Chronic Obstructive Pulmonary Disease

Synonyms

Chronic bronchitis; Pulmonary emphysema

Definition

Chronic obstructive pulmonary disease (COPD) affects over 5% of the adult population, is the fourth leading cause of death worldwide, and is the only major cause of mortality that is increasing worldwide. It is a complex and heterogeneous inflammatory disorder of the lungs, caused mainly, but not exclusively, by cigarette smoking. Fifteen to twenty percent of smokers develop COPD.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD; (http://www.goldcopd.com) has defined COPD as follows: “COPD is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The chronic airflow limitation that characterizes COPD is caused by a mixture of small airways disease (e.g., obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Chronic inflammation causes structural changes, small airways narrowing, and destruction of lung parenchyma. A loss of small airways may contribute to airflow limitation and mucociliary dysfunction, a characteristic feature of the disease.” The severity of COPD is classified on the basis of chronic symptoms (cough, sputum production), spirometric lung function tests, and the history of exacerbations.

Basic Mechanisms

During COPD the following symptoms occur, usually in the order mucus hypersecretion (associated with MUC5AC and MUC5B overexpression), ciliary dysfunction, airflow limitation, pulmonary hyperinflation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale. Acute exacerbations appear to be mainly triggered by bacteria, viruses, or environmental pollutants. They lead to a worsening of lung functions and reduced quality of life and mainly impact on long-term outcome. COPD is considered a systemic disease because cardiovascular disease, sarcopenia, osteoporosis, and diabetes are frequent comorbidities.

COPD is a chronic inflammatory disease that results from prolonged and repeated inhalation of particles and gases, chronic (or latent) infection, or an interaction of these factors. In many cases the inflammation persists even when the exposure (in most cases smoking) is stopped. The inflammation is found predominantly in the smaller airways and in the lung parenchyma. Prominent among the infiltrating leukocytes are neutrophils, CD8⁺ lymphocytes and CD68⁺ monocytic cells (Table 1). The chronic inflammation leads to small airway fibrosis causing airway narrowing and to lung parenchyma stiffening that promotes small airway collapse. Both mechanisms are irreversible and lead to air trapping. Superimposed are reversible cholinergic responses such as small airway contraction and mucus hyperproduction (Barnes 2017).

Table 1 Pathological changes in COPD

Oxidative stress is considered an important pathogenic factor. It may promote COPD by many factors such as induction of pro-inflammatory genes in many cells including epithelial and endothelial cells, inactivation of antiproteases, and key repair molecules such as sirtuin-1, which may contribute to the accelerated aging responses seen in COPD. Reactive oxygen species and other factors such as ceramide or blockade of vascular endothelial growth factor (VEGF) receptors may cause emphysema by induction of apoptosis (in the case of reactive oxygen species also necrosis) in endothelial or epithelial cells. Furthermore, inefficient apoptotic cell clearance (efferocytosis) may also contribute to a probably genetically modulated progressive lung destruction with fibrosis.

The inflammation in COPD appears to be complex and heterogeneous. In general the immune response appears to be skewed – albeit not in a clear-cut manner – toward pro-inflammatory M1-like macrophages and Th1 as well as Th17 responses. Among the typical mediators and effectors found in the disease are TNF, IL-1, IL-8, IP10, LTB₄, and elastolytic enzymes such as matrix metalloproteases and cathepsins. The majority of drugs in development for COPD are based on anti-inflammatory concepts, e.g., antagonists for IL-33, CXCR2, IFNβ, IL-1β, IL-5, IL-13, IL-17A, TNF, or FGF and inhibitors for LOX5, MMP12, PI3Kδ, p38, IKK2, or iNOS (Barnes 2017).

Both elastase and MMPs have physiological antagonists, named α1AT (α1-antitrypsin) (the primary inhibitor of neutrophil elastase) and TIMP (tissue inhibitor of matrix metalloproteases), respectively. Smoke, presumably through oxidative stress, may inactivate these antiproteases. Consequently, it has been suggested that emphysema results from an imbalance of the protease and antiprotease ratio and indeed, hereditary α1AT deficiency is a rare but well-known cause of emphysema. In experimental animals, TIMP-3 deficiency leads to a combination of developmental airspace enlargement combined with progressive destructive emphysema in adults. However, almost certainly, no single protease/antiprotease alone is responsible for the development of COPD.

Today, COPD is regarded as a systemic disease. The different pathomechanisms do not only cause local lung injury and remodelling but also alter systemic structures and function. Relatively little is known about the low-grade systemic inflammation present in COPD that is considered the main cause for the systemic effects. These systemic effects of COPD include involuntary weight loss, muscle atrophy, impaired bone metabolism, reduced functional capacity and health status, and increased cardiovascular morbidity as an important resource-consuming comorbidity. Thus, COPD is multidimensional disease (Singh et al. 2019). To account for the multiple changes in COPD, the BODE index was introduced, a 10-point scale combining measures of BMI (B), the degree of airflow obstruction (O) and dyspnea (D), and exercise capacity (E) (Celli et al. 2004).

Pharmacological Interventions

Usually it takes years of toxin exposure to cause the pathological alterations seen in COPD. In most cases the disease is already well progressed when COPD is diagnosed. Reversal of established chronic inflammatory disease is always extremely difficult to achieve, and at present healing of COPD is impossible. Most of the pharmacological agents that are used in COPD (Fig. 1) have been developed for the treatment of asthma, where their benefit is clearly greater. The comparatively small effect of inhaled β-agonists on airway resistance is even used as a diagnostic criterion to distinguish COPD from asthma. The management of COPD is largely symptom-driven, and there is only an imperfect relationship between the degree of airflow limitation and the presence of symptoms. Currently, there is no effective therapy for the irreversible airflow obstruction that results from airway remodelling, fibrosis, and emphysema. Available pharmacotherapy can reduce or abolish symptoms, increase exercise capacity, reduce the number and severity of exacerbations, and improve health status. The inhaled route is preferred. The mainstay of therapy are anticholinergics, β2-agonists, and steroids, and much effort has been put into evaluating the benefits of single, double, and triple therapies of these three classes. In addition to these drugs, roflumilast or azithromycin may be used to treat exacerbations (van Haarst et al. 2019; Singh et al. 2016, 2019; Woodruff et al. 2015).

Fig. 1

Pharmacotherapy of COPD

Bronchodilators

The primary aim of the current COPD therapy is to reduce airway resistance by reducing bronchial smooth muscle constriction and mucous plugging. β2-adrenoreceptor agonists and anticholinergics are the mainstay of therapy for symptomatic management. These bronchodilators improve symptoms and exercise tolerance and may reduce exacerbations but have little effect on inflammation and on the long-term decline in lung functions. β2-agonists and to some extent also anticholinergics may increase the risk of adverse cardiovascular events, although the cardiovascular risks of the latest drugs are quite low.

β2-adrenoreceptor agonists: β-agonists increase intracellular cAMP, which in turn leads to bronchodilation and improved lung emptying during breathing. Short-acting β-agonists (SABA, half-life <6 h: salbutamol, terbutaline, orciprenaline, fenoterol, albuterol), long-acting β-agonists (LABA, ~12 h: formoterol, salmeterol), and ultra-long-acting β-agonists (uLABA, ~24 h: indacaterol, olodaterol) are used. Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators. There is a relatively small and flat dose-response relationship with all β-agonists. Possible side effects are palpitations and premature ventricular contraction (resulting from stimulation of β₁ receptors in the heart), tremor, sleep disturbances, and hypokalemia (see also “Asthma” entry).

Anticholinergics: Modern long-acting muscarinic receptor antagonists (LAMA) are tiotropium, aclidinium, umeclidinium, and glycopyrrolate. All show higher selectivity for M3-receptors compared to M2-receptors and in addition remain bound to M3-receptors longer than to M2-receptors. They have to be given once or twice daily. Older anticholinergics (e.g., ipratropium, oxytropium) that have to be given up to four times daily are often used as maintenance treatment. Possible side effects are dry mouth, metallic taste after inhalation, and very rarely close angle glaucoma. The effects of anticholinergics and β-agonists show some additive effects (combination therapy).

Anti-inflammatory Therapy

Inhaled corticosteroids. Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone and its derivatives, flunisolide) are typically used in conjunction with LABAs and appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status. Many patients appear to be resistant to steroids, and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid therapy. They appear to work best in patients with frequent exacerbations and with eosinophilia; of note, the IL-5 antibody mepolizumab is currently under debate for use in eosinophilic COPD. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice; in addition systemic side effects such as osteoporosis may develop.

Systemic steroids. Systemic steroids are used to treat acute exacerbations. Here, short-term use of 3–5 days is standard of care. Long-term use of systemic steroids should be avoided in order to prevent steroid-associated side effects. In addition, it has been shown that long-term use of systemic steroids is associated with negative long-term outcome.

Phosphodiesterase inhibitors: The phosphodiesterase-4 (PDE-4) inhibitor roflumilast is approved to reduce the risk of COPD exacerbations in patients with frequent COPD exacerbations despite bronchodilators and inhaled steroids. Its mechanism of action is considered to be largely based on its anti-inflammatory effects; as an example, it decreases TNF expression. Another albeit unspecific phosphodiesterase inhibitor that also hits other targets such as A1-receptors is theophylline; theophylline is a third-line bronchodilator drug in chronic COPD behind inhaled anticholinergics and β2-agonists, with slow-release forms of oral theophylline preferred. Methylxanthines have a narrow therapeutic margin; major side effects are ventricular and atrial dysrhythmias and convulsions. Possible side effects of PDE-4 inhibitors include headache, nausea, vomiting, diarrhea, and heartburn.

Anti-microbial Therapy

The use of antibiotics is not recommended, except for the treatment of infectious exacerbations of COPD and other bacterial infections. An exception are macrolides, in particular azithromycin, that do also have immunomodulatory effects. Azithromycin may be beneficial for older patients with milder disease and for ex-smokers. Known risks are hearing loss and prolonged QTc interval (Woodruff et al. 2015).

Anti-trypsin Augmentation Therapy

Approximately 2% of all COPD patients suffer from homozygous α1-AT deficiency. Intravenous infusion of replacement protein twice weekly in patients with established α₁-antitrypsin deficiency has been approved in both in the USA and in Europe.

Oxygen Therapy

Long-term oxygen therapy (>15 h per day) is introduced in very severe hypoxemic COPD and improves survival, exercise capacity, and cognitive performance. Oxygen therapy is also temporarily used for hospital treatment of hypoxemic COPD exacerbations. In addition to improving oxygenation, oxygen therapy is thought to be effective because it reduces pulmonary hypertension by opposing hypoxic pulmonary vasoconstriction.

Psychopharmacological Therapy

Up to 30% of COPD patients suffer from anxiety disorder or depression and should be treated with conventional pharmacotherapy (Woodruff et al. 2015).

Non-pharmacological Interventions (Singh et al. 2019)

Reduction of Risk Factors

Smoking is the single most important single-risk factor for COPD, and smoking cessation is the single most effective – and cost-effective – intervention to reduce the risk of developing COPD and to stop its progression. Other risk factors include open fire cooking.

Vaccination

Because infections are a common cause of exacerbations, age-appropriate vaccination against influenza and pneumococci is recommended.

Noninvasive Ventilation

Noninvasive ventilation is used to treat acute hypercapnic respiratory failure during an acute exacerbation. This treatment is administered in hospital. Nevertheless, current data have shown that NIV is able to treat chronic hypercapnic respiratory failure as well. Here, NIV is used mainly at home during nighttime for long-term treatment.

Pulmonary Rehabilitation

Pulmonary rehabilitation as add-on to medication and vaccination has proven to be much more efficient in motivated patients than medication alone. It is aiming at self-management and training but also includes nutritional, pharmacological, and psychosocial support. Training increases the proportion of type I (minimal fatiguable aerobic low-velocity fibers) versus type II fibers (vs. the high-velocity anaerobic), stimulates the release of endogenous opioids, provides psychological reinforcement during exercise, and improves self-confidence.

Lung Volume Reduction (Surgery and Endoscopic)

Lung volume reduction surgery is a treatment option for patients with severe emphysema. Endoscopic lung volume reduction using valves, coils, and other approaches are newly developed treatment options that can alternatively be used in COPD patients with severe emphysema.