Chronic Obstructive Pulmonary Disease: Comorbidities or Extrapulmonary Manifestations?

Alexandros G. Mathioudakis MD1, Efstathia I. Evangelopoulou MD2, Georgios A. Mathioudakis MD2
1 Medical Department, Southport and Ormskirk NHS Trust, 2 Respiratory Department, General Hospital of Nikaia St. Panteleimon.

Cite as: Mathioudakis AG, Evangelopoulou EI, Mathioudakis GA. Chronic Obstructive Pulmonary Disease: Comorbidities or Extra-Pulmonary Manifestations? Alveolus 2013; 1(1):16-18.

Among the changes in the last revision of the Global Initiative for Chronic Obstructive Lung Disease's (GOLD) guidelines, was the replacement of the phrase "Extra-pulmonary Manifestations" with the word comorbidities in the definition of the disease[1]. According to the writer's opinion this was the major alteration, it was not necessary and it could cause confusion and unfavourable effects, albeit only a "phrasal" modification.

To begin with, comorbidity is defined as a concomitant but unrelated pathological disease or process (according to the American Heritage Medical Dictionary), one or more coexisting medical conditions or disease processes that are additional to an initial diagnosed illness (Mosby's Medical Dictionary) or the extent to which two pathological conditions occur together in a given population (Miller-Keane Encyclopaedia and Dictionary of Medicine, Nursing and Allied Health), while the designation "extra-pulmonary manifestations" obviously implies a causal link.

In the new guidelines, only weight loss, nutritional abnormalities and skeletal mass dysfunction are recognised as systemic manifestations of the disease, whereas cardiovascular disease, osteoporosis, anxiety and depression, lung cancer, infections, metabolic syndrome and diabetes are characterised comorbidities[1]. This classification is probably based on the fact that smoking, which has been found to cause systemic oxidative stress, to act directly on the endothelium, to cause both humoral and cellular systemic inflammation and to activate coagulation factors, is a common predisposing factor for all the diseases[2-3]. However, many studies show that the systemic inflammation of COPD patients is significantly more pronounced and complicated[4] even in ex-smokers[5], while other studies show increased incidence of the extra-pulmonary manifestations in COPD patients compared to smokers[6-7]. As a result, COPD seems to be a second, independent risk factor for all these diseases, rather than a comorbidity.

Stone IS et al. in their recent review pointed out that apart from the common genetic and environmental risk factors, systemic inflammation, pulmonary hypertension and pulmonary hyperinflation are additional causes of myocardial stress and atheromatous plaque formation[6]. Fuschillo S et al. suggest that the colonisation of the airways by bacteria in COPD could be an additional linking factor between COPD and the increased oxidative stress which links COPD to atherosclerosis[8]. All these suggest that COPD is an independent risk factor - cause of cardiovascular disease. Furthermore, a slightly different mechanism of the CVD is suggested, although further studies are obligatory in order to confirm this hypothesis.

Increased circulatory levels of TNFa, IL-6 and CRP, which have a well documented osteoporotic activity, have been shown in COPD patients[9-11]. Interestingly, both CRP and TNFa have been proved to be increased only in COPD patients and not in smokers[4,12]. Moreover, in one of our studies, we showed that although corticosteroids are a well-known predisposing factor for osteoporosis, low-dose inhaled steroids could protect ex-smokers with COPD from developing osteoporosis. We suggested that this is because of the low circulating levels of steroids in combination with the down-regulation of the pulmonary and as a result the systemic inflammation of these patients[13]. The fact that they were ex-smokers supports the COPD-derived inflammation.

Unfortunately, only epidemiological data support the hypothesis that COPD is an independent risk factor for the rest of the comorbidities/ extrapulmonary manifestations[14]. According to the writer's personal opinion, even if the pathophysiological basis is not definitely clarified yet, extrapulmonary manifestations is  a more appropriate characterisation, because it raises the awareness of the different aspects of COPD and also highlights the role of the respiratory physician and researcher which extends both in the pulmonary and extrapulmonary aspects of the disease.

References:
[1] Global Initiative for Chronic Obstructive Lung Disease (GOLD), Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (Revised 2011). In.; 2011.
[2] Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest. 2007;131(5):1557-1566.
[3] MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):50-60.
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[5] Morales S A, Dreyse D J, Díaz PO et al. [Systemic inflammation among stable ex smokers with chronic obstructive pulmonary disease]. Rev Med Chil. 2010 Aug;138(8):957-64.
[6] Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart. 2012 Jul;98(14):1055-62.
[7] Iwamoto H, Yokoyama A, Kitahara Y et al. Airflow limitation in smokers is associated with subclinical atherosclerosis. Am J Respir Crit Care Med. 2009 Jan 1;179(1):35-40.
[8] Fuschillo S, Martucci M, Donner CF, Balzano G. Airway bacterial colonization: the missing link between COPD and cardiovascular events? Respir Med. 2012 Jul;106(7):915-23. Epub 2012 Apr 29.
[9] Bon JM, Zhang Y, Duncan SR, et al. Plasma inflammatory mediators associated with bone metabolism in COPD. COPD. 2010 Jun;7(3):186-91.
[10] Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity " a common inflammatory phenotype? Respir Res. 2006;7:70.
[11] Ding C, Parameswaran V, Udayan R, et al. Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab. 2008 May;93(5):1952-8.
[12] Liu SF, Chin CH, Wang CC, Lin MC. Correlation between serum biomarkers and BODE index in patients with stable COPD. Respirology. 2009 Sep;14(7):999-1004.
[13] Mathioudakis AG, Amanetopoulou SG, Gialmanidis I et al. Impact of long-term treatment with low-dose inhaled corticosteroids on the bone mineral density of COPD patients: Aggravating or Beneficial? Respirology. 2013;18:147–153. doi: 10.1111/j.1440-1843.2012.02265.x
[14] Kim SH, Kim JS, Choi JY et al. Factors Associated with Depressive Symptom in Chronic Obstructive Pulmonary Disease Based on the Third (2005) and Fourth (2008) Korea National Health and Nutritional Examination Survey (KNHANES III, IV). Korean J Fam Med. 2011 May;32(4):234-42. Epub 2011 May 31.

Conflicts of Interest: None