Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the "spill-over" of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

https://erj.ersjournals.com/content/erj/33/5/1165.full.pdf

Systemic manifestations and comorbidities of COPD

Although total mortality has decreased dramatically over the past 30 years, driven largely by successful reductions in deaths from cardiovascular diseases (CVDs), mortality from chronic obstructive pulmonary disease (COPD) has more than doubled. COPD is currently the 4th leading cause of mortality worldwide, accounting for more than three million deaths per year. Owing to increased prevalence of smoking in developing countries and the aging of the population across Western nations, COPD mortality is expected to more than double over the next 20 years, so that by 2030, it will be responsible for 10% of the world’s total mortality (currently 7%), accounting for seven million deaths annually. Although these figures are truly alarming, they probably underestimate the global impact of COPD on overall mortality, because COPD contributes significantly to other major causes of mortality, such as ischemic heart disease (IHD), stroke, and lung cancer.

https://erj.ersjournals.com/content/erj/28/6/1245.full.pdf

Mortality in COPD: Role of comorbidities.

Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more focused definition allows for classification of patients into distinct prognostic and therapeutic subgroups for both clinical and research purposes. Ideally, individuals sharing a unique phenotype would also ultimately be determined to have a similar underlying biologic or physiologic mechanism(s) to guide the development of therapy where possible. It follows that any proposed phenotype, whether defined by symptoms, radiography, physiology, or cellular or molecular fingerprint will require an iterative validation process in which "candidate" phenotypes are identified before their relevance to clinical outcome is determined. Although this schema represents an ideal construct, we acknowledge any phenotype may be etiologically heterogeneous and that any one individual may manifest multiple phenotypes. We have much yet to learn, but establishing a common language for future research will facilitate our understanding and management of the complexity implicit to this disease.

Chronic obstructive pulmonary disease phenotypes: the future of COPD.

Chronic obstructive pulmonary disease (COPD) is characterised by an inappropriate/excessive inflammatory response of the lungs to respiratory pollutants, mainly tobacco smoking. Recently, besides the typical pulmonary pathology of COPD (i.e. chronic bronchitis and emphysema), several effects occurring outside the lungs have been described, the so-called systemic effects of COPD. These effects are clinically relevant because they modify and can help in the classification and management of the disease. The present review discusses the following systemic effects of chronic obstructive pulmonary disease: 1) systemic inflammation; 2) nutritional abnormalities and weight loss; 3) skeletal muscle dysfunction; and 4) other potential systemic effects. For each of these, the potential mechanisms and clinical implications are discussed and areas requiring further research are highlighted.

https://erj.ersjournals.com/content/erj/21/2/347.full.pdf

Systemic effects of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

Background: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. Methods: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-a (TNF-a), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. Results: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-a levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). Conclusions: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

https://thorax.bmj.com/content/thoraxjnl/59/7/574.full.pdf

S F P Man

Papers

Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis