract][Full Text]
Shaw, D. E., Berry, M. A., Hargadon, B., McKenna, S., Shelley, M. J., Green, R. H., Brightling, C. E., Wardlaw, A. J., Pavord, I. D.
(2007). Association Between Neutrophilic Airway Inflammation and Airflow Limitation in Adults With Asthma. Chest
132: 1871-1875
[Abstract][Full Text]
Aldington, S., Williams, M., Nowitz, M., Weatherall, M., Pritchard, A., McNaughton, A., Robinson, G., Beasley, R.
(2007). Effects of cannabis on pulmonary structure, function and symptoms. Thorax
62: 1058-1063
[Abstract][Full Text]
Sears, M. R.
(2007). Lung function decline in asthma. Eur Respir J
30: 411-413
[Full Text]
Walters, E. H., Reid, D. W., Johns, D. P., Ward, C.
(2007). Nonpharmacological and pharmacological interventions to prevent or reduce airway remodelling. Eur Respir J
30: 574-588
[Abstract][Full Text]
Bai, T. R., Vonk, J. M., Postma, D. S., Boezen, H. M.
(2007). Severe exacerbations predict excess lung function decline in asthma. Eur Respir J
30: 452-456
[Abstract][Full Text]
Bouzigon, E., Siroux, V., Dizier, M-H., Lemainque, A., Pison, C., Lathrop, M., Kauffmann, F., Demenais, F., Pin, I.
(2007). Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families. Eur Respir J
30: 253-259
[Abstract][Full Text]
Mishra, A., Wang, M., Schlotman, J., Nikolaidis, N. M., DeBrosse, C. W., Karow, M. L., Rothenberg, M. E.
(2007). Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L305-L313
[Abstract][Full Text]
Brown, N. J., Salome, C. M., Berend, N., Thorpe, C. W., King, G. G.
(2007). Airway Distensibility in Adults with Asthma and Healthy Adults, Measured by Forced Oscillation Technique. Am. J. Respir. Crit. Care Med.
176: 129-137
[Abstract][Full Text]
James, A. L., Wenzel, S.
(2007). Clinical relevance of airway remodelling in airway diseases. Eur Respir J
30: 134-155
[Abstract][Full Text]
Lloyd, C. M., Robinson, D. S.
(2007). Allergen-induced airway remodelling. Eur Respir J
29: 1020-1032
[Abstract][Full Text]
Dixon, A. E., Yeh, F., Welty, T. K., Rhoades, E. R., Lee, E. T., Howard, B. V., Enright, P. L., for the Strong Heart Study Research Group,
(2007). Asthma in American Indian Adults: The Strong Heart Study. Chest
131: 1323-1330
[Abstract][Full Text]
Min, M. G., Song, D. J., Miller, M., Cho, J. Y., McElwain, S., Ferguson, P., Broide, D. H.
(2007). Coexposure to Environmental Tobacco Smoke Increases Levels of Allergen-Induced Airway Remodeling in Mice. J. Immunol.
178: 5321-5328
[Abstract][Full Text]
Lazarus, S. C., Chinchilli, V. M., Rollings, N. J., Boushey, H. A., Cherniack, R., Craig, T. J., Deykin, A., DiMango, E., Fish, J. E., Ford, J. G., Israel, E., Kiley, J., Kraft, M., Lemanske, R. F. Jr., Leone, F. T., Martin, R. J., Pesola, G. R., Peters, S. P., Sorkness, C. A., Szefler, S. J., Wechsler, M. E., Fahy, J. V., for the National Heart Lung and Blood Institute's,
(2007). Smoking Affects Response to Inhaled Corticosteroids or Leukotriene Receptor Antagonists in Asthma. Am. J. Respir. Crit. Care Med.
175: 783-790
[Abstract][Full Text]
Holgate, S. T., Davies, D. E., Powell, R. M., Howarth, P. H., Haitchi, H. M., Holloway, J. W.
(2007). Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur Respir J
29: 793-803
[Abstract][Full Text]
Torrego, A., Hew, M., Oates, T., Sukkar, M., Fan Chung, K.
(2007). Expression and activation of TGF-{beta} isoforms in acute allergen-induced remodelling in asthma. Thorax
62: 307-313
[Abstract][Full Text]
Henderson, N., Markwick, L. J., Elshaw, S. R., Freyer, A. M., Knox, A. J., Johnson, S. R.
(2007). Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration. Am. J. Physiol. Lung Cell. Mol. Physiol.
292: L1030-L1038
[Abstract][Full Text]
Hylkema, M. N., Sterk, P. J., de Boer, W. I., Postma, D. S.
(2007). Tobacco use in relation to COPD and asthma. Eur Respir J
29: 438-445
[Abstract][Full Text]
Pavord, I. D
(2007). Non-eosinophilic asthma and the innate immune response. Thorax
62: 193-194
[Full Text]
Livingston, E., Chaudhuri, R., McMahon, A. D., Fraser, I., McSharry, C. P., Thomson, N. C.
(2007). Systemic sensitivity to corticosteroids in smokers with asthma. Eur Respir J
29: 64-71
[Abstract][Full Text]
van Veen, IlonkaH., Hiemstra, PieterS., ten Brinke, A., Roos, A., Verhoosel, RenateM., Sont, JaapK., Sterk, PeterJ., Rabe, KlausF., Bel, ElisabethH.
(2006). Mannose binding lectin (MBL) levels predict lung function decline in severe asthma. ERR
15: 224-225
[Abstract][Full Text]
Buist, A. S., Vollmer, W. M., Wilson, S. R., Frazier, E. A., Hayward, A. D.
(2006). A Randomized Clinical Trial of Peak Flow versus Symptom Monitoring in Older Adults with Asthma. Am. J. Respir. Crit. Care Med.
174: 1077-1087
[Abstract][Full Text]
Pegorier, S., Wagner, L. A., Gleich, G. J., Pretolani, M.
(2006). Eosinophil-Derived Cationic Proteins Activate the Synthesis of Remodeling Factors by Airway Epithelial Cells. J. Immunol.
177: 4861-4869
[Abstract][Full Text]
Long, A. J., Sypek, J. P., Askew, R., Fish, S. C., Mason, L. E., Williams, C. M. M., Goldman, S. J.
(2006). Gob-5 Contributes to Goblet Cell Hyperplasia and Modulates Pulmonary Tissue Inflammation. Am. J. Respir. Cell Mol. Bio.
35: 357-365
[Abstract][Full Text]
Anees, W, Moore, V C, Burge, P S
(2006). FEV1 decline in occupational asthma. Thorax
61: 751-755
[Abstract][Full Text]
Kraft, M.
(2006). Asthma and chronic obstructive pulmonary disease exhibit common origins in any country!. Am. J. Respir. Crit. Care Med.
174: 238-240
[Full Text]
Banauch, G. I., Hall, C., Weiden, M., Cohen, H. W., Aldrich, T. K., Christodoulou, V., Arcentales, N., Kelly, K. J., Prezant, D. J.
(2006). Pulmonary Function after Exposure to the World Trade Center Collapse in the New York City Fire Department. Am. J. Respir. Crit. Care Med.
174: 312-319
[Abstract][Full Text]
Kiwamoto, T., Ishii, Y., Morishima, Y., Yoh, K., Maeda, A., Ishizaki, K., Iizuka, T., Hegab, A. E., Matsuno, Y., Homma, S., Nomura, A., Sakamoto, T., Takahashi, S., Sekizawa, K.
(2006). Transcription Factors T-bet and GATA-3 Regulate Development of Airway Remodeling. Am. J. Respir. Crit. Care Med.
174: 142-151
[Abstract][Full Text]
Chaudhuri, R., Livingston, E., McMahon, A. D., Lafferty, J., Fraser, I., Spears, M., McSharry, C. P., Thomson, N. C.
(2006). Effects of Smoking Cessation on Lung Function and Airway Inflammation in Smokers with Asthma. Am. J. Respir. Crit. Care Med.
174: 127-133
[Abstract][Full Text]
Canonica, G. W.
(2006). Treating Asthma as an Inflammatory Disease. Chest
130: 21S-28S
[Abstract][Full Text]
Haahtela, T.
(2006). Lung Function Decline in Asthma and Early Intervention With Inhaled Corticosteroids. Chest
129: 1405-1406
[Full Text]
O'Byrne, P. M., Pedersen, S., Busse, W. W., Tan, W. C., Chen, Y.-Z., Ohlsson, S. V., Ullman, A., Lamm, C. J., Pauwels, R. A.
(2006). Effects of Early Intervention With Inhaled Budesonide on Lung Function in Newly Diagnosed Asthma. Chest
129: 1478-1485
[Abstract][Full Text]
Pavord, I. D., Birring, S. S., Berry, M., Green, R. H., Brightling, C. E., Wardlaw, A. J.
(2006). Multiple inflammatory hits and the pathogenesis of severe airway disease.. Eur Respir J
27: 884-888
[Abstract][Full Text]
Mannino, D. M., Reichert, M. M., Davis, K. J.
(2006). Lung Function Decline and Outcomes in an Adult Population. Am. J. Respir. Crit. Care Med.
173: 985-990
[Abstract][Full Text]
Poulain, M., Doucet, M., Major, G. C., Drapeau, V., Series, F., Boulet, L.-P., Tremblay, A., Maltais, F.
(2006). The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies.. CMAJ
174: 1293-1299
[Abstract][Full Text]
Boulet, L.-P., Lemiere, C., Archambault, F., Carrier, G., Descary, M. C., Deschesnes, F.
(2006). Smoking and Asthma: Clinical and Radiologic Features, Lung Function, and Airway Inflammation. Chest
129: 661-668
[Abstract][Full Text]
Lange, P, Scharling, H, Ulrik, C S, Vestbo, J
(2006). Inhaled corticosteroids and decline of lung function in community residents with asthma. Thorax
61: 100-104
[Abstract][Full Text]
Ernst, P
(2006). Inhaled corticosteroids moderate lung function decline in adults with asthma. Thorax
61: 93-94
[Full Text]
Dijkstra, A, Vonk, J M, Jongepier, H, Koppelman, G H, Schouten, J P, ten Hacken, N H T, Timens, W, Postma, D S
(2006). Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax
61: 105-110
[Abstract][Full Text]
Horvath, G., Wanner, A.
(2006). Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma. Eur Respir J
27: 172-187
[Abstract][Full Text]
Boxall, C., Holgate, S. T., Davies, D. E.
(2006). The contribution of transforming growth factor-{beta} and epidermal growth factor signalling to airway remodelling in chronic asthma. Eur Respir J
27: 208-229
[Abstract][Full Text]
Vestbo, J, Hogg, J C
(2006). Convergence of the epidemiology and pathology of COPD. Thorax
61: 86-88
[Abstract][Full Text]
van Rensen, E. L. J., Sont, J. K., Evertse, C. E., Willems, L. N. A., Mauad, T., Hiemstra, P. S., Sterk, P. J., the AMPUL Study Group,
(2005). Bronchial CD8 Cell Infiltrate and Lung Function Decline in Asthma. Am. J. Respir. Crit. Care Med.
172: 837-841
[Abstract][Full Text]
Schanen, J G, Iribarren, C, Shahar, E, Punjabi, N M, Rich, S S, Sorlie, P D, Folsom, A R
(2005). Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study. Thorax
60: 633-638
[Abstract][Full Text]
Mapp, C. E., Boschetto, P., Maestrelli, P., Fabbri, L. M.
(2005). Occupational Asthma. Am. J. Respir. Crit. Care Med.
172: 280-305
[Abstract][Full Text]
van Diemen, C. C., Postma, D. S., Vonk, J. M., Bruinenberg, M., Schouten, J. P., Boezen, H. M.
(2005). A Disintegrin and Metalloprotease 33 Polymorphisms and Lung Function Decline in the General Population. Am. J. Respir. Crit. Care Med.
172: 329-333
[Abstract][Full Text]
Moerloose, K. B., Pauwels, R. A., Joos, G. F.
(2005). Short-Term Cigarette Smoke Exposure Enhances Allergic Airway Inflammation in Mice. Am. J. Respir. Crit. Care Med.
172: 168-172
[Abstract][Full Text]
Wenzel, S.
(2005). Severe Asthma in Adults. Am. J. Respir. Crit. Care Med.
172: 149-160
[Abstract][Full Text]
Ko, F. W.S., Diba, C., Roth, M., McKay, K., Johnson, P. R.A., Salome, C., King, G. G.
(2005). A Comparison of Airway and Serum Matrix Metalloproteinase-9 Activity Among Normal Subjects, Asthmatic Patients, and Patients With Asthmatic Mucus Hypersecretion. Chest
127: 1919-1927
[Abstract][Full Text]
Fedorov, I A, Wilson, S J, Davies, D E, Holgate, S T
(2005). Epithelial stress and structural remodelling in childhood asthma. Thorax
60: 389-394
[Abstract][Full Text]
Tomlinson, J E M, McMahon, A D, Chaudhuri, R, Thompson, J M, Wood, S F, Thomson, N C
(2005). Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax
60: 282-287
[Abstract][Full Text]
Scichilone, N., Messina, M., Battaglia, S., Catalano, F., Bellia, V.
(2005). Airway hyperresponsiveness in the elderly: prevalence and clinical implications. Eur Respir J
25: 364-375
[Abstract][Full Text]
Homer, R. J., Elias, J. A.
(2005). Airway Remodeling in Asthma: Therapeutic Implications of Mechanisms. Physiology
20: 28-35
[Abstract][Full Text]
James, A. L., Palmer, L. J., Kicic, E., Maxwell, P. S., Lagan, S. E., Ryan, G. F., Musk, A. W.
(2005). Decline in Lung Function in the Busselton Health Study: The Effects of Asthma and Cigarette Smoking. Am. J. Respir. Crit. Care Med.
171: 109-114
[Abstract][Full Text]
Kitch, B. T., Paltiel, A. D., Kuntz, K. M., Dockery, D. W., Schouten, J. P., Weiss, S. T., Fuhlbrigge, A. L.
(2004). A Single Measure of FEV1 Is Associated With Risk of Asthma Attacks in Long-term Follow-up. Chest
126: 1875-1882
[Abstract][Full Text]
Sandstrom, T., Lundback, B.
(2004). Tobacco smoke: old foe more important for asthma than commonly appreciated?. Eur Respir J
24: 720-721
[Full Text]
Thomson, N.C., Chaudhuri, R., Livingston, E.
(2004). Asthma and cigarette smoking. Eur Respir J
24: 822-833
[Abstract][Full Text]
Freyer, A. M., Billington, C. K., Penn, R. B., Hall, I. P.
(2004). Extracellular Matrix Modulates {beta}2-Adrenergic Receptor Signaling in Human Airway Smooth Muscle Cells. Am. J. Respir. Cell Mol. Bio.
31: 440-445
[Abstract][Full Text]
Pedersen, S.
(2004). Progression of Asthma: Small Steps and a Long Way to Go. Am. J. Respir. Crit. Care Med.
170: 206-207
[Full Text]
Covar, R. A., Spahn, J. D., Murphy, J. R., Szefler, S. J.
(2004). Progression of Asthma Measured by Lung Function in the Childhood Asthma Management Program. Am. J. Respir. Crit. Care Med.
170: 234-241
[Abstract][Full Text]
Postma, D. S., Boezen, H. M.
(2004). Rationale for the Dutch Hypothesis: Allergy and Airway Hyperresponsiveness as Genetic Factors and Their Interaction With Environment in the Development of Asthma and COPD. Chest
126: 96S-104S
[Abstract][Full Text]
Sciurba, F. C.
(2004). Physiologic Similarities and Differences Between COPD and Asthma. Chest
126: 117S-124S
[Abstract][Full Text]
Bumbacea, D., Campbell, D., Nguyen, L., Carr, D., Barnes, P.J., Robinson, D., Chung, K.F.
(2004). Parameters associated with persistent airflow obstruction in chronic severe asthma. Eur Respir J
24: 122-128
[Abstract][Full Text]
Silva, G. E., Sherrill, D. L., Guerra, S., Barbee, R. A.
(2004). Asthma as a Risk Factor for COPD in a Longitudinal Study. Chest
126: 59-65
[Abstract][Full Text]
Melgert, B. N., Postma, D. S., Geerlings, M., Luinge, M. A., Klok, P. A., van der Strate, B. W. A., Kerstjens, H. A. M., Timens, W., Hylkema, M. N.
(2004). Short-Term Smoke Exposure Attenuates Ovalbumin-Induced Airway Inflammation in Allergic Mice. Am. J. Respir. Cell Mol. Bio.
30: 880-885
[Abstract][Full Text]
Rennard, S. I., Farmer, S. G.
(2004). Exacerbations and Progression of Disease in Asthma and Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc
1: 88-92
[Abstract][Full Text]
Spahn, J. D., Cherniack, R., Paull, K., Gelfand, E. W.
(2004). Is Forced Expiratory Volume in One Second the Best Measure of Severity in Childhood Asthma?. Am. J. Respir. Crit. Care Med.
169: 784-786
[Full Text]
Cho, S. H., Ryu, C. H., Oh, C. K.
(2004). Plasminogen Activator Inhibitor-1 in the Pathogenesis of Asthma. Exp. Biol. Med.
229: 138-146
[Abstract][Full Text]
Vestbo, J
(2004). COPD in the ECRHS. Thorax
59: 89-90
[Full Text]
Bel, E. H.
(2003). Smoking: A Neglected Cause of Glucocorticoid Resistance in Asthma. Am. J. Respir. Crit. Care Med.
168: 1265-1266
[Full Text]
Chaudhuri, R., Livingston, E., McMahon, A. D., Thomson, L., Borland, W., Thomson, N. C.
(2003). Cigarette Smoking Impairs the Therapeutic Response to Oral Corticosteroids in Chronic Asthma. Am. J. Respir. Crit. Care Med.
168: 1308-1311
[Abstract][Full Text]
Vignola, A.M., Bonanno, A., Profita, M., Riccobono, L., Scichilone, N., Spatafora, M., Bousquet, J., Bonsignore, G., Bellia, V.
(2003). Effect of age and asthma duration upon elastase and {alpha}1-antitrypsin levels in adult asthmatics. Eur Respir J
22: 795-801
[Abstract][Full Text]
Jenkins, H. A., Cherniack, R., Szefler, S. J., Covar, R., Gelfand, E. W., Spahn, J. D.
(2003). A Comparison of the Clinical Characteristics of Children and Adults With Severe Asthma. Chest
124: 1318-1324
[Abstract][Full Text]
Adams, R J, Wilson, D H, Appleton, S, Taylor, A, Dal Grande, E, Chittleborough, C R, Ruffin, R E
(2003). Underdiagnosed asthma in South Australia. Thorax
58: 846-850
[Abstract][Full Text]
Holgate, S.T., Davies, D. E., Puddicombe, S., Richter, A., Lackie, P., Lordan, J., Howarth, P.
(2003). Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma. Eur Respir J
22: 24s-29s
[Full Text]
The ENFUMOSA Study Group,
(2003). The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J
22: 470-477
[Abstract][Full Text]
Edwards, C. A., Osman, L. M., Godden, D. J., Douglas, J. G.
(2003). Wheezy Bronchitis in Childhood: A Distinct Clinical Entity With Lifelong Significance?. Chest
124: 18-24
[Abstract][Full Text]
Pelaia, G., Cuda, G., Vatrella, A., Fratto, D., Grembiale, R. D., Tagliaferri, P., Maselli, R., Costanzo, F. S., Marsico, S. A.
(2003). Effects of Transforming Growth Factor-{beta} and Budesonide on Mitogen-Activated Protein Kinase Activation and Apoptosis in Airway Epithelial Cells. Am. J. Respir. Cell Mol. Bio.
29: 12-18
[Abstract][Full Text]
Sandstrom, T., Frew, A.J., Svartengren, M., Viegi, G.
(2003). The need for a focus on air pollution research in the elderly. Eur Respir J
21: 92S-95s
[Abstract][Full Text]
Vonk, J M, Jongepier, H, Panhuysen, C I M, Schouten, J P, Bleecker, E R, Postma, D S
(2003). Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax
58: 322-327
[Abstract][Full Text]
Walter, R. E., Beiser, A., Givelber, R. J., O'Connor, G. T., Gottlieb, D. J.
(2003). Association between Glycemic State and Lung Function: The Framingham Heart Study. Am. J. Respir. Crit. Care Med.
167: 911-916
[Abstract][Full Text]
Cerveri, I., Corsico, A., Zoia, M. C., Vestbo, J., Lange, P.
(2003). Gold Stage 0. Am. J. Respir. Crit. Care Med.
167: 936-936
[Full Text]
Eden, E., Hammel, J., Rouhani, F. N., Brantly, M. L., Barker, A. F., Buist, A. S., Fallat, R. J., Stoller, J. K., Crystal, R. G., Turino, G. M.
(2003). Asthma Features in Severe {alpha}1-Antitrypsin Deficiency: Experience of the National Heart, Lung, and Blood Institute Registry. Chest
123: 765-771
[Abstract][Full Text]
Boulet, L.-P.
(2003). Asymptomatic Airway Hyperresponsiveness: A Curiosity or an Opportunity to Prevent Asthma?. Am. J. Respir. Crit. Care Med.
167: 371-378
[Full Text]
Beckett, P A, Howarth, P H
(2003). Pharmacotherapy and airway remodelling in asthma?. Thorax
58: 163-174
[Abstract][Full Text]
Fabbri, L. M., Romagnoli, M., Corbetta, L., Casoni, G., Busljetic, K., Turato, G., Ligabue, G., Ciaccia, A., Saetta, M., Papi, A.
(2003). Differences in Airway Inflammation in Patients with Fixed Airflow Obstruction Due to Asthma or Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med.
167: 418-424
[Abstract][Full Text]
Sherrill, D., Guerra, S., Bobadilla, A., Barbee, R.
(2003). The role of concomitant respiratory diseases on the rate of decline in FEV1 among adult asthmatics. Eur Respir J
21: 95-10
[Abstract][Full Text]
Lange, P., Parner, J., Schnohr, P., Jensen, G.
(2002). Copenhagen City Heart Study: longitudinal analysis of ventilatory capacity in diabetic and nondiabetic adults. Eur Respir J
20: 1406-1412
[Abstract][Full Text]
2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-392. [Abstract]
Previous
