Abstract
Chronic obstructive pulmonary disease (COPD) represents an important and increasing burden throughout the world. Classically, COPD has been considered a respiratory condition only, mainly caused by tobacco smoking. However, COPD has important manifestations beyond the lungs, the so-called systemic effects. These include unintentional weight loss, skeletal muscle dysfunction, an increased risk of cardiovascular disease, osteoporosis, and depression, among others. Low-grade, chronic systemic inflammation is one of the key mechanisms underlying these systemic effects. Because these extra-pulmonary manifestations of COPD are common and/or may have significant implications for the patient wellbeing and prognosis, they warrant systematic screening and appropriate management in order to provide optimal medical care.
INTRODUCTION
The most recent update of the GOLD guidelines defines chronic obstructive pulmonary disease (COPD) as “a preventable and treatable disease with some significant extra-pulmonary effects that may contribute to the severity in individual patients” ([1]). This definition implies a very significant change from the traditional view of the disease, which was basically centred around the presence of chronic airflow obstruction. This new understanding of the disease has implications for patient care. Here, we review the research evidence that underlies this change and we discuss their clinical impact and relevance.
COPD, A SYSTEMIC INFLAMMATORY DISEASE
An abnormal inflammatory response of the lungs to noxious particles or gases is believed to be a key pathogenic driver of COPD ([1]). A similarly abnormal inflammatory reaction can also be detected in the systemic circulation ([2], [3], [4]). Recently, Fabbri and Rabe have proposed that COPD should be considered a “chronic systemic inflammatory syndrome” to encompass both domains ([5]). The experimental evidence supporting this proposal is reviewed next.
Several authors have reported evidence of systemic oxidative stress, including decreased anti-oxidant capacity and increased levels of products of lipid peroxidation in plasma ([6]) and increased urinary levels of isoprostane F2α -III, a stable prostaglandin isomer formed by peroxidation of arachidonic acid ([7]).
Likewise, several circulating inflammatory cells appear abnormal in these patients. Neutrophils show evidence of enhanced chemotaxis and extra-cellular proteolysis ([8]), enhanced production of reactive oxygen species ([9]), up regulation of several surface adhesion molecules, particularly Mac-1 (CD11b) ([10]). Circulating monocytes (the precursor of alveolar macrophages) from patients with COPD produced more TNFα when stimulated in vitro than those obtained from healthy controls, particularly in those patients with low body weight ([11]). Finally, circulating lymphocytes also appear activated in patients with COPD ([12]), although the proportion of CD4+ to CD8+ cells in the peripheral circulation does not seem to be abnormal ([13]).
Numerous studies have reported increased plasma levels of TNFα, its receptors (TNFR-55 and TNFR-75), IL-6, IL-8, C-reactive protein, LPS binding protein, Fas and Fas-L ([2], [3], [4]). These abnormalities were seen in patients considered clinically stable but were generally more pronounced during exacerbations of the disease ([2], [3], [4]).
The origin of systemic inflammation in COPD is unclear and requires further investigation ([3]). Several mechanisms are possible. First, it may originate at the inflammed pulmonary parenchyma, either by spill-over of pro-inflammatory molecules from the lung and/or by activation of inflammatory cells (neutrophils, monocytes, lymphocytes) during their transit through the pulmonary circulation ([3]). Second, it is equally possible that other organs (e.g., skeletal muscle, liver, bone marrow) may contribute to the production of pro-inflammatory cytokines ([3]). Finally, it should not be forgotten that cigarette smoke, which is the main risk factor of COPD, has by itself the potential to produce systemic inflammation, as shown by the occurrence of coronary artery disease (also an inflammatory disease) in smokers, independently of the presence or absence of COPD ([3]).
Irrespective of its origin, it is generally accepted that systemic inflammation is one of the key drivers of many of the systemic effects of COPD discussed below (Table 1), albeit other potential contributing mechanisms may include sedentarism, tissue hypoxia, ageing, malnutrition and the effects of several drugs, among others ([2], [3], [4], [14]).
Table 1 Systemic effects of COPD
SYSTEMIC EFFECTS OF COPD
Weight loss and nutritional abnormalities
Unexplained weight loss is one of the most often recognized systemic effects of COPD. It occurs in about 50% of patients with severe COPD, but it can be seen also in about 10–15% of patients with mild to moderate disease, and this is mostly due to loss of skeletal muscle mass ([15]). Weight loss occurs whenever caloric intake and consumption are not matched. Decreased caloric intake does not appear to be very prominent in these patients, except during the episodes of exacerbation of the disease. Thus, it is unlikely to determine unexplained weight loss in a significant proportion of individuals. In contrast, most patients with COPD have increased basal metabolic rate ([16]). If this is not met by a parallel increase in caloric intake, weight loss does happen. Systemic inflammation, tissue hypoxia, and drugs used in the treatment of COPD (e.g., β 2 agonists) can contribute to the increased metabolic rate seen in COPD ([16]). Among them, the former is now considered a key pathogenic element ([16]).
Unexplained weight loss carries a poor prognosis in COPD ([17], [18], [19], [20]). Interestingly, however, prognosis is reversible if the patients gain weight ([17]). Even more importantly, this prognostic value is independent of other indicators, such as FEV1 or PaO2, that assess the degree of pulmonary dysfunction ([17]). Therefore, weight loss identifies a new systemic domain of COPD that needs to be taken into consideration in the clinical management of patients with COPD. The so-called BODE index (a composite score that includes Body weight (as reflected by the body mass index), the degree of airflow Obstruction (as indicated by the FEV1 value, expressed as percentage of the reference value), the degree of Dyspnoea perceived by the patient (as quantified by the MMRC questionnaire) and the Exercise capacity of the individual (as determined by the 6 minutes walking test)) has been shown to predict mortality in COPD better than FEV1 alone ([21]).
Skeletal-muscle dysfunction
Dyspnoea on exertion is one of the more frequent complaints of patients with COPD. Traditionally, this has been explained on the basis of the increased work of breathing caused by airflow obstruction. Yet, this view was originally challenged by Killian and co-workers when they showed that a significant percentage of COPD patients stop exercise because of leg fatigue –not dyspnoea ([22]). Since then, several publications have confirmed that many patients with COPD present skeletal muscle dysfunction (SMD) and that this contributes significantly to limit their exercise capacity and quality of life. In fact, given the clinical relevance of this observations, the ATS and the ERS have produced a joint position paper on the subject ([23]).
SMD in COPD is characterised by two different, but related, phenomena: ([1]) net loss of muscle mass; and ([2]) dysfunction or malfunction of the remaining muscle ([23]). The mechanisms underlying these abnormalities are not precisely defined, but they are probably multiple and likely interdependent, including: ([1]) Sedentarism. Patients with COPD often adopt a sedentary lifestyle due to dyspnoea on exertion. Physical inactivity causes net loss of muscle mass, reduces the force generation capacity of the muscle and decreases its resistance to fatigue. These effects can be improved by rehabilitation; ([2]) Systemic inflammation. In patients with COPD, cytokines, particularly TNFα, can activate the NF-KB pathway ([24]), induce the expression of a variety of genes, such as the inducible form of the nitric oxide synthase (iNOS) ([24]), facilitate the degradation of myosin heavy chains through the ubiquitin-proteasome complex ([25], [26]) and contribute to programmed cell death ([27]); ([3]) Oxidative stress causes muscle fatigue and facilitates proteolysis. This would be particularly relevant since the regulation of glutathione (GSH), the most important intra-cellular anti-oxidant, is abnormal in skeletal muscle of patients with COPD ([28]); and, ([4]) Tissue hypoxia suppresses protein synthesis in muscle cells, causes net loss of amino acids and reduces the expression of myosin heavy chain isoforms ([29], [30], [31]).
SMD in COPD contributes to weight loss and limit exercise capacity. The former is, as discussed above, a poor prognostic factor ([17], [18], [19], [20]). The latter has a profound impact on the quality of life of these patients ([32]).
Cardiovascular disease
There is strong epidemiological evidence to conclude that reduced FEV1, independent of cigarette smoking, cholesterol and hypertension, is a marker for cardiovascular morbidity and mortality ([33]).
Atherosclerosis of coronary arteries is characterized by endothelial dysfunction and an inflammatory process in the atherome plaque with presence of macrophages, T cells and increased pro inflammatory cytokines and C reactive protein. It is remarkable to observe the similarities of cardiac inflammation with lung inflammation ([34]).
Cardiac failure, possibly in relation to coronary atherosclerosis, has been found in about 20% of COPD patients ([35]). Often it is difficult to diagnose in COPD patients due to common symptoms, mostly dyspnea on exercise. A combination of clinical and electrocardiogram data with serum N-terminal fragment of brain-type natriuretic peptide (NTproBNP) can predict the probability to detect left ventricular failure ([35]). In the Lung Health Study, cardiovascular causes accounted for 42% of first hospitalizations and 44% of second hospitalizations in these patients with relatively mild COPD, higher than for respiratory causes (14%) ([36]).
The underlying mechanisms linking COPD with cardiovascular disease are not fully understood. Cigarette smoking is a common risk factor of both diseases but several studies established that the association between COPD and cardiovascular diseases remains independent of established risk factors. It is generally believed that systemic inflammation, albeit in mild-moderate degree, may contribute to increased cardiovascular morbidity and mortality in patients with COPD ([34]). Actually, both systemic inflammation and endothelial dysfunction are key pathogenic mechanisms for atherosclerosis ([37]).
Diabetes and glucose intolerance
The risk of developing type-2 diabetes is increased 1.8 times in women with COPD as compared with those without ([38]). On the other hand, hyperglycaemia is associated with poor outcomes in patients admitted to hospital with exacerbations of the disease ([39]). There are several potential mechanisms that could explain this association: 1) oxidative stress, present in COPD, has been implicated in insulin resistance; 2) CRP, IL-6, and TNFα have been implicated in the pathogenesis of insulin resistance and type 2 diabetes; and, 3) steroid treatment could induce hyperglycemia in both stable state and during exacerbations. Type-2 diabetes is linked to hypertension in more than 70% of individuals and to cardiovascular diseases and obesity in more than 80%, all of them with the potential to further worsen the severity of COPD ([40]).
Osteoporosis and fractures
Osteoporosis with subsequent fractures is a significant problem in patients with advanced COPD. Compared to controls without COPD, patients with COPD seen in primary care were at increased risk for osteoporosis and fractures (RR, 3.1 and 1.6, respectively) ([41]). Thirty-six to 70% of COPD patients have osteoporosis and its proportion increases proportionally with the severity of COPD ([42], [43]). Risk factors for osteoporosis include smoking, vitamin D deficiency, low body mass index, hypogonadism, decreased mobility, systemic inflammation and glucocorticoid use. Most of them are present in patients with COPD ([42]). Chronic oral glucocorticoid therapy reduces bone mineral density, but studies disagree on the effects of inhaled steroids. The main consequence of osteoporosis are fractures, particularly thoracic vertebral fractures that compromise lung function, and hip fractures that decrease mobility and are associated with significant mortality ([43]).
Depression
Depression and anxiety are common in patients with any chronic medical condition but new evidence indicates they have been grossly neglected and underestimated in COPD patients ([44]). Individuals with COPD have a higher prevalence of depression than either the general population or patients with other chronic illnesses. Some estimates report a prevalence of approximately 40% in COPD patients, compared to 15% in the general adult population ([45]).
Depression in COPD patients leads to a lower quality of life, greater objective impairment in function, and decreased adherence to therapeutic interventions. Recently, an association of depression with increased mortality and other relevant COPD endpoints was also postulated (46). Despite this, the effect of antidepressants on relevant clinical outcomes has not been systematically investigated.
Anaemia
Preliminary studies suggest that anaemia is present in 10–15% of patients suffering from severe forms of COPD ([47]). Like in other chronic diseases, systemic inflammation can contribute to anaemia ([45]). In COPD anaemia can contribute to exercise limitation, increased morbidity and reduced survival ([47]).
Autoimmune disorders
Several lines of evidence suggest an impaired immune response in patients with COPD, including increased lymphocyte T cell accumulation in the lungs, increased bronchus associated lymphoid tissue (BALT), expansion of the population of antigen presenting cells on the epithelial surface of the lower respiratory tract, increased antinuclear antibodies titres in blood, development of an autoimmune experimental model of emphysema and identification of anti-endothelial cell antibodies in the serum of patients with end stage emphysema ([48]). For all of previous reasons it has been hypothesized that COPD can have an autoimmune component ([49]).
The prevalence of autoimmune disorders in patients with COPD is unknown but two studies suggest a possible link. Birring et al. found in patients with COPD who never smoked an association with organ autoimmune disease, particularly thyroid disease ([50]). Similarly, Wisnieski et al. found an association between hypo-complementemia, and urticarial vasculitis syndrome in patients with COPD ([51]). There are several ongoing studies investigating the prevalence of autoantibodies in patients with COPD and more information on this topic will likely be available shortly.
Other systemic effects
Other extra-pulmonary effects frequently associated with COPD include cataracts, reportedly increased in patients treated with inhaled steroids, glaucoma, peptic ulcer, impotence, and gastro-esophageal reflux, among others. Their clinical impact is still to be established.
Systemic effects by severity of airflow obstruction
Current literature is scanty on describing the systemic effects and the number and quality of co-morbidities with increasing severity of airflow obstruction. It is generally accepted that systemic inflammation and the presence of several systemic effects, such as weight loss, cardiovascular disease, osteoporosis, and anaemia, show a direct relationship with the severity of airflow obstruction. However, not all studies found this association. For instance in a study by Yeo et al., quality of life, co-morbidity and health service utilization measurements were not significantly different within COPD severity groups ([52]).
Systemic effects in women with COPD
There has been a dramatic change in the sex ratio of COPD at the population and clinical level. Classical textbooks recommended clinicians to tease out COPD in patients with the triad of elderly, male, smokers. Some large COPD randomized controlled trials (RCT) conducted in the past did not even include women at all. To many, it was therefore surprising to see that in 2000 there were more deaths in the USA from COPD among females than males ([53]). Similar trends have been observed in Canada, the United Kingdom, Finland, and other countries ([54]).
A demographic change has been observed, with females living longer and smoking harder, therefore being more at risk of developing COPD. Worldwide, it is worth noting that in all countries but three (Norway, Sweden and New Zealand), and in these ones only since 2003, females have never smoked as much as males. Most recent population surveys identify as many women as men with COPD ([55]) and recent, large RCTs have no problem in including COPD women. It is expected that female specific comorbidities, like gynecological and peri- and post-menopausal disorders will be observed within the COPD spectrum.
CLINICAL IMPLICATIONS: MANAGEMENT OF CO-MORBIDITIES
In clinical practice, many “systemic effects of COPD” translate into specific co-morbid conditions. There is no universally accepted definition of co-morbidity. Traditionally, it has been defined as a disease coexisting with the primary disease of interest. In COPD, however, the definition of co-morbidity becomes problematic as certain coexisting illnesses may be a consequence of the patients' underlying COPD (systemic effects). For the purposes of this review, we define comorbidities as the presence of one or more distinct disorders (or diseases) in addition to COPD, regardless of whether the co-morbid conditions are or are not directly related to COPD, and irrespective of whether they are/are not part of the spectrum of the natural history of COPD.
There are few general population assessments that systematically review the distribution of co-morbidities in COPD patients. Patient data from the UK General Practice Research Database were analyzed to quantify baseline rates of co-morbidities in 2,699 patients with COPD (46% were current smokers) compared with age-, gender-, practice- and time-matched controls (21% were current smokers) ([41]). Angina, cataracts and osteoporosis all had a frequency of greater than 1% within the first year after COPD diagnosis ([41]). Furthermore, compared with controls, COPD patients had a significantly increased risk of co-morbidities and other medical events. It was concluded that COPD is associated with many comorbidities, particularly those related to cardiovascular, bone- and other smoking-related conditions, that previously had not been systematically documented ([41]).
The current GOLD guidelines identify four main goals of COPD management, namely to assess and monitor the disease, to reduce risk factors, to manage stable COPD, and to manage exacerbations ([1]). Optimal treatment should not focus exclusively on treating chronic airflow obstruction. It should also consider the potential impact of co-morbidities and treat them accordingly. For instance, comorbidities that might exacerbate symptoms like heart failure or sleep apnea should be treated. Depressive symptoms are also common, especially in patients with severe disease ([44], [45]). It is therefore important to search for symptoms of depression and treat them appropriately. During exacerbations of COPD, particularly if the patient requires hospitalization, the potential presence of cardiac arrhythmias, congestive heart failure, diabetes mellitus, liver or kidney failure, should be looked for as well. Assessment of comorbidities is key for an integrated care at any level of COPD progression, and should be a reason for referral to a more specialized care ([52]).
This holistic approach as well as the realization that systemic inflammation seems to be a key pathogenic driver of many of the systemic effects of COPD prompted Fabbri and Rabe to propose recently the term “chronic systemic inflammatory syndrome” ([5]). The term syndrome derives from the Greek and means literally “run together.” Medically speaking, a syndrome is defined by the association of several clinically recognizable features, signs (discovered by a physician), symptoms (reported by the patient), phenomena or characteristics which often occur together, so that the presence of one feature alerts the physician to the presence of the others ([5]). In the case of COPD, the high prevalence of several co-morbidities (or systemic effects) discussed above, as well as the fact that most of them are treatable, highlights the importance of an active search process and, eventually, adequate therapy for the optimal management of the disease.
CONCLUSIONS
COPD is associated with low-grade chronic systemic inflammation which is thought to underline many of the systemic effects described to date. In clinical practice, these systemic effects translate into the frequent occurrence of a number of co-morbidities, which have a significant impact on patient's well-being and prognosis. Moreover, most of them are treatable, thus highlighting the importance of an active search and treatment for an optimal, comprehensive management of the disease.
To date, however, evidence-based diagnostic and treatment strategies generally overlooked comorbidities ([56]). Further, despite the support that disease-specific guidelines give, these guidelines may introduce more problems than they solve when used in patients with co-morbidities ([57]). Co-morbidities may become harder to manage when COPD is present, either because COPD adds to the total level of disability or because COPD therapy adversely affects the co-morbid disorder. Until more integrated guidance about disease management for specific co-morbid problems becomes available, the focus should be on the identification and management of these individual problems in line with local treatment guidelines.
A new view of COPD is emerging, and previous lack of attention on local and systemic inflammation, as well as of comorbidities, is likely to be revised upwardly. Searching for the most frequent chronic co-morbidities of COPD will be a helpful reminder to clinicians of the complexity of the effects of both smoking and COPD.
Supported, in part, by ABEMAR and Govern Balear.
| • | Weight loss and nutritional abnormalities |
| • | Skeletal-muscle dysfunction |
| • | Cardiovascular diseases |
| • | Diabetes/glucose intolerance |
| • | Osteoporosis and fractures |
| • | Depression |
| • | Autoimmune disorders |
| • | Other: cataracts, glaucoma, peptic ulcer, impotence, gastroesophageal reflux |
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