VOLUME 38 | ISSUE 2 | MARCH-APRIL 2018

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Endobronchial biopsy in the final diagnosis of chronic obstructive pulmonary disease and asthma: a clinicopathological study

Maria Abdulrahim Arafah,a Emad Raddaoui,b Faisal Al Kassimi,c Esam H. Alhamad,c Ahmed Amer Alboukai,c Ahlam Abdullah Alshedoukhy,b Abderrahman Oubanb

From the aDepartment of Pathology, King Saud University, Riyadh, Saudi Arabia; bDepartment of Pathology, Alfaisal University, Riyadh, Saudi Arabia; cDepartment of Medicine, King Saud University, Riyadh, Saudi Arabia; dDepartment of Radiology, King Saud University, Riyadh, Saudi Arabia

How to cite this article:

Arafah MA, Raddoui E, Al Kassimi F, Alhamad EH, Alboukai AA, Alshedoukhy AA, et al. Endobronchial biopsy in the final diagnosis of chronic obstructive pulmonary disease and asthma: a clinicopathological study. Ann Saudi Med 2018; 38(2): 118-124.

DOI: 10.5144/0256-4947.2018.118

Abstract

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are chronic conditions with an increasing prevalence in developing countries. The evaluation of endobronchial biopsies has emerged as a tool to differentiate between both conditions via the measurement of the reticular basement membrane (RBM) thickness with various conclusions drawn from different studies.

 

OBJECTIVES: Compare the thickness of the RBM between asthma and COPD and evaluate other histomorphological features in both groups.

 

DESIGN: Prospective, descriptive and analytical.

 

SETTING: University teaching hospital.

 

PATIENTS AND METHODS: The study included patients with COPD and irreversible and reversible asthma with diagnosis based on clinical assessment, pulmonary function tests and high-resolution computed tomography scans. Endobronchial biopsies were obtained from all patients and, using a light microscope and a computerized image analyzer, the thickness of the reticular basement membrane was calculated in all patients. We also made a qualitative assessment of other histo-morphological features.

 

MAIN OUTCOME MEASURES: Mean RBM thickness.

 

SAMPLE SIZE: Thirty male patients.

 

RESULTS: The mean RBM thickness in asthmatic patients was 8.9 (2.4) µm. The mean RBM thickness in COPD patients was 5.3 (1.1) µm. However, there was no thickening of the RBM in patients with reversible asthma. The RBM was significantly thicker in patients with irreversible asthma than in patients with COPD or reversible asthma. There were no significant differences in epithelial desquamation or metaplasia, mucosal or submucosal inflammation, the presence of eosinophils, submucosal glandular hyperplasia or submucosal smooth muscle hyperplasia between groups.

 

CONCLUSIONS: The thickness of the RBM is the only reproducible histopathological feature to differentiate COPD from irreversible asthma.

 

LIMITATIONS: The study included a limited number of patients. A qualitative approach was used to compare epithelial cell injury, inflammation, submucosal glandular and muscular hyperplasia. 

 

CONFLICT OF INTEREST: None. 

 

 

 

INTRODUCTION

 

Asthma and chronic obstructive pulmonary dis.ease (COPD) are the two most commonly encountered chronic respiratory diseases worldwide. In 2015, both conditions affected 18.4 million and 12.8 million people in the United States, respectively.1 Asthma commonly causes reversible airway obstruction while COPD, by definition, is invariably irreversible by spirometry. Therefore the two conditions are distinguishable clinically and physiologically in the majority of cases. However, about 20% of asthmatics progress into airway remodeling associated with irreversible airways. Currently, differentiation between irreversible asthma in smokers and COPD patients is not always achievable. The 2017 version of the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) states that “in some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiological testing techniques”.2 High resolution computed tomography (HRCT) has shown promising results in discriminating these two conditions, but it is still not recognized as a differentiating tool. Thus, the evaluation of endobronchial biopsies, in particular the qualitative and quantitative assessment of inflammatory cells and the measurement of the reticular basement membrane (RBM), has emerged as a potential tool for a proper diagnosis. 

 

Several studies aimed to assess the structural abnormalities and airway remodeling in patients with asthma and COPD. James et al showed that, in autopsy samples, the thickness of the RBM in central airways, assessed by endobronchial biopsies, correlates with cartilaginous airway wall dimension.3 The study concluded that the RBM thickness can be used as an index of airway remodeling in asthma.3 The literature however is not unanimous as to whether the RBM is thickened in COPD with several studies reaching different conclusions. Some studies showed an increase in the RBM thickness though to a smaller extent than asthma.4-9 A normal RBM thickness in COPD was reported by others.10-12 Milanese et al studied a group of 33 patients including 11 patients with perennial allergic asthma, 8 patients with allergic rhinitis, 5 patients with seasonal allergic rhinitis and 9 patients with COPD.8 The RBM thickness was significantly thicker in asthma (10.1 [3.7] μm) in comparison to COPD (5.2 [0.7] μm).8 On the other hand, Liesker et al compared the RBM thickness between 24 asthmatic patients and 17 patients with COPD and found no significant difference between both groups, though both had a significantly thicker RBM when compared to healthy controls.11 Some of the differences could be attributed to the variable degrees of airway obstruction within the studied groups,4,5,11 the inclusion of healthy individuals with no history of smoking9 or the limited number of patients within the study.10 The aim of this study was to compare the RBM thickness in clinically defined patients with asthma and COPD and to evaluate the inflammatory cellular infiltrate and epithelial changes in both groups. 

 

 

Patients and Methods

 

Patients were recruited by convenience from the outpatient respiratory care clinics. Inclusion criteria were that patients be ≥ 40 years of age with a previous or an active history of smoking of at least ten pack years for more than ten years. Other inclusion criteria were a history of chronic cough or dyspnea, forced expiratory volume in 1 second (FEV1) <80% predicted or emphysema diagnosed by CT scan involving five lobes of the lung regardless of spirometric values and FEV1/FVC <70%.

 

The study was approved by the Clinical Ethics Committee (No. E-12-667) and conducted at a teaching university hospital between 2011 and 2015 All subjects had signed an informed consent, agreeing to undergo the procedure. 

 

Asthma was defined (as stated by the Global Initiative for Asthma) as “a chronic condition characterized by the presence of wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory flow limitation”.13 In addition the CT scan had to be free of bronchiectasis and emphysema. Similarly, the carbon monoxide diffusion coefficient had to be equal or greater than 80% predicted. Studies are unanimous that asthma, even when severe or irreversible, is associated with normal diffusion studies.14-16 Irreversible asthma is defined as patients with asthma who may have an accelerated decline in lung function and who develop airway limitation that is not fully reversible.13 The COPD definition was adopted from GOLD as “chronic cough or sputum production and dyspnea in the presence of a history of smoking >10 pack/year and a post broncho-dilator FEV1/FVC <0.70”.2 In addition a CT scan had to show emphysema and Krogh factors (KCO) were below 80% predicted. Postmortem studies document emphysema to be uniformly present in COPD.17 Similarly antemortem surveys document that patients free of emphysema by CT scan display features of asthma.18-21 All patients were ≥40 years of age with no clinical history of atopy. All patients were either active smokers or had a previous history of smoking of at least ten pack years for more than 10 years. Inhaled corticosteroids (ICS) were discontinued for 4 weeks and tiotropium (Spiriva Handihaler; Boehringer Ingelheim; Ingelheim, Germany) 18 ug was prescribed once daily. Lung function tests comprised spirometry performed with reversibility, carbon monoxide transfer coefficient (KCO) and arterial blood gases. A KCO <80% predicted was considered indicative of emphysema and was followed by a HRCT scan of the lungs. The above described criteria have been used to differentiate between asthma and COPD in our hospital since 2009.22 

 

All patients were started on budesonide 320 g/ formoterol 9 μg (Symbicort Turbuhaler; AstraZeneca, London, UK) twice daily and salbutamol 200–400 μg (Ventolin inhaler; GlaxoSmithKline, Brentford, UK) as required. Guided by the response to a 12-month trial of inhaled corticosteroids/ long-acting b2 agonists and the results of the above-described investigations, further therapy was aimed at an asthma or COPD phenotype.22 

 

Fiberoptic bronchoscopy was performed under local anesthesia in all 30 patients. After visual inspection of the lower airways, 4 -5 biopsies were taken from a lobar bronchus of the lower lobe. The specimens were fixed in formalin (4% buffered) and routinely processed to paraffin blocks. Four microsections were stained with a routine hematoxylin and eosin stain. Additional special stains for the basement membrane including Periodic Acid-Schiff (PAS) and Trichrome stain were obtained for all cases.

 

The slides were examined under a light microscope (Olympus, Tokyo, Japan) at x400 magnification (x40 objective lens, x10 eyepiece). Only sections perpendicular to the epithelial surface and the reticular basement membrane were evaluated. Inadequate specimens (small, squashed) were excluded. Point-to-point measurements of the reticular basement member at regular intervals of 20 μm, as described by Sullivan et al, were taken.23 For each subject, at least 40 measurements were recorded by a pathologist and a clinician. A computerized image analyzer (NIS-Elements V.4, Nikon) was used to take the measurements and the mean RBM thickness in an individual subject was calculated as a mean of all measurements recorded by the observers. 

 

HRCT images, using LightSpeed 16 or VCT XT; GE Medical Systems, Milwaukee, WI, USA, were scored by three observers (a radiologist and two clinicians) based on the Goddard’s quantitative visual scoring of emphysema.24 A score of 0 was assigned if there was no abnormality. A score of 1 was assigned if less than 25% of the parenchyma showed abnormalities suggestive of emphysema; if 25%–50% of the parenchyma had abnormalities suggestive of emphysema, a score of 2 was given; if however 51%–75% of the parenchyma had abnormalities suggestive of emphysema a score of 3 was assigned and if more than 75% of the parenchyma had abnormalities suggestive of emphysema, a score of 4 was given. The images were evaluated at the level of the arch of the aorta, the bifurcation of the trachea and above the diaphragm. Emphysema was considered significant if the average scoring of the three cuts was ≥1 and a consensus score was reached in cases of inter-observer variability. 

 

Categorical variables were summarized as percent.ages and continuous variables as medians and interquartile ranges. The nonparametric Mann-Whitney U-test was used for testing mean differences in variables with non-normal distribution. The chi-square test was used for categorical data. Two-tailed P value <.05 was considered statistically significant. 

 

 

Results

 

All 30 patients were males. Twelve patients (40%) with COPD had a mean age of 64.3 years. Eight patients were active smokers at the time of the study while the remaining four were ex-smokers. The diagnosis of COPD was made on HRCT in 11 patients and KCO in 12 patients, showing an agreement between both modalities in 96.7% of all patients. A total of eighteen pa.tients (60%), 7 active smokers and 11 ex-smokers, had asthma and were significantly younger than the former group (mean age=55.8 years). Although their FEV1 was higher, 29% of patients had an FEV1 ≤50% predicted. KCO levels were within normal limits in all asthmatic pa.tients (≥80% predicted). They also had higher PaO2 and lower PaCO2 levels. All COPD patients had lower FEV1 level and low KCO except one. This patient had an emphysema score of 1.16 and a KCO level of 90% predicted. A misclassified diagnosis by HRCT was suspected as the patient displayed a positive response to ICS. Table 1 summarizes the comparative clinical characteristics of both groups. 

 

The number of collected biopsies was 4-5 biopsies per patient. The mean number of RBM thickness mea.surements was similar in both groups of patients. The mean RBM thickness in asthma patients was 8.9 (2.4) μm compared with 5.3 (1.1) in COPD subjects. The difference in the RBM thickness was statistically significant between groups (P=.00032). The RBM was not thickened in any patient with COPD (Figure 1). It was, on the other hand, thickened in 15 out of 18 patients with asthma (Figure 2). Three patients within the asthma group failed to show a thickened RBM. These 3 patients had reversible asthma as their initial FEV1 was 75-78% predicted and normalized subsequently upon receiving ICS. 

 

Though epithelial metaplastic changes were prominent in COPD patients, there were no statistically significant differences in the extent of epithelial desquamation or metaplasia between groups (Figure 3). Eosinophils and other inflammatory cells including lymphocytes, plasma cells and less frequently neutrophils were noted in biopsies of both groups. Though more pronounced in asthmatic patients, there was no significant difference in the numbers or distribution of inflammatory cells between groups. Submucosal glandular hyperplasia was a common feature in COPD and asthmatic patients (40% and 50%, respectively). Smooth muscle hyperplasia was more dominant in asthmatics however did not reach a statistical significance (Figure 4). Table 2 summarizes the comparative histopathologi-cal characteristics of both groups. 



Discussion

 

Structural changes, remodeling and airway flow limitation characterize both asthma and COPD with noticeable pathological differences. The most frequently studied marker of airway remodeling is the thickness of the RBM. Our study confirms the considerable thickening of the RBM in asthmatic patients in comparison to patients with COPD. This finding is consistent with the results of other published studies.8,25,26 The mean RBM thickness in asthmatics was significantly higher than in COPD subjects (8.9 μm in asthmatics vs. 5.35 μm in COPD patients). The measurements of the RBM of the three patients with reversible asthma were 4.05 μm, 5.1 μm and 5.9 μm. Thus, upon excluding these 3 patients, there was no overlap between the ranges of RBM thickness in both groups (2.6-7 μm in COPD vs. 7.3-13.1 μm in asthma patients). These observations confirm that the thickness of the RBM cannot differentiate between reversible asthma and COPD, a finding that has been reported by previous studies.11,27,28 Among 72 patients studied by Cohen et al, 31 patients had severe asthma, 9 had mild asthma, 11 were patients with chronic bronchitis and 21 were healthy controls.28 It was observed that the RBM thickness was greater in subjects with severe asthma compared to the other groups, however it could not differentiate between patients with mild asthma, COPD or healthy individuals.28 The absence of an overlap in the thickness of the RBM between asthmatic patients and patients with COPD has also been demonstrated previously.7,22 Fabbri et al compared COPD patients with patients with irreversible asthma and found that the RBM thickness ranges between 6.6-7.4 μm in the latter group compared to 4.2-6.2 μm in the former.7 Bourdin et al found that a threshold of 6.65 μm differentiated between patients with irreversible asthma and COPD with a sensitivity of 89% and specificity of 68%, though the RBM thickness could not distinguish mild asthma from COPD, irrespective of the method used to measure it.27 This observation is interesting because the only significant difference we found between patients with COPD and irreversible asthma was the thickness of RBM. 

 

In this study, none of the other evaluated features including epithelial desquamation or metaplasia, mucosal or submucosal inflammation, the presence of eosinophils, submucosal glandular hyperplasia nor submucosal smooth muscle hyperplasia, was significantly different between the groups. Several studies have evaluated the extent of epithelial destruction and type of inflammation in asthma and COPD. Many of these studies were unable to find any differences in epithelial damage between healthy individuals, asthmatics, and COPD patients.26-30 Kosciuch et al compared 20 patients with asthma to 12 with COPD and found no differences in the extent of epithelial damage, regardless of the extent or severity of the disease.26 A total of 46 patients were included in the study by Fabbri et al. The group reported that, in comparison to patients with COPD (27 subjects), patients with asthma (19 subjects) had significantly more eosinophils and fewer neutrophils in sputum, bronchoalveolar lavage and tissue biopsies. In addition to a higher CD4+/CD8+ ratio of infiltrating T-lymphocytes within the mucosa.7 Epithelial metaplasia and goblet cell hyperplasia are, on the other hand, reported to be more frequently encountered in biopsies from COPD patients.31,32 However, studies of submucosal smooth muscle hyperplasia in COPD have shown mixed results, with approximately half showing either an increase33,34 or no significant change.35,36 

 

Our study has numerous limitations. The study groups were relatively small. Valuable comparative data could have been obtained by adding a control group of healthy subjects. There were some clinical differences between both groups (e.g. mean age and duration of smoking) that could have affected our findings. In addition, the qualitative and relatively subjective way of evaluating the uneven distribution of inflammatory cells and submucosal glandular and muscular hyperplasia might have also limited our conclusions. 

 

In summary, though the evaluation of surgically obtained endobronchial biopsies for differentiating asthma from COPD is not a common practice, the measurement of the RBM thickness is a reproducible tool that can serve this purpose. Larger scale studies, with a quantitative approach, are needed to support our results. 



References

1. Blackwell DL, Villarroel MA [Internet]. Tables of Summary Health Statistics for U.S. Adults: 2015 National Health Interview Survey. National Center for Health Statistics. 2016. [cited 2017 June 3]. Available from: http://www.cdc.gov/nchs/nhis/SHS/tables.htm. 

2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Dis.ease (GOLD) 2017 [Internet]. [cited 2017 June 3]. Available from: http://goldcopd.org 

3. James AL, Maxwell PS, Pearce-Pinto G, El.liot JG, Carroll NG. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002;166(12 Pt 1):1590-5. 

4. Lacoste JY, Bousquet J, Chanez P, Van Vyve T, Simony-Lafontaine J, Lequeu N, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 1993;92(4):537-48. 

5. Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):591-9. 

6. Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167(10):1360-8. 

7. Fabbri LM, Romagnoli M, Corbetta L, Ca-soni G, Busljetic K, Turato G, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003 Feb 1;167(3):418-24. 

8. Milanese M, Crimi E, Scordamaglia A, Riccio A, Pellegrino R, Canonica GW, et al. On the functional consequences of bronchial basement membrane thickening. J Appl Physiol. 2001;91(3):1035-40. 

9. Pesci A, Majori M, Cuomo A, Borciani N, Bertacco S, Cacciani G, Gabrielli M. Neutrophils infiltrating bronchial epithelium in chronic obstructive pulmonary disease. Respir Med. 1998;92(6):863-70. 

10. Ollerenshaw SL, Woolcock AJ. Charac.teristics of the inflammation in biopsies from large airways of subjects with asthma and subjects with chronic airflow limitation. Am Rev Respir Dis. 1992;145(4 Pt 1):922-7. 

11. Liesker JJ, Ten Hacken NH, Zeinstra-Smith M, Rutgers SR, Postma DS, Timens W. Reticular basement membrane in asthma and COPD: similar thickness, yet different composition. Int J Chron Obstruct Pulmon Dis. 2009;4:127-35. 

12. Chanez P, Vignola AM, O’Shaugnessy T, Enander I, Li D, Jeffery PK, et al. Corticosteroid reversibility in COPD is related to features of asthma. Am J Respir Crit Care Med. 1997;155(5):1529-34. 

13. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017 [Internet]. [cited 2017 June 3]. Available from: www.ginasthma.org 

14. Boulet LP, Turcotte H, Hudon C, Carrier G, Maltais F. Clinical, physiological and radiological features of asthma with incomplete reversibility of airflow obstruction compared with those of COPD. Can Respir J. 1998;5(4):270-7. 

15. Simpson JL, Milne DG, Gibson PG. Neutrophilic asthma has different radiographic features to COPD and smokers. Respir Med. 2009;103(6):881-7. 

16. Mitsunobu F, Mifune T, Ashida K, Hosaki Y, Tsugeno H, Okamoto M, et al. Influence of age and disease severity on high resolution CT lung densitometry in asthma. Thorax. 2001;56(11):851-6. 

17. Mitchell RS, Stanford RE, Johnson JM, Silvers GW, Dart G, George MS. The morphologic features of the bronchi, bronchioles, and alveoli in chronic airway obstruction: a clinicopathologic study. Am Rev Respir Dis. 1976;114(1):137-45. 

18. Al-Kassimi FA, Alhamad EH, Al-Hajjaj MS, Raddaoui E, Alzeer AH, Alboukai AA, et al. Can computed tomography and car.bon monoxide transfer coefficient diagnose an asthma-like phenotype in COPD? Respirology. 2017;22(2):322-328. 

19. Tatsumi K, Kasahara Y, Kurosu K, Tanabe N, Takiguchi Y, Kuriyama T; Respiratory Failure Research Group in Japan. Clinical phenotypes of COPD: results of a Japanese epidemiological survey. Respirology. 2004;9(3):331-6. 

20. Hersh CP, Jacobson FL, Gill R, Silverman EK. Computed tomography phenotypes in severe, early-onset chronic obstructive pul.monary disease. COPD. 2007;4(4):331-7. 

21. Fujimoto K, Kitaguchi Y, Kubo K, Honda T. Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography. Respirology. 2006;11(6):731-40. 

22. Al-Kassimi FA, Abba AA, Al-Hajjaj MS, Alhamad EH, Raddaoui E, Shaikh SA. Asthma masquerading as chronic obstructive pulmonary disease: a study of smokers fulfilling the GOLD definition of chronic obstructive pulmonary disease. Respiration. 2011;82(1):19-27. 

23. Sullivan P, Stephens D, Ansari T, Costello J, Jeffery P. Variation in the measurements of basement membrane thickness and inflammatory cell number in bronchial biopsies. Eur Respir J. 1998;12(4):811-5. 

24. Goddard PR, Nicholson EM, Laszlo G, Watt I. Computed tomography in pulmonary emphysema. Clin Radiol. 1982;33(4):379-87. 

25. Soltani A, Reid DW, Sohal SS, Wood-Baker R, Weston S, Muller HK, et al. Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study. Respir Res. 2010;11:105. 

26. Kosciuch J, Krenke R, Gorska K, Baran W, Kujawa M, Hildebrand K, Chazan R. Comparison of airway wall remodeling in 

asthma and COPD: biopsy findings. Respir Care. 2012;57(4):557-64. 

27. Bourdin A, Serre I, Flamme H, Vic P, Neveu D, Aubas P, Godard P, Chanez P. Can endobronchial biopsy analysis be recommended to discriminate between asthma and COPD in routine practice? Thorax. 2004;59(6):488-93. 

28. Cohen L, E X, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, et al. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med. 2007;176(2):138-45. 

29. Ordoez C, Ferrando R, Hyde DM, Wong HH, Fahy JV. Epithelial desquamation in asthma: artifact or pathology? Am J Respir Crit Care Med. 2000;162(6):2324-9. 

30. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, et al. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med. 2000;161(3 Pt 1):1016-21. 

31. Lee JS, Lippman SM, Benner SE, Lee JJ, Ro JY, Lukeman JM, et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous meta-plasia. J Clin Oncol. 1994;12(5):937-45. 

32. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Paré PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645-53. 

33. Kuwano K, Bosken CH, Paré PD, Bai TR, Wiggs BR, Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1993;148(5):1220-5. 

34. Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, Macklem PT. The relations between structural changes in 

small airways and pulmonary-function tests. N Engl J Med. 1978;298(23):1277-81. 

35. Tiddens HA, Paré PD, Hogg JC, Hop WC, Lambert R, de Jongste JC. Cartilaginous airway dimensions and airflow obstruction in human lungs. Am J Respir Crit Care Med. 1995;152(1):260-6. 

36. Miravitlles M, Calle M, Soler-Catalua JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48(3):86.98. 

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