Natalia El-Merhie1, Eistine Boateng1, Srinu Tumpara1, Omelyan Trompak2, Michael Seimetz3, Adrian Pilatz4, Eveline Baumgart-Vogt1, Srikanth Karnati1
1) Institute for Anatomy and Cell Biology II, Division of Medical Cell Biology, Justus Liebig University, Giessen, Germany
2) Institute of Neuropathology, Justus Liebig University, Giessen, Germany
3) Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
4) Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Germany
Chronic obstructive pulmonary disease (COPD) is a progressive disorder which is characterized by airflow limitation that is not fully reversible 1 . It affects central airways causing chronic bronchitis, peripheral airways leading to small airway disease, and the lung parenchyma giving rise to emphysema 2 . Further, COPD has already become the third leading cause of death worldwide 3 . The major therapeutic goal is prevention of further exacerbations, yet the currently available treatment options are not considered to be very effective. Hence, implementing the onset biomarkers for the early diagnosis of the disease could improve the clinical assessment of COPD. Here we summarize the currently available markers and methods for COPD evaluation and diagnosis.
Generally, the assessment of COPD is based on physiological, symptomatic and nowadays – on newly emerging biological markers. Physiological markers are not straightforward to identify and validate, further requiring a standardized approach.
These markers include:
Spirometry – this is used to measure the volume of forcibly exhaled air in 1 second (FEV1)/forced vital capacity FVC 4, which is a marker for determination of staging, diagnosis, and treatment of the disease 5 . A fixed ratio of (FEV1/FVC)<70% defines airflow limitation. COPD patients lose lung function over a period of time, thus, a decline in FEV1 is used as an indicator of disease progression 6 . However, spirometry has its limitations. Since lung volumes are also affected during the normal process of aging, this method tends to be biased towards over diagnosis of the disease in some elderly patients 4 . Moreover, COPD is a complex disease which is accompanied by numerous pathological complications that are often ignored due to the poor understanding of the relationship between spirometry and the symptoms 6 .
Lung volume or lung hyperinflation characterizes an increase in the gas volume in the lungs in comparison to the predicted value7. It is another marker for the evaluation of COPD and determination of disease severity. Absolute lung volume is evaluated by measuring the increase in total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV) and the decrease in inspiratory capacity (IC)8 . Conventionally, lung hyperinflation is said to exist when the values of TLC, FRC and RV exceed 120–130% of the predicted volume7. These values are considered to be clinically relevant, however, cut-offs remain invalidated7. Moreover, high variability among COPD patients is a major problem in reproducing the cut-off values,and remains to be addressed in future studies7 .
Gas exchange (DL,CO) relies on the diffusing capacity of the lungs and is measured via the transfer of carbon monoxide from the airspace to the pulmonary capillary blood 9 . This method is used in the diagnosis of patients with emphysema10 . A major draw-back in assessing DL,CO is the high price of the necessary equipment making it less available in the primary care units. Moreover, it requires specific training for the technical staff and its reproducibility depends on the expertise of the staff 9 . Furthermore, Salzman and colleagues argue that DL,CO cannot be definitive for either confirming or excluding the diagnosis of emphysema because a reduction in DLCO accompanied by normal lung mechanics values (FEV1, FVC, FEV1/FVC, and lung volumes) might be suggestive of an emphysema, whereas normal DLCO does not rule it out11.
Exercise capacity or a 6-Minute Walk Test (6MWT) is the estimation of the distance covered during a 6-min walk where oxygen saturation, cardiac frequency, and respiratory intensity are recorded12. There are many sources of variability for this test, such as patients’ age, sex, weight, height, etc., making this test highly unreliable in diagnosing COPD 8,13 .
The body mass index (BMI) and the BODE index. TheBMI is calculated as weight/height squared in kg/m2. Body mass in this case is assumed to be comprised of fat mass and fat free mass (FFM). After accounting for BMI, FFM, airflow limitation (expressed by the FEV1), Dyspnea (expressed with the modified MRC scale), and exercise capacity (expressed with the 6-minute walking distance) an integral value is calculated – the so called “BODE index”, which provides information for COPD staging. In addition, the BODE index can serve as a prognostic factor of COPD where the decrease in BMI and FFM are associated with the impairment of the muscle function, health status, exercise capacity, and decreased survival of COPD patients14,15 .
Imaging includes computed tomography (CT), functional positron emission tomography (PET) and magnetic resonance imaging (MRI). CT reflects the morphologic changes in the lung parenchyma, pulmonary vasculature, central and peripheral airways16. In addition, CT is the best way to assess the severity of emphysema17 . A disadvantage of this technique is associated with radiation risk, limiting the multiple longitudinal scans in clinical trials. In contrast, MRI does not involve radiation and can be used as a substitute in the clinics18 . However, MRI is more time-consuming and expensive19. Finally, functional imaging through (MRI) and (PET) using hyperpolarized helium and xenon can be done20,21 . However, further standardization is necessary to achieve optimal results.
Exacerbations are short periods of worsening of the patients’ symptoms and characterized by as sputum hyper-production, increased cough, and dyspnoea22 . Exacerbations represent the disease progression and clinical instability, and are associated with an increased risk of mortality23 . Exacerbations are recorded by the patients by using a questionnaire or a diary card where they provide the information on the frequency, time of onset, severity, and duration of the periods of worsening symptoms. However, lack of standardized criteria makes the evaluation and comparison of clinical studies difficult4 , resulting in a poor correlation between manifestation of exacerbations and pathological changes occurring in the lung19 .
Other markers used for the assessment of COPD belong to the symptomatic group. These markers are assessed by medical doctors by recording frequency and nature of coughing, colouring of sputum, shortness of breath, and wheeze 6 . However, there is no agreed form for quantifying symptomatic data, response options and the equivalence between different questionnaires 6. The symptomatic measures of COPD comprise the following:
Baseline/Transition Dyspnea Index (BDI/TDI), Borg-Scale, and MRC (Medical Research Council) scale are the most frequently used scales for the identification of dyspnoea in clinical practice. The BDI/TDI is based on an interview conducted by the staff which converts the patients’ experience of dyspnoea into numerical parameters8 . Such studies are limited, biased, and lack standardization when translating patient’s answers into parameters24. The Borg-scale (or CR-10), is a 10 point category scale that incorporates the description of the severity corresponding numbers25. CR-10 requires a detailed instruction for the patients on how to use this scaling system26 . The MRC scale is a five-point scale that describes breathlessness and the severity of dyspnoea27. This method is also limited by bias28 .
St. George's Respiratory Questionnaire (SGRQ) covers three domains: frequency and severity of symptoms, activities that cause or are limited by breathlessness, and the impact these disturbances have on patients’ life, which is reflected in the end as an integral score. However, these scores are influenced by patient’s age, sex, education, and comorbidities29 .
Moreover, pulmonary biomarkers can also be used to assess the COPD disease status. These group of markers comprises an estimate of the presence and involvement of inflammatory cells (macrophages, neutrophils, and lymphocytes), levels of cytokines (IL-6, IL-8, TNF-α) myeloperoxidases (MPO), neutrophil elastases (NE), expired nitric oxide (NO), and carbon monoxide (CO), which can be sampled from either sputum, blood, bronchoalveolar lavage (BAL), exhaled breath, or bronchial biopsies12 .
Bronchial biopsies provide the information on the structural changes in the epithelium, muscles, and glands where structural components can be dissected and studied separately30 . The interaction between inflammatory and resident cells can be investigated by immunostaining12. However, there are several drawbacks to bronchial biopsies. First, this procedure is invasive and unsafe to patients with a severe disease stage31 . Second, the airway wall examined during biopsy might not reflect the pathological alterations in the lung parenchyma and peripheral airways.
Bronchoalveolar lavage (BAL) allows the study of chemical and cellular components in the epithelial lining fluid of the peripheral airways32 . Unfortunately, the low sample numbers obtained from BAL are not sufficient for statistical analysis.
Sputum analysis provides the information of the mediators in the central airways33. However, this analysis is not representing the environment in the distal airways that might be important for the diagnosis of COPD. Moreover, sputum contains thick mucus that has to be removed before processing the sample, and dithiothreitol (DTT) used to solubilize the sputum alters the proteins making them unrecognizable by the antibodies34,35.
Exhaled gas analysis is a non-invasive method for monitoring COPD airways inflammation12. It measures exhaled nitric oxide (eNO) and exhaled carbon monoxide (CO) in breath. Unfortunately, reproducibility and sensitivity issues are not yet been clarified12.
Blood samples; there are several studies suggesting that CRP, TNF-α, IL-6 and IL-8 play a role in COPD and in its exacerbations36,37 . However, blood sampling requires more randomized studies with larger sample sizes in order to confirm the sensitivity and specificity of this method38.
Summary and questions for interactive discussion
We summarized the available COPD assessment methods and their limitations. Currently, there exists no consensus concerning the best criteria to be used for the assessment of COPD despite the variety of markers and methods available for diagnosing this disease. However, reproducibility and effectiveness of the methods were shown to be limited. Moreover, by the time COPD patients seek medical help, they already manifest significant (and often severe) symptoms of the disease. Therefore, we would like to forward the following questions to the scientific community worldwide: how reliable are the biological markers for COPD? What are the best and most specific markers to be used for assessment of COPD? What are the markers that will allow the early diagnosis of COPD?
We would like to invite all those interested in this field to reply and express their views on this topic in the next volume of PVRI Chronicle.
1. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001, 163(5):1256-1276.
2. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 2004, 59 Suppl 1:1-232.
3. WHO WHO: The top 10 causes of death Fact sheet N°310 Deaths across the globe: an overview. 2013.
4. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007, 176(6):532-555.
5. Hankinson JL, Crapo RO, Jensen RL: Spirometric reference values for the 6-s FVC maneuver. Chest 2003, 124(5):1805-1811.
6. Jones PW, Agusti AG: Outcomes and markers in the assessment of chronic obstructive pulmonary disease. Eur Respir J 2006, 27(4):822-832.
7. O'Donnell DE, Laveneziana P: The clinical importance of dynamic lung hyperinflation in COPD. COPD 2006, 3(4):219-232.
8. Glaab T, Vogelmeier C, Buhl R: Outcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations. Respir Res, 11:79.
9. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique--1995 update. Am J Respir Crit Care Med 1995, 152(6 Pt 1):2185-2198.
10. Sherrill DL, Enright PL, Kaltenborn WT, Lebowitz MD: Predictors of longitudinal change in diffusing capacity over 8 years. Am J Respir Crit Care Med 1999, 160(6):1883-1887.
11. Salzman SH: Which pulmonary function tests best differentiate between COPD phenotypes? Respir Care, 57(1):50-57; discussion 58-60.
12. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR et al: Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008, 31(2):416-469.
13. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002, 166(1):111-117.
14. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP: Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999, 160(6):1856-1861.
15. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF: Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 2005, 82(1):53-59.
16. Sverzellati N, Molinari F, Pirronti T, Bonomo L, Spagnolo P, Zompatori M: New insights on COPD imaging via CT and MRI. Int J Chron Obstruct Pulmon Dis 2007, 2(3):301-312.
17. Newell JD, Jr., Hogg JC, Snider GL: Report of a workshop: quantitative computed tomography scanning in longitudinal studies of emphysema. Eur Respir J 2004, 23(5):769-775.
18. de Lange EE, Altes TA, Patrie JT, Battiston JJ, Juersivich AP, Mugler JP, 3rd, Platts-Mills TA: Changes in regional airflow obstruction over time in the lungs of patients with asthma: evaluation with 3He MR imaging. Radiology 2009, 250(2):567-575.
19. Barker BL, Brightling CE: Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clin Sci (Lond), 124(6):371-387.
20. Jones HA, Marino PS, Shakur BH, Morrell NW: In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma. Eur Respir J 2003, 21(4):567-573.
21. Suga K, Tsukuda T, Awaya H, Matsunaga N, Sugi K, Esato K: Interactions of regional respiratory mechanics and pulmonary ventilatory impairment in pulmonary emphysema: assessment with dynamic MRI and xenon-133 single-photon emission CT. Chest 2000, 117(6):1646-1655.
22. Schmier JK, Halpern MT, Higashi MK, Bakst A: The quality of life impact of acute exacerbations of chronic bronchitis (AECB): a literature review. Qual Life Res 2005, 14(2):329-347.
23. Anzueto A, Sethi S, Martinez FJ: Exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2007, 4(7):554-564.
24. Campbell ML: Dyspnea prevalence, trajectories, and measurement in critical care and at life's end. Curr Opin Support Palliat Care, 6(2):168-171.
25. Borg GA: Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982, 14(5):377-381.
26. Mador MJ, Rodis A, Magalang UJ: Reproducibility of Borg scale measurements of dyspnea during exercise in patients with COPD. Chest 1995, 107(6):1590-1597.
27. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH: The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J 1959, 2(5147):257-266.
28. Rennard S, Decramer M, Calverley PM, Pride NB, Soriano JB, Vermeire PA, Vestbo J: Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey. Eur Respir J 2002, 20(4):799-805.
29. Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, Masa JF, Viejo JL, Jimenez-Ruiz CA, Miravitlles M: Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur Respir J 2002, 19(3):405-413.
30. Fuke S, Betsuyaku T, Nasuhara Y, Morikawa T, Katoh H, Nishimura M: Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2004, 31(4):405-412.
31. Hattotuwa K, Gamble EA, O'Shaughnessy T, Jeffery PK, Barnes NC: Safety of bronchoscopy, biopsy, and BAL in research patients with COPD. Chest 2002, 122(6):1909-1912.
32. Koutsokera A, Kostikas K, Nicod LP, Fitting JW: Pulmonary biomarkers in COPD exacerbations: a systematic review. Respir Res, 14:111.
33. Alexis NE, Hu SC, Zeman K, Alter T, Bennett WD: Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique. Am J Respir Crit Care Med 2001, 164(10 Pt 1):1964-1970.
34. Djukanovic R: Induced sputum--a tool with great potential but not without problems. J Allergy Clin Immunol 2000, 105(6 Pt 1):1071-1073.
35. Kelly MM, Keatings V, Leigh R, Peterson C, Shute J, Venge P, Djukanovic R: Analysis of fluid-phase mediators. Eur Respir J Suppl 2002, 37:24s-39s.
36. Gan WQ, Man SF, Senthilselvan A, Sin DD: Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004, 59(7):574-580.
37. Agusti AG: Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005, 2(4):367-370; discussion 371-362.
38. Wouters EF: Local and systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005, 2(1):26-33.