COPD and Inflammation

Abstract

COPD is associated with chronic inflammation of the airways, which causes damage to defense and repair mechanisms, resulting in remodeling processes in the bronchi and bronchioles. This leads to fibrosis of the lung tissue, increased smooth muscle tension, swelling of bronchial mucosa, loss of cilia function with accumulation of mucus, and finally to chronic pulmonary obstruction and possibly emphysema, with the main symptoms of dyspnea, coughing, and expectoration. Inhaled pollutants can activate immune cells like macrophages, T-lymphocytes, and subsequently neutrophilic granulocytes. Together, they release various pro-inflammatory messenger substances and enzymes. As a relevant example, they secrete proteases and disable antiproteases, an imbalance that destabilizes lung tissue. Of particular importance are several cytokines that are significantly elevated in the plasma of patients with COPD signals. In addition to the pathophysiologically clearly defined neutrophilic inflammation, there are also COPD patients with a predominantly eosinophilic inflammation, which could overlap with allergic bronchial asthma. Furthermore, inhaled pollutants can lead to oxidative stress, which increases inflammation and remodeling. Respiratory infections, in most cases bacterial infections, can trigger an exacerbation of already established COPD, in most cases bacterial infections. In addition to conventional medication, in case of refractory therapy, treatment with biologics could be an option.

1. Introduction

COPD (chronic obstructive pulmonary disease) is a disease of the lungs with permanent narrowing of the bronchial system, resulting from chronic inflammation of the small airways. This obstructive bronchiolitis causes increased mucus production. Lung tissue remodeling occurs and finally fibrosis and destruction of lung tissue lead to pulmonary emphysema. This causes a collapse of the small airways during exhalation. The patients suffer from coughing, massive sputum production, and shortness of breath [1, 2, 3, 4].

This book chapter describes the underlying inflammatory processes. The players involved in inflammation are described in more detail, various forms of inflammation or damage are distinguished from one another, and the role of respiratory infections as a trigger is highlighted.

2. Players involved in inflammation

Leukocytes as macrophages, T-lymphocytes, and neutrophilic granulocytes are involved in the inflammation processes in COPD. These cells can be activated by pollutants, such as cigarette smoke or fine dust, and by infections [5, 6, 7].

Macrophages have the following functions: As M1 macrophages, they promote inflammatory reactions by secreting cytokines, such as IL-6 (interleukin-6) or TNF- α (tumor necrosis factor-α), at the site of inflammation. In this way, they initiate and regulate the body’s defense reactions. They phagocytize foreign cells. They act as professional antigen-presenting cells by presenting antigen fragments coupled to MHC (major histocompatibility complex) class II proteins to adaptive immunity cells. They remove cellular debris via phagocytosis. As M2 macrophages, they promote the healing process of inflammation (inflammatory resolution) and secrete messenger substances with an anti-inflammatory effect. As a result, they support wound healing, among other things. The mobilization of leukocytes from the blood and their migration to the site of infection in peripheral tissues is a major step in innate immunity. Macrophages make up only about 10% of all macrophages in the bronchial secretion of healthy people, but up to 90% in the secretion of people with COPD. But in macrophages of patients with COPD, the clearance of the bacteria is decreased. These macrophages also show a defective clearance of apoptotic cells, leading to accumulation of necrotic material in the lungs, causing chronic inflammation. The accumulation of these inflammatory macrophages in the lung seems to be supported by an epigenetic factor called PRMT7 (protein arginine methyltransferase7). In people with COPD, PRMT7 is increased in the progenitor cells from which the macrophages develop. The number of macrophages and thus the severity of COPD are related to the increased PRMT7 values in the lung tissue. Investigated in a mouse model, the animals do not develop COPD when the production of PRMT7 is inhibited. In future, PRMT7 could be a suitable target for future therapeutic or even preventive approaches to COPD in humans [4, 5, 6, 7].

T-lymphocytes are divided into two main groups, which differ in their function and the expression of their surface molecules CD4 or CD8: CD4+ T cells differentiate into helper cells or regulatory cells (Tregs) and induce or inhibit other immune cells. Naive CD4+ T cells can be stimulated through direct contact with antigen-presenting cells, such as dendritic cells. Tregs inhibit autoimmune processes and can suppress increased inflammation. Depending on the surrounding cytokine milieus, they can be divided into different subgroups, which have distinct immunomodulatory effector functions. The two most obvious subgroups are the natural Tregs and the inducible or adaptive ones. The natural Tregs leave the thymus as an effector cell and are essential for the formation of self-tolerance, whereas the inducible Tregs develop in the periphery and are activated by exogenous antigens. Tregs transmit their suppressive effects on other T cells or antigen-presenting dendritic cells via contact-dependent mechanisms. Smokers with COPD and emphysema have significantly less Tregs in the lungs, in comparison to control groups (smokers without COPD and healthy nonsmokers). The CD8+ T cells are in front, especially effector cells of the adaptive immune system. After the primary activation, the CD8+ T cells start their proliferation and differentiation into a cytotoxic effector cell. Its key role is to control inflammation by targeting infected cells [4, 5, 6, 7].

Neutrophilic granulocytes are recruited to the inflamed areas in the lung, where they become activated and thereby their inflammatory mediators. Increased numbers of activated neutrophils are found in the sputum and bronchoalveolar lavage fluid of patients with COPD and correlate with disease severity, although few neutrophils are seen in the airway wall and lung parenchyma, reflecting their rapid transit through these tissues. Smoking has a direct stimulating effect on neutrophilic granulocyte production and release. Recruitment of neutrophilic granulocytes to the airways involves initial adhesion to endothelial cells through E-selectin, which is up-regulated on endothelial cells in the airways of patients with COPD. Activated neutrophilic granulocytes also release proteolytic enzymes, such as the neutrophil elastase, cathepsin G, and proteinase-3, leading to a proteinase/antiproteinase imbalance. Neutrophil elastase leads to proteolysis in the lungs and degrades many components of the extracellular matrix [4, 5, 6, 7, 8].

Dendritic cells are a link between innate and adaptive immunity. The respiratory system contains a network of dendritic cells localized near the surface, and they are ideally located to signal the entry of inhaled foreign substances. Dendritic cells can activate a variety of other immune cells, including macrophages, T-lymphocytes, and neutrophilic granulocytes, and therefore dendritic cells play a significant role in the pulmonary response to cigarette smoke and other inhaled noxious agents. Dendritic cells are activated in the lungs of patients with COPD and are linked to disease severity [5, 6, 7].

Cytokines, which are produced and secreted among others by T-lymphocytes, function as players in the humoral system and form together with the cellular system a generalized orchestra of immune response. In several studies, the expression of cytokines was measured in patients with COPD compared with healthy persons. Furthermore, in the population of COPD patients, the correlation between cytokine expression and clinical characteristics or severity was investigated. As result, significant correlations were found in the way that in the plasma of COPD patients, elevated levels of cytokines were identified compared to healthy controls. But there is a large variation between different studies with contradicting results. A selection of the probably most relevant cytokines is briefly presented below [6, 7, 9].

IL-1ß is produced by activated macrophages and plays a role in apoptosis as well as in cell proliferation and differentiation. It is involved in the development of chronic inflammatory diseases, such as COPD. IL-1ß activates macrophages from patients with COPD to secrete inflammatory cytokines, chemokines, and matrix metalloproteinase. There is an increase in the concentration of IL-1ß in sputum of COPD, which is correlated with disease severity [6, 7, 9, 10, 11, 12].

IL-2 is also called T-cell growth factor because it stimulates the proliferation and differentiation of T and B lymphocytes. Additionally, it stimulates the production of various other interleukins, INF-γ (interferon-γ) and TNF-α. Cytotoxic cells, such as natural killer cells, lymphokine-activated killer cells, and tumor-infiltrating lymphocytes, which also express the IL-2 receptor, are activated as well [6, 7, 11, 13].

IL-5 is produced by Th2 lymphocytes and in high expression in COPD patients. It seems feasible to inhibit IL-5 to achieve suppression of inflammatory and oxidative stress responses. There is a close association between IL-5 and the aggregation and differentiation of eosinophil. Sputum levels of IL-5 in patients with stable COPD correlate with the degree of eosinophilia [6, 7, 10, 12, 14, 15, 16].

IL-6 binds to specific membrane-bound IL-6 receptors found exclusively on hepatocytes and leukocytes. These receptors initiate an intracellular signaling cascade via the membrane-bound gp130 (glycoprotein 130), which is found on the cell membranes of many cell types and leads to trans-signaling cascades. In addition, IL-6 binds to the soluble IL-6 receptor. This complex also binds to the glycoprotein 130. The activation of glycoprotein 130 causes the phosphorylation of JAK (Janus-activated kinase), leading to the activation of several signaling pathways important for the immune response. The activated MAP (mitogen-activated protein) kinase pathway and the likewise activated JAK-STAT (signal transducers and activators of transcription) signaling pathway lead to the intracellular transcription of specific target genes relevant to the immune response. This process characterizes interleukin-6 as a lymphocyte-stimulating factor or as an activator of acute-phase proteins. Furthermore, IL-6 participates in the regulation of leukocyte apoptosis, namely with proapoptotic and antiapoptotic active components. In the case of activated T-lymphocytes, the soluble IL-6 receptor is necessary for mediating these effects because activated T-lymphocytes usually have no membrane-bound IL-6 receptors [6, 7, 9, 10, 11, 12, 13].

IL-8 is also known as a neutrophilic chemotactic factor. It can be secreted by any cells with toll-like receptors that engage in the innate immune response. As a local inflammatory mediator, it mobilizes neutrophilic granulocytes through chemotactic stimuli and supports their degranulation. In addition to stimulating neutrophilic granulocytes, interleukin-8 also recruits basophilic granulocytes and T-lymphocytes. IL-8 also stimulates phagocytosis. In its target cells, IL-8 can increase intracellular Ca²⁺ and the respiratory burst, which means the release of reactive oxygen species by macrophages and neutrophilic granulocytes during phagocytosis [6, 7, 11, 12, 13, 15].

IL-10 is mainly secreted by monocytes and T-lymphocytes. It plays a significant role in modulating inflammatory processes by preventing an excessive immune response. It is one of the most important anti-inflammatory cytokines and is important for the development of immune tolerance. It directs the T-lymphocyte response more from T-helper cell Th1 to Th2. The anti-inflammatory effects include the inhibition of activated macrophages, which produce IL-10 themselves as a negative feedback regulation. Furthermore, they include the inhibition of the production of pro-inflammatory factors, such as IFN-γ, TNF-α, and other cytokines. The ability of monocytes to present antigens is suppressed. They are stimulated more by phagocytosis. However, dendritic cells that have already differentiated are not inhibited by IL-10 because they no longer have an IL-10 receptor [5, 6, 7, 9, 12, 13].

IL-12 is produced by activated macrophages, dendritic cells, and airway epithelial cells. It plays a vital role in differentiating and activating Th1 cells, particularly in the production of IFN-γ. By influencing the cell’s own defense mechanisms in this way, IL-12 also influences the intensity and duration of intracellular infections [6, 7, 9, 11].

IL-13 is produced among others by Th2 helper cells and stimulates the differentiation of B-lymphocytes. It is involved as a messenger in processes of the immune system, especially in triggering allergic reactions. IL-13 is a relevant mediator for triggering asthma attacks. IL-13 induces matrix metalloproteinases in the airways. These enzymes are required to induce the aggression of inflammatory cells into the airways. IL-13 can also induce collagen expression by fibroblasts [3, 6, 7, 12, 13].

IL-17 family contains six isoforms. IL-17A signaling drives several effector functions, including chemokine induction, cell infiltration, antimicrobial peptide production, tissue barrier function, and remodeling. The levels of IL-17A, the predominant cytokine of Th17 cells, are increased in the sputum of COPD patients. Furthermore, increased Th17 cells can be detected in bronchial biopsies of COPD patients. IL-17B is a pro-inflammatory mediator that accelerates neutrophil recruitment and migration, and it attenuates mucosal inflammation. IL-17C is known to be important for host defense against pathogens such as pseudomonas aeruginosa. IL-17D triggers the secretion of several inflammatory cytokines, such as IL-6 and IL-8. IL-17E-mediated responses depend on the airway epithelium, mast cells, eosinophils, and Th2 cells, thereby contributing to the immunopathogenesis of asthma. IL-17F plays a critical role in inflammatory responses and mucosal barrier maintenance, and it plays a central role in allergic airway diseases [6, 7, 9, 10, 12, 13].

IL-18 is produced by a variety of cells, including macrophages and dendritic cells. Together with interleukin-12, it induces (in cooperation with IL-12) the cell-mediated immune defense after a confrontation with microbial lipopolysaccharides. When stimulated with IL-18, natural killer cells and certain T cells secrete IFN-γ and type II interferon, which play an important role in stimulating macrophages [6, 7, 9, 10, 12].

IL-23 is an inflammatory cytokine, which plays a key role in regulating Th17 cells, and there is an increased expression in the bronchial mucosa of patients with COPD [6, 7, 10, 11].

IL-32 is secreted by T-lymphocytes, natural killer cells, and monocytes. L-32 acts as a regulator of innate and adaptive immune responses and has been confirmed to participate in the inflammatory process of COPD as a proinflammatory factor. While IL-32 induces next to other cytokines TNF-α, its depletion reduces IFN-γ production, suggesting a regulatory feedback mechanism. IL-32 is highly expressed in the lung tissue of patients with COPD, and alveolar wall and bronchial epithelial cells are the main expression sites. There is a strong positive correlation between serum IL-32 concentration and GOLD (global initiative for obstructive lung disease) score, which suggested that IL-32 might be a molecular biomarker that reflects the severity of COPD [6, 7, 9].

IL-33 is a cytokine belonging to the IL-1 superfamily that also includes IL-1α, IL-1β, and IL-18. IL-33 induces T-lymphocytes and other leukocytes, such as mast cells, eosinophilic, and basophilic granulocytes, to produce type 2 cytokines. IL-33 has been associated with inflammatory diseases, such as bronchial asthma and allergy. It could also be of importance in COPD. Previous studies have shown that the IL-33 level in the blood is increased during acute exacerbations of COPD [6, 7, 10, 16, 17].

INF-γ is formed by T-lymphocytes after contact with antigen-presenting macrophages and is characterized by its immune-stimulating, especially antiviral and antitumor effects. An important task of INF-γ is the activation of macrophages and thus the stimulation and support of the cellular defense. It promotes the production of bactericidal substances, such as nitric oxide and reactive oxygen species, by the macrophages and optimizes the process of fusion of phagosomes with lysosomes inside the macrophage. One importance of IFN-γ in the immune system is its ability to inhibit viral replication directly. Aberrant IFN-γ expression is associated with some autoinflammatory and autoimmune diseases [6, 7, 9, 11, 12].

TGF-ß (transforming growth factor-ß) induces the proliferation of fibroblasts and airway smooth muscle cells. It is generated from a latent precursor through oxidative stress and various proteases. TGF-ß regulates the proliferation, differentiation, apoptosis, and adhesion of cells. The expression is increased by airway epithelial cells and macrophages from small airways of patients with COPD [6, 7, 9].

TNF-α is produced mainly by macrophages, which are stimulated to phagocytosis. In the liver, the formation of acute phase proteins, such as CRP, is stimulated. TNF-α promotes a local inflammatory response in foreign stimuli or bacterial infections. Furthermore, TNF-α polymorphism may play an important role in COPD susceptibility. TNF-α stimulates and activates the transcription factor NF-κB (nuclear factor “kappa-light-chain-enhancer” of activated B-cells), which occurs in every human cell, but mainly in B-lymphocytes. NF-κB is of immense importance in the regulation of the immune response, cell proliferation, and apoptosis. NF-κB act as a principal component for several common respiratory illnesses, such as COPD [5, 6, 7, 9, 10, 11, 12, 13, 15, 18].

TSLP (thymic stromal lymphopoietin) is a cytokine belonging to the IL-7 family. It is increased in the airway epithelium of patients with COPD. Under certain pathological conditions, increased formation of TSLP can occur. TSLP can be released as a danger signal to allergens or microorganisms. The result is increased activation of dendritic cells, which causes Th2 cells to mature. Furthermore, TSLP causes activation of macrophages, which produce chemokines that attract neutrophilic and eosinophilic granulocytes and mast cells [6, 7, 9, 10, 16].

GM-CSF (granulocyte-macrophage colony-stimulating factor) is part of the immune response to antigens and mitogens. It owes its name to its ability to stimulate the differentiation of hematopoietic stem cells in the bone marrow into macrophages and granulocytes. It is released by alveolar macrophages of patients with COPD and is involved in the differentiation and survival of macrophages and neutrophilic granulocytes [6, 7, 9, 11, 12].

3. Forms of inflammation or damage

Neutrophilic inflammation can be induced by cigarette smoke, fine dust, bacteria, and viruses, resulting in the release of neutrophilic mediators, including IL-8, which signal through its receptor on neutrophils. Macrophages are activated as well, and attract Th17 cells to release IL-17, which stimulates the release of IL-6 and IL-8 from epithelial cells. Neutrophils are maintained in the airway by TNF-α and GM-CSF (granulocyte-macrophage colony-stimulating factor) and release neutrophil elastase. Neutrophils also generate oxidative stress, which further activates inflammation and induces corticosteroid resistance. The neutrophilic inflammation in COPD is unresponsive to corticosteroids, even in high doses. Other therapies directed toward neutrophilic inflammation, including antibodies against TNF-α, have been largely clinically ineffective as well. A CXCR2 (chemokine receptor-2) antagonist, which blocks the chemotactic effect of IL-8 and related chemokines, is at least able to reduce the neutrophils in the sputum of COPD patients but has no clinical benefit on lung function, symptoms, or exacerbations. Neutrophil elastase is a major proteinase in primary granules in neutrophils that participates in the microbicidal activity. It induces airway remodeling with increased mucin secretion and impaired ciliary motility, it interrupts epithelial repair by promoting cellular apoptosis, and it activates inflammation by increasing cytokine expression [1, 4, 5, 6, 7, 8, 14].

Eosinophilic inflammation is well-known in patients with bronchial asthma. Some people have clinical features from both diseases, bronchial asthma and COPD. In case of such overlap, airway epithelial cells can release the upstream cytokines TSLP and IL-33 in response to cigarette smoke and virus infection, which recruit Th2 and type 2 innate lymphoid cells, which secrete IL-5, resulting in eosinophilic inflammation. Eosinophils may be attracted into the lungs by CCL5 (chemokine (C-C motif) ligand) and maintained in the lungs by IL-5 and GM-CSF. Patients with so-called eosinophilic COPD may have a better response to corticosteroid therapy and more reversibility to bronchodilators, and these patients show an increase in sputum eosinophils and an increased FeNO, which are characteristic features of asthma [1, 5, 6, 7, 14].

Protease-antiprotease imbalance means that inhaled pollutants, such as cigarette smoke and fine dust, activate immune cells like macrophages and T-helper cells, which release inflammatory messengers. These signals cause neutrophilic granulocytes to migrate into the bronchial mucosa. Together with the macrophages, they release cell-damaging proteases. And at the same time, protective antiprotease is disabled. According to current knowledge, this imbalance of proteases and antiproteases favors the formation of pulmonary emphysema. Various proteases produced by inflammatory cells and epithelial cells are elevated in many people with COPD [3, 19].

Oxidant-antioxidant imbalance leads to inflammatory reactions due to oxidative stress. As a result, pulmonary cells are damaged, and inflammation is further promoted. This accelerates the development of COPD or emphysema. Oxidative stress also increases mucus production, the formation of proteases, and the migration of neutrophilic granulocytes into the bronchial mucosa. An oxidant-antioxidant imbalance also occurs in other lung diseases, such as pulmonary fibrosis or bronchial asthma [3, 5, 15, 19].

Apoptosis is critical for the maintenance of normal tissue homeostasis and is in equilibrium with proliferation and differentiation. There is increasing evidence that disturbance of the balance between apoptosis and proliferation in lung tissue contributes to the pathogenesis of COPD. Several experimental studies in animal models of COPD provide more insight into the association between cigarette smoking, apoptosis, and the development of emphysema. Epithelial cells in the small airways express TGF-β, which then induces local fibrosis. VEGF (vascular endothelial growth factor) appears to be necessary to maintain alveolar cell integrity, and blockade of VEGF receptors in rats induces apoptosis of alveolar cells and an emphysema-like pathology [19].

4. Infections and inflammation

Epidemiological studies point to a connection between respiratory infections in the past and the incidence of COPD. For example, viral pneumonia in childhood increases the risk for the later development of COPD. With an already existing COPD, acute respiratory infections can trigger an exacerbation. In most cases, bacterial infections cause a trigger. Streptococcus pneumoniae, haemophilus influenzae, moraxella catarrhalis, and pseudomonas aeruginosa have been identified to act as triggers, also tuberculosis can cause an exacerbation of COPD. Furthermore, fungi are potential triggers as well. Viruses have not been found to be common triggers; exceptions are rhinoviruses and SARS-CoV-2 [7].

Patients with underlying COPD are vulnerable to COVID-19, and in fact, COPD is one of the high-risk factors for severe illness associated with COVID-19. This may be related to poor underlying lung reserves and increased expression of ACE-2 (angiotensin-converting enzyme-2) receptor in small airways. One research group established an airway epithelium model to study SARS-CoV-2 infection in healthy and COPD lung cells. They found that both the entry receptor ACE2 and the cofactor transmembrane protease TMPRSS2 are expressed at higher levels on non-ciliated goblet cell, a novel target for SARS-CoV-2 infection. They observed that SARS-CoV-2 induced due to an infection of goblet cells syncytium formation and cell sloughing.They also found that SARS-CoV-2 replication is increased in the COPD airway epithelium, likely due to COPD-associated goblet cell hyperplasia [20, 21, 22].

5. Use of biologics in refractory therapy of COPD

Drug therapy of COPD includes various pharmaceuticals, some of which are inhaled and some orally used, in various combinations. These include muscarinic antagonists, ß2-sympathomimetics, corticosteroids, mucolytics, antitussives, beta-blocker, N-acetyl-L-cysteine, antibiotics, oxygen, and vaccinations against pneumococcus infection, pertussis, influenza, and COVID-19. The administration of the phosphodiesterase-4 inhibitor roflumilast is possible as add-on therapy in patients with COPD who repeatedly exacerbate despite therapy, who are assigned to the chronic bronchitis phenotype, and who have an FEV1 (forced expiratory pressure in 1 s) <50% [2, 3, 15].

Furthermore, there are several biologics which could be used in the case of refractory therapy of COPD, especially if there is a combination with bronchial asthma. The following shows a representative selection of biologics, which are mostly used in the treatment of other inflammatory diseases, but which can be considered in individual cases of COPD in particularly severe courses that are resistant to conventional treatment options:

• Benralizumab (Fasenra®) is a humanized monoclonal antibody that binds with high affinity and specificity to the IL-5 receptor. This receptor is localized on the surface of eosinophilic granulocytes. Apoptosis of the granulocytes occurs and leads to a reduction in the inflammatory reaction. Benralizumab is a potential add-on therapy in adult patients with severe eosinophilic COPD as well as bronchial asthma. Application of benralizumab is subcutaneous injection [1, 6, 15, 16].

• Brodalumab (Kyntheum®) is a recombinant human monoclonal antibody. It binds selectively to subunit A of the IL-17 receptor. This blocks the activity of IL-17A and IL-17F and inhibits the inflammatory process. It is used to treat psoriasis. Brodalumab is given as a subcutaneous injection [6, 23].

• Canakinumab (Ilaris®) is a human monoclonal antibody that inhibits the activity of IL-1β, thereby inhibiting the inflammatory processes. Canakinumab is indicated for the treatment of periodic fever syndromes, familial Mediterranean fever, systemic juvenile idiopathic arthritis, and gouty arthritis. Canakinumab is administered subcutaneously [1, 6].

• Dupilumab (Dupixent®) is a humanized monoclonal antibody that binds to the alpha subunit of the IL-4 receptor, blocking IL-4 and IL-13 signaling. The antibody had shown good efficacy in patients with bronchial asthma and elevated eosinophils. Furthermore, in severe atopic dermatitis and rhinosinusitis dupilumab may help as well. In therapy-refractory COPD, the use of dupilumab can be considered. Application is by subcutaneous injection [6, 16, 23].

• Etanercept (Enbrel®) is a selective immunosuppressive and anti-inflammatory drug from the group of TNF-α inhibitors. It is a dimeric fusion protein composed of the extracellular ligand-binding domain of TNF receptor-2 and the Fc (fragment crystallizable) domain of human IgG1 (immunoglobulin G1). It binds to TNF-α and blocks its effects. Etanercept is used in the therapy of psoriasis and rheumatic diseases. The solution for injection is administered subcutaneously [1, 6, 15].

• Infliximab (Remicade®) is a chimeric monoclonal antibody against TNF-α and blocks its inflammatory effects. Infliximab is used as an immunosuppressant. Main indications for therapy are Crohn’s disease and rheumatoid arthritis. In the case of severe and therapy-resistant COPD, the administration of infliximab may be an option. The medicine is given as an intravenous infusion [1, 6, 15].

• Mepolizumab (Nucala®) is a humanized monoclonal antibody against IL-5 and inhibits the binding of IL-5 to its receptor on the cell surface of eosinophils. Some authors regard therapy with mepolizumab as a therapeutic advance for a subgroup of patients with severe eosinophilic COPD or bronchial asthma. Mepolizumab is given as a solution for subcutaneous injection [1, 6, 15, 16].

• Omalizumab (Xolair®) is a humanized monoclonal antibody against IgE and thereby suppresses an allergic reaction. It is used therapeutically in the fourth step of asthma step therapy for severe allergic bronchial asthma, and in chronic spontaneous urticaria, if the conventional therapy does not improve the disease properly. In the case of COPD and allergic bronchial asthma overlap, omalizumab may be helpful. It is injected subcutaneously [6, 16, 23].

• Reslizumab (Cinqaero ®) is a humanized monoclonal antibody against IL-5 and reduces the number of eosinophils, which leads to lower inflammatory activity. Reslizumab is available as a concentrate solution for intravenous infusion [6, 16].

• Secukinumab (Cosentyx ®) is a recombinant human monoclonal antibody that acts by selectively binding to IL-17A and blocks its interaction with the IL-17 receptor, preventing the release of proinflammatory cytokines. It is mainly used in psoriasis. Secukinumab is administered subcutaneously [6, 23].

• Tezepelumab (Tezspirie ®) is a monoclonal antibody from the group of TSLP inhibitors. The effects are based on binding to TSLP, which inhibits interaction with its receptor. Tezepelumab is approved for adjunctive maintenance therapy for the relief of severe, uncontrolled bronchial asthma. The solution for injection is given subcutaneously [6, 23].

Other biologics are currently in clinical trials and will be launched in near future. An example is itepekimab, which is under investigation in a phase 3 study. In a current study, the researchers first carried out genetic investigations to determine whether genetic variants within the IL-33 signaling pathways are associated with the risk of COPD. They found that genetic variants that resulted in loss of IL-33 function reduced the risk of COPD. Variants that caused IL-33 to be more active increased the risk of COPD. In addition, they examined the safety and effectiveness of the IL-33-antibody itepekimab in moderate to severe COPD. Itepekimab targets IL-33, thereby inhibiting the activity of the protein. 343 patients between the ages of 40 and 75 were included in the study. All were current or former smokers with a COPD diagnosis of at least 1 year. They were randomly assigned either to the itepekimab or placebo group. In addition to standard therapy, people in the itepekimab group received the antibody as injections every 2 weeks. The other group received a drug-free placebo instead of the antibody. The effect of itepekimab on the annual rate of acute COPD exacerbations and lung function was analyzed. When both groups were compared, there were initially no significant differences. However, a subgroup analysis found that itepekimab significantly reduced exacerbation rates and improved lung function in ex-smokers with COPD. The positive effects also persisted during the 20-week follow-up period after treatment. The side effects were about the same in both groups. According to the researchers, the study does not show any advantage of itepekimab for current smokers with COPD. However, for ex-smokers with COPD, this biological therapy could be an option to improve the rate of disease worsening and lung function. Future studies should therefore focus even more on this subgroup of patients. Two-phase three clinical trials are already underway to confirm and better understand the potential of the novel therapy in ex-smokers with COPD [3, 6, 23, 24].