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Responsiveness to Three Bronchial Provocation Tests in Patients With Asthma^*

^* From the Department of Respiratory Medicine (Drs. Koskela and Hyvärinen), Kuopio University Hospital, Kuopio, Finland; Department of Respiratory Medicine (Drs. Brannan and Anderson), Royal Prince Alfred Hospital, Camperdown, NSW, Australia; and Department of Pharmacy (Dr. Chan), University of Sydney, NSW, Australia.

Correspondence to: Heikki Koskela, MD, Department of Respiratory Medicine, Kuopio University Hospital, PL 1777, 70210 Kuopio, Finland; e-mail: heikki.koskela{at}kuh.fi

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study objectives: To compare a new bronchial provocation test, the mannitol challenge, with cold air and histamine challenges to demonstrate airway hyperresponsiveness (AHR) in patients with difficult-to-diagnose asthma.

Design: A prospective study.

Participants: Thirty-seven consecutive patients with recently diagnosed, steroid-naive, mild, or atypical asthma fulfilling the diagnostic criteria of Finnish Social Insurance Institution, and 10 healthy control subjects.

Interventions: Each subject completed a symptom questionnaire and underwent spirometry, diffusion capacity measurement, skin-prick tests, and bronchial provocations with mannitol, histamine, and cold air. The severity of asthma was classified according to the Global Initiative for Asthma (GINA).

Results: Fifty-one percent of the asthmatic patients responded to mannitol ( 15% fall in FEV₁), 24% to cold air ( 9% fall in FEV₁), and 81% or 49% to histamine (provocative dose causing a 15% fall in FEV₁ [PD₁₅] < 1.0 mg or < 0.4 mg, respectively). None of the healthy control subjects responded. The GINA classification was not associated with responsiveness to any of the challenges.

Conclusions: Mannitol is more sensitive than cold air in demonstrating AHR in patients with mild or atypical asthma. Histamine was more sensitive than both mannitol and cold air if 1.0 mg was used as a cut-off value for histamine PD₁₅. However, if the cut-off value for histamine PD₁₅ is lowered to 0.4 mg, which represents a specific diagnosis of asthma according to previous studies, the sensitivity values of mannitol and histamine challenges are comparable.

Key Words: asthma • asthma diagnosis • bronchial hyperresponsiveness • bronchial provocation • cold air • histamine • mannitol • mild asthma

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Diagnosis of asthma is not always easy. In Finland, the national asthma program suggests that the diagnosis should be set at primary health-care level, by general practitioners.¹ Consequently, mainly patients with diagnostic difficulties have been referred to tertiary referral respiratory clinics like that of the authors, creating an opportunity to assess a group of patients with mild and atypical symptoms.

When there are diagnostic difficulties, objective tests are needed, such as tests to demonstrate airway hyperresponsiveness (AHR). These tests fall into two categories, those that act directly on smooth muscle and those that cause the airways to narrow indirectly by a release of endogenous mediators. The indirect stimuli may be more suitable for confirming asthma due to their high specificity.^{2 3} However, the sensitivity of indirect tests to identify subjects with asthma may be lower than that of direct challenges.⁴ Cold air hyperventilation is an indirect test that has been in clinical use for > 20 years.⁵ We have previously reported a low sensitivity of cold air in identifying adult asthmatic patients referred to a tertiary hospital. In that study of 113 newly diagnosed, steroid-naive patients with asthma, only 32% responded to a cold air challenge.⁶ We therefore wanted to study whether the mannitol challenge, a novel indirect test for AHR,⁷ would be more sensitive than cold air hyperventilation to demonstrate AHR in patients with difficult-to diagnose asthma. This study is the first to compare mannitol and cold air challenges. The histamine challenge, a direct test, was included for comparison. We classified the severity of symptoms according to the Global Initiative for Asthma (GINA)⁸ to find out which tests would best reflect the severity of asthmatic symptoms.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Subjects
We recruited consecutive patients with a new diagnosis of asthma in our outpatient clinic over an 18-month period. The exclusion criteria were previous usage of inhaled or oral corticosteroids, febrile respiratory tract infection within 4 weeks, and FEV₁ < 50% of predicted.^{9 10} Patients were also excluded if the staff physician considered COPD as the most probable diagnosis, even if reversibility criteria were fulfilled. The diagnosis of asthma was based on patient history and clinical examination, in addition to objective evidence of reversible airway obstruction, according to the Finnish Social Insurance Institute criteria.¹¹ At least one of the following criteria had to be fulfilled: (1) at least 15% fall in FEV₁ after exercise challenge, (2) at least 15% improvement in FEV₁ after inhaled bronchodilating drug in spirometry, (3) at least 20% spontaneous diurnal peak expiratory flow variation in ambulatory peak flow monitoring on at least 2 days, or (4) at least 15% improvement in peak expiratory flow after inhaled bronchodilating drug in ambulatory peak flow monitoring on at least 2 days.

Forty-two subjects were included. However, five subjects discontinued the study, three due to personal reasons not related to the study, one due to unstable asthma, and one due to acute sinusitis. The remaining 37 subjects form the material of this study (Tables 1 , 2 ). Subjects refrained from taking short-acting ß₂-agonists for 6h, inhaled anticholinergic drugs for 8 h, and theophylline preparations for 24 h before the challenges. In addition, 10 healthy volunteers were recruited. They had no chronic respiratory diseases or symptoms and were life-long nonsmokers.

Protocol
The subjects completed a symptoms questionnaire. Spirometry (Model M9449; Medikro Ltd; Kuopio, Finland) was carried out before and 15 min after 0.4 mg of inhaled salbutamol according to the American Thoracic Society guidelines.¹² Diffusion capacity of the lung for carbon monoxide (DLCO) was measured by the single-breath method (2200 Pulmonary Function Laboratory; SensorMedics; Aachen, Germany). Skin-prick tests were carried out against common aeroallergens. This was followed by challenges to mannitol, cold air, and histamine in random order, within 2 weeks, at least 2 nights between the challenges. The challenges were performed at approximately the same time of a day, by the same research nurse. The study was completed in each case within 3 weeks after the establishment of a new diagnosis of asthma.

Questionnaire
The subjects were asked in a self-administered questionnaire if their symptoms were seasonal or perennial. If the symptoms were seasonal, the subjects were asked about which months the symptoms were usually most severe. The duration of asthma symptoms and the frequency of dyspnea, cough, wheezing, and sputum production during the last month were asked. The severity of asthma was classified using the GINA classification.⁸ The triggers (22 alternatives) of the symptoms as well as nocturnal symptoms were asked. The daily use of bronchodilating drugs during the last month was defined, as well as smoking habits.

Skin-Prick Tests
Skin-prick tests were performed on the volar side of forearm. A panel of 16 allergens was used (Soluprick SQ; ALK-Abelló; Horsholm, Denmark). Atopy was defined as at least a 3-mm wheal reaction to any of the allergens. Prick sum was calculated by adding the wheals to all allergens together. Dermatographism was defined as a > 2-mm wheal reaction to the negative control solution.¹³ In case of dermatographism, the size of the wheal to negative control was subtracted from the responses to all allergens when calculating the prick sum.

Mannitol Challenge
Spray-dried mannitol powder, packed in gelatin capsules containing 5 mg, 10 mg, 20 mg, and 40 mg, was inhaled in doubling doses up to 160 mg and repeated three times, using an Inhalator (Boehringer Ingelheim; Ingelheim, Germany).⁷ The test continued until the FEV₁ had fallen 15%, or the maximal cumulative dose of 635 mg had been administered. The provocative dose causing a 15% fall in FEV₁ (PD₁₅) was calculated by linear interpolation of the relationship between the percentage decrease in FEV₁ and the cumulative dose of mannitol required to provoke this decrease. The response dose ratio (RDR) was calculated as the percentage fall in FEV₁ after the last dose, divided by the cumulative dose, in milligrams. The test result was considered positive if FEV₁ fell > 15% regardless of the dose to provoke this response.⁷

Cold Air Challenge
Patients breathed frigid air (range – 14.6 to – 10.2°C) for 4 min at a specified minute ventilation calculated as prechallenge FEV₁ x 25.⁶ In order to maintain eucapnia, the inflow of carbon dioxide was calculated as target minute ventilation x 0.05. Spirometry was performed in triplicate before the challenge and in duplicate at 3 min, 5 min, and 10 min after the end of the challenge. The greater of the two FEV₁ values at each time point was used for the analysis. The response was calculated as prechallenge FEV₁ minus the lowest value for FEV₁ measured after the challenge, divided by the prechallenge FEV₁, and expressed as percentages. A cut-off value for a positive response was defined as a 9% fall in FEV₁.⁶

Histamine Challenge
Histamine was administered using a dosimetric nebulizer (Spira Electro 2; Respiratory Care Center; Hämeenlinna, Finland).¹⁴ The nebulization time was 0.4 s, set to start 100 ms after the beginning of inspiration. The peak inspiratory flow did not exceed 0.5 L/s, and the nebulization pressure was 2 bars. These settings give a calibrated output of 6.5 µL per inhalation. Histamine diphosphate was inhaled at a starting dose of 25 µg, with fourfold increments until the FEV₁ had fallen 15%, or until the maximal dose of 1,600 µg had been administered.¹⁴ The PD₁₅ and RDR values were calculated as above, but using noncumulative doses. Two cut-off values for a positive response were used, PD₁₅ 1.0 mg and PD₁₅ 0.4 mg.¹⁴

Statistical Analysis
The results are expressed as means and 95% confidence intervals (CIs). However, geometric means and 95% CIs were used for duration of asthmatic symptoms, RDR, and PD₁₅ values. These values were log-transformed before statistical analysis. Sensitivity was defined as number of asthmatics with a positive test result divided by the total number of asthmatics, expressed in percentages.¹⁵ The Pearson correlation was used to investigate the relationship between the responses to the challenges. Binary logistic regression, linear regression, and unpaired t tests were used to explore the association of the responsiveness to the challenges with various background features and with clinical indexes of asthma activity. In the binary logistic regression analysis, the responsiveness to the challenges was analyzed as yes or no. In the multiple linear regression analysis the responsiveness was expressed as continuous variables, as RDR values for mannitol and histamine challenges, and as a percentage fall in FEV₁ for the cold air challenge; p < 0.05 was accepted as the level of significance. All analyses were carried out using SPSS for Windows 9.0 (SPSS; Chicago, IL).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
According to GINA asthma classification by symptoms only,⁸ three patients had intermittent asthma, 15 had mild persistent asthma, and 19 had moderate persistent asthma. When the FEV₁ percentage of predicted was included in the classification, 1 patient had intermittent asthma, 7 patients had mild persistent asthma, and 29 patients had moderate persistent asthma. The most frequent symptom was sputum production (27 of 37 patients), followed by cough (19 of 37 patients), dyspnea (18 of 37 patients), and wheezing (8 of 37 patients). Several patients defined more than one symptom as most frequent. There were seven patients who had seasonal symptoms and in whom the challenges took place during the less symptomatic time of year, defined as "seasonal asthma-out of season" group. In the rest of the patients, the symptoms were either perennial or seasonal, but the challenges took place during the months with most severe symptoms.

Responsiveness of the Subjects to the Challenges
There were large differences in the sensitivity values of the challenges (Table 3 ). These values remained virtually the same even when only the life-long nonsmokers were included in the analysis. Mannitol was clearly more sensitive than cold air, whereas the sensitivity of histamine challenge was dependent on the cut-off value of a positive response. The patients who did not respond to mannitol but responded to histamine showed clearly higher histamine PD₁₅ values than the patients who responded to both mannitol and histamine (0.46 mg [range, 0.24 to 0.88 mg] vs 0.16 mg [range, 0.10 to 0.25 mg]; p = 0.008). Mannitol challenge was positive in 16 of the 18 patients with histamine PD₁₅ 0.4 mg; however, histamine PD₁₅ was 0.4 mg in 16 of the 19 patients responding to mannitol. The responsiveness to mannitol was more closely associated with the responsiveness to histamine (Fig 1 ) than with the responsiveness to cold air (Fig 2 ). One of the 10 healthy subjects demonstrated a fall of > 15% in FEV₁ in histamine challenge with a PD₁₅ of 1.6 mg, but none of them responded to the other two challenges.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Association between the responsiveness to mannitol and histamine challenges, both expressed as log-transformed RDR (n = 37, rp = 0.63, p < 0.001).

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Association between the responsiveness to mannitol and cold air challenges. Mannitol responsiveness is expressed as log-transformed RDR, and cold air responsiveness as maximal percentage changes in FEV1 (n = 37, rp = 0.49, p = 0.002).

In the binary logistic models, no statistically significant associations between the responsiveness to the challenges and the clinical indexes of asthma severity could be found. However, in the linear regression model, responsiveness to mannitol challenge was significantly milder in the patients in the seasonal asthma-out of season group than in the rest of the patients (change in r², 0.20; p = 0.006). In addition, histamine responsiveness was negatively associated with prechallenge FEV₁ (change in r², 0.12; p = 0.04). There were no other statistically significant associations between the responsiveness to the challenges and indexes of asthma severity, including the GINA classification with or without lung function information.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
This study describes a group of steroid-naive patients with a recent diagnosis of asthma. The patients showed many features that are known to cause diagnostic difficulties.^{16 17 18 19 20} Their symptoms were mild to moderate, and atypical in that sputum production and cough were the predominant symptoms over dyspnea or wheezing. Their lung function abnormalities and bronchodilator reversibility were minor. Many of the patients were ex-smokers or current smokers. Most of the patients were elderly and nonatopic. Since bronchial provocation tests are mainly used to confirm or exclude the diagnosis of asthma in a situation where there is a high level of uncertainty,²¹ we believe that the patient material of the present study is well suited for comparison of bronchial provocation tests.

Our study is the first to compare mannitol with cold air and shows that mannitol is much more sensitive in demonstrating AHR in adults with mild or atypical asthma. An important factor affecting the sensitivity to cold air is likely to be the age of the patients. The attenuation of the responsiveness to cold air with aging is evident both in the present and previous studies.^{6 22} Furthermore, the responsiveness to cold air was associated with skin test reactivity and thus with atopic asthma. A similar association has been demonstrated between atopy and responsiveness to exercise.^{23 24} These features of cold air challenge may explain the low sensitivity of cold air in the present study, in which 76% of patients were > 40 years old and 62% of patients were nonatopic. Thus, the traditional indirect challenge with cold air appears to lack sensitivity in elderly subjects and in those with intrinsic asthma. It may therefore be more suitable for pediatric than adult use. In contrast, the new indirect challenge, mannitol, seems to be equally sensitive for demonstrating AHR in those with intrinsic and extrinsic asthma, as well identifying AHR over a wide age range encompassing both children²⁵ and the elderly.

Not surprisingly, the sensitivity of histamine challenge was dependent on the cut-off value for a positive response. In the original article where Sovijärvi et al¹⁴ first described this method, they suggested two cut-off values of PD₁₅, 0.4 mg and 1.0 mg. The value of 0.4 mg was suggested because all patients with PD₁₅ below it had asthma. This cut-off value gave a sensitivity of 39% in patients with recently diagnosed, steroid-naive asthma. The value of 1.0 mg was suggested because the PD₁₅ did not fall below it in any of the 31 healthy subjects. This cut-off value gave a sensitivity of 74%. Thus, our results are in agreement with that study, with sensitivity values of 49% and 81%, respectively. Importantly, many nonasthmatic patients with chronic cough or chronic rhinitis showed PD₁₅ values between 0.4 mg and 1.0 mg in the study of Sovijärvi et al.¹⁴ Thus, if this histamine challenge method is to be used for a confirmation of asthma, a cut-off value of 0.4 mg should be chosen. Our study showed that with the 0.4 mg cut-off value, the sensitivity of histamine challenge is very similar to that of mannitol challenge and that the two tests identified almost the same patients. In other words, mannitol challenge could identify patients with moderate or severe histamine responsiveness but not those with mild histamine responsiveness.

An alarming finding was that neither the presence nor severity of AHR to any challenges could be predicted by the international GINA classification or other clinical signs of asthma severity. The only exception was the ability of mannitol challenge to separate those who were studied outside the most symptomatic period of the year from those who were studied during the most symptomatic period. The GINA classification has been developed to aid in choosing antiasthma therapy.⁸ Our findings are in keeping with those of previous studies, demonstrating that neither questionnaire information²⁶ nor physicians’ estimates²⁷ can predict AHR. It has recently been shown that AHR is associated with airway inflammation and remodeling,²⁸ as well as with accelerated pulmonary-function decline in long-term follow-up and, hence, with the development of fixed airway obstruction.^{29 30} Since GINA classification did not correlate with AHR, reliance on this classification, or on symptoms in general, when choosing the antiasthma therapy does not take into account these serious long-term consequences of asthma. This finding supports a more frequent testing of AHR in the patient management.

The purpose of the present study was to gain information about bronchial provocation tests that could be applied to everyday clinical practice. We therefore avoided strict selection of patients and also accepted ex-smokers and current smokers. One could thus think that some of our patients had COPD instead of asthma. To avoid this bias, we excluded patients in whom the staff physician considered COPD as the most probable diagnosis, even if the reversibility criteria were fulfilled. It is worthy to note that all smokers in the present study had their DLCO > 73% of predicted, indicating that marked emphysema was not present. However, we are aware that the differential diagnosis of asthma and COPD is difficult, and sometimes impossible.³¹ Therefore, it is possible that some patients had a component of COPD in their disease. This possibility, however, does not affect the main results, which were virtually the same even if only the life-long nonsmokers were included in the analysis.

In conclusion, this study compared the sensitivity of three bronchial provocation tests in demonstrating AHR in patients with difficult-to-diagnose asthma. It showed that the new indirect bronchial provocation test, mannitol challenge, is far more sensitive than the older indirect test, cold air challenge. Histamine challenge, a direct test, seemed to be more sensitive than both mannitol and cold air. However, if the cut-off value for a positive response to histamine is lowered to a level representing a specific diagnosis of asthma, the sensitivity values of mannitol and histamine challenges are comparable.

	Acknowledgements

 
The authors thank Pirjo Vänttinen, RN, for her assistance.

	Footnotes

 
Abbreviations: AHR = airway hyperresponsiveness; CI = confidence interval; DLCO = diffusion capacity of the lung for carbon monoxide; GINA = Global Initiative for Asthma; PD₁₅ = provocative dose causing a 15% fall in FEV₁; RDR = response dose ratio

This work was performed at Kuopio University Hospital, Kuopio, Finland.

Financial support was provided by Kuopio University Hospital.

Received for publication December 26, 2002. Accepted for publication June 10, 2003.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

1. Astmaohjelma 1994–2004 1994,62 Sosiaali- ja terveysministeriö. Helsinki, Finland:
2. Leuppi, JD, Brannan, JD, Anderson, SD Bronchial provocation tests: the rationale for using inhaled mannitol as a test for airway hyperresponsiveness. Swiss Med Wkly 2002;132,151-158[Medline]
3. Van Schoor, J, Joos, GF, Pauwels, RA Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur Respir J 2000;16,514-533[Abstract]
4. Fowler, SJ, Dempsey, OJ, Sims, EJ, et al Screening for bronchial hyperresponsiveness using methacholine and adenosine monophosphate: relationship to asthma severity and ß₂-receptor genotype. Am J Respir Crit Care Med 2000;162,1318-1322[Abstract/Free Full Text]
5. Deal, EC, Jr, McFadden, ER, Jr, Ingram, RH, Jr, et al Airway responsiveness to cold air and hyperpnea in normal subjects and in those with hay fever and asthma. Am Rev Respir Dis 1980;121,621-628[ISI][Medline]
6. Koskela, HO, Räsänen, SH, Tukiainen, HO The diagnostic value of cold air hyperventilation in adults with suspected asthma. Respir Med 1997;91,470-478[CrossRef][ISI][Medline]
7. Anderson, SD, Brannan, J, Spring, J, et al A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997;156,758-765[Abstract/Free Full Text]
8. National Heart Lung and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention; NHLBI/WHO workshop report. 1995 National Heart Lung and Blood Institute. Bethesda, MD: publication No. 95–3659
9. Viljanen, AA, Halttunen, PK, Kreus, K-E, et al Spirometric studies in non-smoking, healthy adults. Scand J Clin Lab Invest 1982;42,5-20[ISI]
10. Viljanen, AA, Viljanen, BC, Halttunen, PK, et al Pulmonary diffusing capacity and volumes in healthy adults measured with the single breath technique. Scand J Clin Lab Invest 1982;42,21-34
11. Peittola, S, Ruponen, M Pharmaca Fennica. 2002,2408 Lääketietokeskus. Rauma, Finland:
12. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152,1107-1136[ISI][Medline]
13. Wong, RC, Fairley, JA, Ellis, CN Dermographism: a review. J Am Acad Dermatol 1984;11,643-652[Medline]
14. Sovijärvi, AR, Malmberg, LP, Reinikainen, K, et al A rapid dosimetric method with controlled tidal breathing for histamine challenge: repeatability and distribution of bronchial reactivity in a clinical material. Chest 1993;104,164-170[Abstract/Free Full Text]
15. Feinstein, AR Clinical epidemiology 1st ed. 1985,612 W.B. Saunders Company. Philadelphia, PA:
16. Banerjee, DK, Lee, GS, Malik, SK, et al Underdiagnosis of asthma in the elderly. Br J Dis Chest 1987;81,23-29[CrossRef][ISI][Medline]
17. Enright, PL, McClelland, RL, Newman, AB, et al Underdiagnosis and undertreatment of asthma in the elderly: Cardiovascular Health Study Research Group. Chest 1999;116,603-613[Abstract/Free Full Text]
18. Nathell, L, Larsson, K, Jensen, I Determinants of undiagnosed asthma. Allergy 2002;57,687-693[CrossRef][ISI][Medline]
19. Nish, WA, Schwietz, LA Underdiagnosis of asthma in young adults presenting for USAF basic training. Ann Allergy 1992;69,239-242[ISI][Medline]
20. Boushey, HA Clinical diagnosis in adults. Barnes, PJ Grunstein, MM Leff, ARet al eds. Asthma 1st ed. 1997,1391-1403 Lippincott-Raven publishers. New York:
21. Hunter, CJ, Brightling, CE, Woltmann, G, et al A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;121,1051-1057[Abstract/Free Full Text]
22. Weiss, ST, Tager, IB, Weiss, JW, et al Airways responsiveness in a population sample of adults and children. Am Rev Respir Dis 1984;129,898-902[ISI][Medline]
23. Frischer, T, Meinert, R, Karmaus, W, et al Relationship between atopy and frequent bronchial response to exercise in school children. Pediatr Pulmonol 1994;17,320-325[Medline]
24. Koh, YI, Choi, IS, Lim, H Atopy may be related to exercise-induced bronchospasm in asthma. Clin Exp Allergy 2002;32,532-536[Medline]
25. Subbarao, P, Brannan, JD, Ho, B, et al Inhaled mannitol identifies methacholine-responsive children with active asthma. Pediatr Pulmonol 2000;29,291-298[Medline]
26. Dales, RE, Ernst, P, Hanley, JA, et al Prediction of airway reactivity from responses to a standardized respiratory symptom questionnaire. Am Rev Respir Dis 1987;135,817-821[Medline]
27. Dales, RE, Nunes, F, Partyka, D, et al Clinical prediction of airways hyperresponsiveness. Chest 1988;93,984-986[Abstract/Free Full Text]
28. Ward, C, Pais, M, Bish, R, et al Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 2002;57,309-316[Abstract/Free Full Text]
29. O’Connor, GT, Sparrow, D, Weiss, ST A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: the Normative Aging Study. Am J Respir Crit Care Med 1995;152,87-92[Abstract]
30. Rijcken, B, Schouten, JP, Xu, X, et al Airway hyperresponsiveness to histamine associated with accelerated decline in FEV₁. Am J Respir Crit Care Med 1995;151,1377-1382[Abstract]
31. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive lung disease (COPD) and asthma. Am Rev Respir Dis 1987;136,225-244[ISI][Medline]

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Koskela, H. O. Articles by Anderson, S. D. Search for Related Content PubMed PubMed Citation Articles by Koskela, H. O. Articles by Anderson, S. D.