Diagnosis and markers for the assessment of COPD: can a consensus be reached?

PVRI Member Authors: Michael Seimetz, Eveline Baumgart-Vogt, Srikanth Karnati

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

 

Prelude

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.

Chronicle image 2.png

Figure 1: Current available methods and markers of COPD assessment

Abbreviations: IL interleukin, MPO myeloperoxidase, NE neutrophil elastase, TNFα tumor necrosis factor alpha, CRP C-reactive protein  , BAL: Bronchoalveolar lavage, NO nitric oxide, CO carbon monoxide, SGRQ St. George's Respiratory Questionnaire, MRC Medical research council, CT computed tomography, MRI magnetic resonance imaging, DL,CO diffusing capacity of the lung for carbon monoxide, PET functional positron emission tomography 

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PVRI Chronicle Vol 3: Issue 2 cover image

August 2016

PVRI Chronicle Vol 3: Issue 2

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