Chronic obstructive pulmonary disease

of stages of COPD The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as a lung condition with multiple underlying causes, characterized by long-lasting respiratory symptoms (shortness of breath, cough, and mucus) which can flare up intermittently. Symptoms are due to impairments of the airways (bronchitis, bronchiolitis) or small air sacs of the lungs (emphysema) that cause persistent, often progressive, airflow obstruction. Shortness of breath A cardinal symptom of COPD is chronic and progressive shortness of breath. Breathlessness is often the most distressing symptom, causing anxiety and the level of disability that is experienced. Symptoms of wheezing and chest tightness associated with breathlessness can vary over the course of a day or between days and are not always present. Chest tightness often follows exertion. People experiencing distress may naturally adopt a sitting posture, leaning forward with their hands on their knees, known as the tripod position. This can help to decrease breathlessness by stabilizing and lifting the shoulder girdle. People with more advanced COPD may also breathe through pursed lips, which can improve shortness of breath. Shortness of breath often results in reduced physical activity, and low levels of physical activity are associated with worse outcomes. People with COPD often have increased breathlessness and frequent colds before seeking treatment. In severe and very severe cases there may be constant tiredness, weight loss, muscle loss and anorexia. Cough The first symptom of COPD to appear is usually a chronic cough, which may or may not bring up thick slippery fluid (referred to as sputum, mucus or phlegm). Coughing up of mucus can be intermittent and may be difficult to evaluate. A productive cough that brings up mucus is seen in less than 30% of cases. Sometimes, limited airflow may develop in the absence of a cough. Symptoms are usually worse in the morning. Depending on social or cultural factors, mucus may be swallowed or spat out. A chronic productive cough may result from the release of too much mucus within airways. When it persists for more than three months each year for at least two years, it is called chronic bronchitis. Chronic bronchitis can occur before the restricted airflow diagnostic of COPD. People tend to under-report symptoms, and may assume that symptoms result from short-term irritation rather than underlying changes in lung function. In severe COPD, vigorous coughing may lead to rib fractures or to a brief loss of consciousness. Exacerbations An acute exacerbation is a sudden flare-up or worsening of signs and symptoms that lasts from several days to two weeks. Worsening of symptoms can involve increased breathlessness, increase in mucus volume, change in mucus character, or change in cough or wheeze. Bacterial respiratory infections are the second most frequent triggers, including Haemophilus influenzae, Environmental insults that can trigger acute flare-ups include exposure to smoking, use of solid fuels, and other sources of indoor or outdoor air pollution. Smoke from wildfires is an increasing risk in many parts of the world due to climate change. Government agencies have published protective advice on their websites. In the US the EPA recommends the use of well-fitting particulate masks, which give more effective protection than dust masks when dealing with the fine particles from wildfires. This same advice is offered in Canada and Australia regarding forest fires. The risk of developing a COPD flare-up is higher in women; in people with one or more flare-ups in the last year; in those with more severe COPD as measured by lung function tests; and in those with chronic bronchitis or related conditions such as gastroesophageal reflux, pulmonary hypertension People with two or more flare-ups a year are associated with worse disease progression and are classed as frequent exacerbators. More flare-ups are associated with more rapid decline in lung function, lower quality of life, and higher morbidity and mortality. == Other conditions ==

COPD often occurs along with multiple other conditions (comorbidities) affecting the body's systems. This reflects both shared risk factors and the role of inflammation as a mechanism by which illness develops. and skeletal muscle dysfunction). Metabolic syndrome has been seen to affect up to 50% percent of those with COPD and significantly affects the outcomes. When metabolic syndrome occurs with COPD, there is more systemic inflammation. Of the people with COPD listed for lung transplantation, 82% were documented as having pulmonary hypertension. Tuberculosis is a risk factor for the development of COPD, and is also a potential comorbidity. Differentiating COVID-19 symptoms from an exacerbation is difficult; where symptoms include loss of taste or smell, COVID-19 is to be suspected. People with COPD have more additional health issues than those without COPD. People with COPD are more likely to die of respiratory or heart-related causes than those without COPD, and to die at younger ages. == Categorization ==

Categorizing COPD in terms of subtypes can support more targeted treatment approaches for patients. A phenotype refers to a collection of observable characteristics including symptoms, frequency of episodes, and other details of patient history that are used in clinical practice. An endotype links such observable traits to underlying mechanisms. One phenotype may be related to multiple endotypes. Chronic bronchitis is defined as a productive cough that is present for at least three months each year for two years. It does not always result in airflow limitation, although the risk of developing COPD is great. Early categorizations grouped patients on the basis of physical symptoms as type A and type B. Type A (emphysema types) were known as pink puffers due to their pink complexion, fast breathing rate and pursed lips. Type B (chronic bronchitic types) were referred to as blue bloaters due to low oxygen levels causing a bluish color to the skin and lips and swollen ankles. Recently, it has been suggested that these early phenotypes may reflect unique underlying mechanisms: an "emphysematous phenotype" that involves destruction of air sacs (alveoli) and a "chronic bronchitis phenotype" associated with airway inflammation. Most people with COPD have a combination of symptoms reflecting both emphysema and airway disease. A common phenotype is the frequent exacerbator, someone who has had two or more flare-ups within a year. Frequent exacerbators have a poor prognosis, so identifying them and preventing further flare-ups is a major concern. A molecular phenotype of CFTR dysfunction is shared with cystic fibrosis. A combined phenotype of chronic bronchitis and bronchiectasis has been described, with a difficulty noted in determining the best treatment. The identification and recognition of different phenotypes can guide appropriate treatment approaches. Two well-defined COPD endotypes are related to inflammation mechanisms of white blood cells in the immune system. The types of white blood cells involved are neutrophils and eosinophils. Etiotypes In 2023, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recognized the variety of causes contributing to COPD by introducing a new classification system categorizing COPD in terms of underlying causes and risk factors, or etiotypes. The 2023 GOLD report identifies seven distinct etiotypes: • cigarette smoking COPD (COPD-C) • biomass and pollution exposure COPD (COPD-P) • genetically determined COPD (COPD-G) • COPD due to abnormal lung development (COPD-D) • COPD with asthma (COPD-A) • COPD due to infections (COPD-I) • COPD of unknown cause (COPD-U) This framework better reflects variation in COPD causes and disease progression in global populations. In low-and middle-income countries, COPD related to the burning of organic materials as fuels (COPD-P) and to repeated childhood respiratory infections (COPD-I) are more common. Identification of causes has implications for disease management. Some etiotypes can be related to specific clinical phenotypes. For example, biomass and pollution-associated COPD (COPD-P) tends to involve greater tissue damage to small airways and obstruction of airflow, while tobacco-related disease (COPD-C) involves more damage to air sacs and reduces oxygen transfer to the bloodstream. Identification of such differences emphasizes the need to address underlying issues. Health programs to improve early-life lung development can be part of COPD prevention and management. Providing clean energy cooking fuels can reduce biomass exposure. Vaccination can help to prevent respiratory infections such as influenza, pneumococcus, and RSV, and reduce dangerous COPD flare-ups. ==Causes==

COPD tends to develop as a result of exposure to harmful particles or gases, including tobacco smoke, that irritate the lung. This causes significant or long-term inflammation that interacts with individual host factors. The greatest risk factor for the development of COPD is tobacco smoke, accounting for up to 70% of cases in first-world countries. These include exposure to indoor and outdoor pollutants, particulate matter, allergens, occupational exposure, and host factors. and construction. The three main types of construction dust are silica dust, non-silica dust (e.g., dust from gypsum, cement, limestone, marble and dolomite) and wood dust. Host factors include genetic susceptibility. Alpha-1 antitrypsin deficiency (A1AD) is an important genetic risk factor for COPD. It is advised that everybody with COPD be screened for A1AD. Other host factors are associated with poverty, physical inactivity and ageing. The role of changes in lung function throughout life is increasingly being recognized in COPD. Early-life factors can contribute to abnormal lung development and increase the risk of COPD in later life. Many early-life risk factors could be prevented, such as poor nutrition, low physical activity, early alcohol consumption, and exposure to smoking and biomass fumes. In Europe, airway hyperresponsiveness is rated as the second most important risk factor after smoking. It can contribute to asthma, which is recognized as an additional risk factor. Alcohol abuse can lead to alcoholic lung disease and is seen to be an independent risk factor for COPD. Mucociliary clearance is disrupted by chronic exposure to alcohol; macrophage activity is diminished and an inflammatory response promoted. The damage leads to a susceptibility for infection, including COVID-19, which is increased when combined with smoking. Smoking induces the upregulation of the expression of ACE2, a receptor for the SARS-CoV-2 virus. Tobacco Smokers and ex-smokers have a higher rate of developing COPD. About 20% of those who smoke will develop COPD, and about 50% of heavy smokers will get COPD. Several studies indicate that women are more susceptible than men to the harmful effects of tobacco smoke. Given the same amount of cigarette smoking, women have a higher risk of COPD than men. Women who smoke during pregnancy, and during the early life of their child, also increase risk of their child's later development of COPD. Epigenetic studies support this link, showing that ACSF3 is differentially methylated in smoke-exposed fetal lungs, and an integrative study identified it as a key regulator of COPD. Inhaled smoke triggers the excessive release of proteases. This degrades elastin, the major component of the walls of alveoli, the small air sacs in the lungs. Damage to the cell walls interferes with their ability to transfer oxygen from the lungs to the bloodstream. Marijuana Marijuana is the second most commonly smoked substance. Tobacco smoke has a bronchoconstrictive effect that tightens smooth muscle in the lungs, contributing to coughing, wheezing, and tightness in the chest. In contrast, marijuana use has a bronchodilatory effect that can temporarily counteract airflow obstruction. At lower levels (a few joints per month) cannabis smoking may not cause the type of structural damage in small airways that occurs in tobacco smoking, and leads to airflow limitation and severe shortness of breath. spontaneous pneumothorax, and lung cancer. Pollution and clean cooking facilities as of 2023 Air pollution is a major cause of COPD, contributing an estimated 50% of the total attributable risk of COPD worldwide. The harmfulness of particulate matter depends on the size, structure and composition of the particles involved. Particulate matter can carry toxic metals and organic matter and transport them through the lower and upper respiratory tracts deep into the lungs. Exposure to particulates can contribute to the development of COPD and trigger flare-ups either directly through irritation or indirectly due to infections. Major sources of ambient air pollution include suspended dusts, combustion of fossil fuels and biofuels, industrial emissions, and wildfire smoke. Combustion releases fine and ultrafine particulates, greenhouse gases and other pollutants. Photochemical reactions between sunlight, nitrogen oxides (NOx) and volatile organic compounds (VOCs) produce ozone, Smoking is a major contributor to indoor air pollution, as is the burning of wood and other biomass fuels for heating and cooking. Building materials and furnishings can be sources of formaldehyde, asbestos, and lead dust. Chemicals in cleaning products, paints, varnishes, pesticides, fragrances, air fresheners, and office equipment can release VOCs and aerosols. Microorganisms include mold, fungi, bacteria, and dust mites. cleaning solutions and pesticides. Radon gas occurs naturally and can enter buildings through cracks in foundations and walls. Pollutants from outdoor air can also enter buildings. Areas with poor outdoor air quality, including that from exhaust gas, generally have higher rates of COPD. 97% of the major cities in the world fail to meet the World Health Organization (WHO)'s safety standards for particulate matter in ambient air. Measures to prevent and control air pollution and reduce emissions have been taken by some governments, and have significantly reduced both pollution and COPD incidence. When pollution levels outdoors are high, people can reduce risk by wearing personal protective equipment such as an N95 mask, and by reducing the time and intensity of outdoor activities. Quitting smoking, using clean fuels for heating and cooking, and improving ventilation are important steps for improving indoor air quality and reducing COPD risk. Poorly ventilated open fires and simple stoves used for cooking and heating often use biomass fuels, kerosene, or coal, generating very high levels of indoor air pollution. Globally, 50% of all households and 90% of rural households are estimated to use such fuels. Exposure to indoor biomass smoke has been associated with acute lower respiratory infections in children younger than five, and with COPD in men and women age 30 or more. The overall risk of COPD for indoor biomass exposure was estimated at 3.2 for women and 1.8 for men. and never-smokers. and irritant gases used in industrial production and in cleaning (e.g. nitrous fumes, sulphur dioxide and chlorine). The negative effects of occupational exposure and smoking are interrelated and the two factors may be additive or synergisticly reinforce each other. This risk is particularly high if someone deficient in alpha-1 antitrypsin (AAT) also smokes. It is responsible for about 1–5% of cases and the condition is present in about three to four in 10,000 people. Mutations in MMP1 gene that encodes for interstitial collagenase are associated with COPD. The COPDGene study is an ongoing longitudinal study into the epidemiology of COPD, identifying phenotypes and looking for their likely association with susceptible genes. Genome-wide analyses in concert with the International COPD Genetics Consortium has identified more than 80 genome regions associated with COPD. Whole genome sequencing is an ongoing collaboration (2019) with the National Heart, Lung and Blood Institute (NHLBI) to identify rare genetic determinants. Abnormal lung development The role of lung function throughout life is increasingly being recognized. Mechanisms such as abnormal lung development and accelerated lung function decline, beginning early in life, can lead to COPD in late adulthood. Some early-life factors that contribute to poor lung development may be preventable, such as poor nutrition, low physical activity, early alcohol consumption, and exposure to smoking. In Europe, airway hyperresponsiveness (AHR) is rated as the second most important risk factor after smoking. In AHR, smooth muscle in airways becomes more sensitive. It is more likely to tighten in response to stimuli in the environment (direct AHR), or chemical messengers released by mast cells (indirect AHR). This drives eosinophilic and type 2 helper T lymphocyte-driven airway inflammation. It may lead to airway structural changes known as remodeling and airflow obstruction. In those with asthma, AHR can contribute to breathlessness, wheeze, and chest tightness. AHR may be a treatable trait. Asthma A history of asthma in childhood is associated with decreases in adult lung function and higher susceptibility to COPD. Asthma is a recognized risk factor: the comorbidity of COPD is reported to be 12 times higher in patients with asthma after adjusting for smoking history. Asthma commonly starts in childhood, with variable symptoms of breathlessness, chest tightness, cough and wheeze. Appearance of symptoms may relate to times of day and to identifiable triggers such as dust, pollen, and grass. In contrast, COPD has a later onset and is progressive; airflow limitation in COPD is poorly reversible; and respiratory symptoms in COPD are persistent. Infections A history of respiratory infections in childhood is associated with decreases in adult lung function and higher susceptibility to COPD. Both tuberculosis and pneumonia in childhood are risk factors for COPD, with adult COPD patients experiencing worse symptoms and poorer lung function as measured by spirometry. COPD and non-COPD patients tend to experience different types of infections. COPD patients are more likely to report infections from gram-negative bacteria (Pseudomonas aeruginosa, Haemophilus influenzae) and fungal pathogens. ==Pathophysiology==

s shown in upper diagram. Lungs damaged by COPD in the lower diagram with an inset showing a cross-section of bronchioles blocked by mucus and damaged alveoli. COPD is a progressive lung disease characterized by narrowed airways, which prevent air from moving freely; excess mucus, which clogs air passages; and breakdown of lung tissue in small air sacs, which then fail to transfer oxygen into the bloodstream efficiently. Poor airflow due to lung damage (airflow limitation) tends to be chronic and incompletely reversible. Small airway disease (SAD) is the main driver of airflow limitation, through mechanisms of narrowing, chronic inflammation, and airway remodeling, while emphysema destroys air sacs and limits the transfer of oxygen. Those with COPD may have difficulty in breathing out fully (air trapping). If air cannot fully escape the lungs, the lungs may expand past their normal size (hyperinflation), increasing breathing difficulty. The relative contributions of small airway disease and emphysema vary from person to person. There are sex differences in the anatomy of the respiratory system between men and women. Women tend to have smaller airway lumens and thicker airway walls, which may contribute to increased severity of COPD symptoms and frequency of COPD flare-ups for women. Small airway disease (sometimes called chronic bronchiolitis) appears to be the precursor for the development of emphysema. Clearance of mucus from the airways is also altered with a dysregulation of cilia and mucus production. The inflammatory cells involved can include neutrophils, eosinophils, and macrophages, types of white blood cells. Those who smoke additionally have cytotoxic T cell involvement. Part of this cell response is brought on by inflammatory mediators such as chemotactic factors. Other processes involved with lung damage include oxidative stress produced by high concentrations of free radicals in tobacco smoke and released by inflammatory cells and breakdown of the connective tissue of the lungs by proteases (particularly elastase) that are insufficiently inhibited by protease inhibitors. The destruction of the connective tissue of the lungs leads to emphysema, which then contributes to the poor airflow and finally, poor absorption and release of respiratory gases. General muscle wasting that often occurs in COPD may be partly due to inflammatory mediators released by the lungs into the blood. showing emphysema (left – large empty spaces) and lung tissue with relative preserved alveoli (right) Narrowing of the airways occurs due to inflammation and subsequent scarring within them. This contributes to the inability to breathe out fully. The greatest reduction in air flow occurs when breathing out, as the pressure in the chest is compressing the airways at this time. This can result in more air from the previous breath remaining within the lungs when the next breath is started, resulting in an increase in the total volume of air in the lungs at any given time, a process called air trapping which is closely followed by hyperinflation. Hyperinflation from exercise is linked to shortness of breath in COPD, as breathing in is less comfortable when the lungs are already partly filled. Hyperinflation may also worsen during an exacerbation. There may also be airway hyperresponsiveness to irritants similar to those found in asthma. Low oxygen levels and eventually, high carbon dioxide levels in the blood, can occur from poor gas exchange due to decreased ventilation from airway obstruction, hyperinflation and a reduced desire to breathe. During exacerbations, airway inflammation is also increased, resulting in increased hyperinflation, reduced expiratory airflow and worsening of gas transfer. This can lead to low blood oxygen levels, which, if present for a prolonged period, can result in narrowing of the arteries in the lungs, while emphysema leads to the breakdown of capillaries in the lungs. Both of these conditions may result in pulmonary heart disease also classically known as cor pulmonale. == Diagnosis ==

. Smaller handheld devices are available for office use. The diagnosis of COPD should be considered in anyone over the age of 35 to 40 with shortness of breath, a chronic cough, coughing up of mucus, or frequent winter colds and a history of exposure to risk factors for the disease. Spirometry is then used to confirm the diagnosis. GOLD initially classified COPD in terms of a 4-level staging system based on severity of functional impairment. The 2023 GOLD report introduced a new definition of COPD, a new taxonomic classification of COPD based on contributory causes or etiotypes, and revised recommendations for diagnosis and assessment. Two main components are measured to make the diagnosis, the forced expiratory volume in one second (FEV1), which is the greatest volume of air that can be breathed out in the first second of a breath and the forced vital capacity (FVC), which is the greatest volume of air that can be breathed out in a single large breath. Normally, 75–80% of the FVC comes out in the first second However, NICE was updated in 2019. NICE and GOLD are now in agreement in requiring only the presence of clinical symptoms confirmed by airflow obstruction with a reduced FEV1/FVC ratio less than 0.7. GOLD recommends further testing if symptoms seem out of proportion to degree of obstruction. Pulmonary function tests (PFTs) such as diffusing capacity of the lung for carbon monoxide, airway resistance, and respiratory oscillometry may help to better assess lung function by detecting static lung hyperinflation, airway obstruction, and small airway dysfunction. In those without symptoms, screening using spirometry is generally not recommended. However, active case finding and use of primary care data to identify those with risk factors, followed by spirometry, is recommended by GOLD 2024 as likely to lead to earlier diagnosis of COPD. The MRC breathlessness scale or the COPD assessment test (CAT) are simple questionnaires that may be used. Scores on CAT range from 0–40 with the higher the score, the more severe the disease. As of 2023, GOLD updated its guidelines, revising its assessment approach. Once a COPD diagnosis has been confirmed by spirometry, assessment focuses on the degree of airflow limitation, type and degree of other current symptoms, history of exacerbations, and multimorbidities. GOLD's 2023 model recognizes that exacerbations are an important risk factor independent of the level of other symptoms. Patients are classed as A, B, or E. Patients are considered class E if they have a history in the past year of 1 or more exacerbations leading to hospitalization, or 2 or more moderate exacerbations. Patients in Class A or B cannot have more than 1 moderate or severe exacerbation in the past year, not requiring hospital admission. Patients in Class A display a low symptom burden and low exacerbation risk Patients in Class B display a higher symptom burden. Initial pharmacological treatment guidelines are suggested based on presence in these categories. Other tests A chest X-ray is not useful to establish a diagnosis of COPD, but it can be used in either excluding other conditions or including comorbidities such as pulmonary fibrosis and bronchiectasis. Characteristic signs of COPD on X-ray include hyperinflation (shown by a flattened diaphragm and an increased retrosternal air space) and lung hyperlucency. A saber-sheath trachea is a tracheal deformity that is also indicative of COPD. A CT scan is not routinely used except for the exclusion of bronchiectasis. Pulse oximetry measurement of peripheral oxygen saturation is recommended in people with clinical signs of respiratory failure or right heart failure. An analysis of arterial blood is recommended in those with a peripheral oxygen saturation of 92% or less to determine actual blood oxygen level and assess for high levels of carbon dioxide in the blood, which may have therapeutic implications such as need for non-invasive ventilation or oxygen supplementation. ==Prevention==

Many cases of COPD are potentially preventable through decreasing exposure to tobacco smoke and other indoor and outdoor pollutants. It also may be possible to prevent development of COPD in later life by improving conditions that affect lung development in early life, such as frequent respiratory illness, poor nutrition, low physical activity, and early alcohol consumption. In the short term, quitting smoking can reduce respiratory symptoms. In the longer term, quitting can improve lung function, exercise capacity, perceived quality of life, and survival of those with COPD. Even at a late stage of the disease, it can reduce the rate of worsening lung function and delay the onset of disability and death. Attempts over 5 years lead to success in nearly 40% of people. Some smokers can achieve long-term smoking cessation through willpower alone. Smoking, however, is highly addictive, and many smokers need further support. The chance of quitting is improved with social support, engagement in a smoking cessation program and the use of medications such as nicotine replacement therapy, bupropion, or varenicline. Combining smoking-cessation medication with behavioral therapy is more than twice as likely to be effective in helping people with COPD stop smoking, compared with behavioral therapy alone. Occupational health Measures to reduce occupation exposure in at-risk industries include public policy and regulation to support healthy workplaces; identifying risky work settings and exposures; actionable steps to reduce exposure to risk factors and triggers for flare-ups; education of workers, management and medical professionals about risks, diagnosis, and management; promoting smoking cessation; checking workers for early signs of COPD; and using equipment such as respirators for better control of dust and gases. Employers must provide a safe working environment, safeguarding employees through the use of ventilation, personal protection equipment, and regular air quality monitoring. Improving ventilation and using water spraying and dust suppressant techniques can help to reduce respirable dust. Education and training are important in ensuring that methods are properly used. Pollution control Both indoor and outdoor air quality can be improved, which may prevent COPD and slow the worsening of existing disease. This may be achieved through public policy efforts, cultural changes and personal involvement. Some countries have successfully improved outdoor air quality through regulations, resulting in improvements in the lung function of their populations. Individuals are often advised to avoid or reduce exposure to irritants in indoor and outdoor pollution through smoking cessation, engaging in activities at times and places when exposure to pollutants is lower, and using protective gear (e.g. N95 masks, air filtration). It is becoming increasingly possible to monitor individual exposures to air pollution and adapt behavior accordingly. In developing countries, a key effort is to reduce exposure to smoke from cooking and heating fuels through improved ventilation of homes and user of cleaner fuels, stoves and chimneys. Proper stoves may improve indoor air quality by 85%. Using alternative energy sources such as solar cooking and electrical heating is also effective. However, poverty is often a barrier to the adoption of better fuels. Higher-income families may use modern fuels such as natural gas or electricity, which cause less pollution and can lead to better health outcomes. Electricity supply, however, is often insufficient to meet a family's heating needs. If electricity is supplemented with low-quality biofuels, indoor air-pollution levels will increase and negatively affect health outcomes. == Management ==

COPD currently has no cure, but the symptoms are treatable and its progression can be delayed, particularly by stopping smoking. In cases of early and mild COPD, pulmonary rehabilitation may help to improve exercise capacity and quality of life. A major goal of management is to reduce exposure to risk factors including offering non-pharmacological treatments such as help with stopping smoking. Stopping smoking can reduce the rate of lung function decline and also reduce mortality from smoking-related diseases such as lung cancer and cardiovascular disease. Other recommendations include pneumococcal vaccination and yearly influenza vaccination to help reduce the risk of flare-ups; as of 2024 CDC and GOLD also recommend RSV vaccine for individuals above 60 years. When self-management interventions, such as taking corticosteroids and using supplemental oxygen, are combined with action plans, health-related quality of life is improved compared to usual care. In those with COPD who are malnourished, supplementation with vitamin C, vitamin E, zinc and selenium can improve weight, strength of respiratory muscles and health-related quality of life. Significant vitamin D deficiency is common in those with COPD and can cause increased exacerbations. Supplementation when deficient can give a 50% reduction in the number of exacerbations. Several medical treatments are used in the management of stable COPD and exacerbations. These include bronchodilators, corticosteroids and antibiotics. In hospitalized patients and those with a severe exacerbation, antibiotics can improve outcomes. The FDA recommends against the use of fluoroquinolones when other options are available due to higher risks of serious side effects. Non-invasive ventilation may be used to support breathing and also reduce daytime breathlessness. Patients with COPD exacerbations can display acute hypercapnic respiratory failure (acutely raised levels of carbon dioxide). Bilevel positive airway pressure (BPAP) is preferred to continuous positive airway pressure (CPAP) in treating cases of cardiogenic pulmonary edema with hypercapnia. In those with end-stage disease, palliative care is focused on relieving symptoms. Morphine can improve exercise tolerance. Bronchodilators Inhaled short-acting bronchodilators are the primary medications used on an as needed basis; their use regularly is not recommended. The two major types are beta2-adrenergic agonists and anticholinergics; either in long-acting or short-acting forms. Short-acting bronchodilators have an effect for four hours and for maintenance therapy long acting bronchodilators with an effect of over twelve hours are used. In times of more severe symptoms, a short-acting agent may be used in combination. An inhaled corticosteroid used with a long-acting beta-2 agonist is more effective than either one on its own. The 2018 NICE guideline recommends use of dual long-acting bronchodilators with economic modelling suggesting that this approach is preferable to starting one long-acting bronchodilator and adding another later. The GOLD 2022 report recommends pharmacological treatment with a long-acting muscarinic antagonist (LAMA) such as tiotropium or a long-acting beta agonist (LABA) as initial monotherapy for most patients. Dual bronchodilator therapy (LABA+LAMA) is recommended for more severe symptoms. Other guidelines vary in recommending whether to try LABA or LAMA first. Several short-acting β2 agonists are available, including salbutamol (albuterol) and terbutaline. They provide relief of symptoms for four to six hours. A long-acting beta agonist (LABA) such as salmeterol, formoterol and indacaterol is often used as maintenance therapy, with a duration of action of 12 to 24 hours. Indacaterol requires an inhaled dose once a day and is as effective as the other long-acting β2 agonist drugs that require twice-daily dosing for people with stable COPD. Long-term use of LABAs and LAMAs separately or in combination appear safe for COPD, with combination therapy improving lung function and quality of life and reducing COPD symptoms, first moderate/severe exacerbation risk, risk of first clinically important deterioration (CID), and use of rescue medication. In patients with a high risk of pneumonia, LABA+LAMA may be a safer treatment option than all three together (LABA+LAMA+ICS) since adding ICS increases the risk of pneumonia. The two main anticholinergics used in COPD are ipratropium and tiotropium. Ipratropium is a short-acting muscarinic antagonist (SAMA), while tiotropium is long-acting muscarinic antagonist (LAMA). Tiotropium is associated with improved lung function, quality of life, and exercise endurance, and reduced shortness of breath, hyperinflation, exacerbations, rescue medication use, hospitalization rates, and mortality. Tiotropium provides those benefits better than ipratropium. and urinary tract symptoms (in men) . Long-acting antimuscarinic agents (LAMA) have not been found to be associated with increased risk of heart disease. Aclidinium, another long-acting agent, also shows less shortness of breath, increases in lung function and improved quality of life. The LAMA umeclidinium bromide is another anticholinergic alternative. When compared to tiotropium, the LAMAs aclidinium, glycopyrronium, and umeclidinium appear to have a similar level of efficacy, with all four being more effective than placebo. Corticosteroids Inhaled corticosteroids are anti-inflammatories that are recommended by GOLD as a first-line maintenance treatment in COPD cases with repeated flare-ups. Their regular use increases the risk of pneumonia in severe cases. Studies have shown that the risk of pneumonia is associated with all types of corticosteroids: it is related to the disease severity and a dose-response relationship has been noted. Five days of steroids work as well as ten or fourteen days. The use of corticosteroids is associated with a decrease in the number of lymphoid follicles (in the bronchial lymphoid tissue). A triple inhaled therapy of LABA/LAMA/ICS improves lung function, reduces symptoms and exacerbations and is seen to be more effective than mono or dual therapies. NICE guidelines recommend the use of ICSs in people with asthmatic features or features suggesting steroid responsiveness. A major concern is the development of bacterial resistance, which has been shown. Long-term use may also reduce microbial diversity in the respiratory tract. Other side effects include hearing loss, Whether this is a result of antibacterial or immunomodulant properties is not clear. Effects on airway inflammation are uncertain, but reductions in neutrophil cell counts are significant. Erdosteine is recommended by NICE. GOLD also supports the use of some mucolytics that are advised against when inhaled corticosteroids are being used and singles out erdosteine as having good effects regardless of corticosteroid use. Erdosteine also has antioxidant properties, but there is not enough evidence to support the general use of antioxidants. Erdosteine has been shown to significantly reduce the risk of exacerbations, shorten their duration and hospital stays. Cough medicines are not recommended. Beta blockers are not contraindicated for those with COPD and should only be used where there is concomitant cardiovascular disease. Recent studies show that metformin plays a role in reducing systemic inflammation by reducing biomarker levels that are increased during COPD exacerbations. Oxygen therapy Supplemental oxygen is recommended for those with low oxygen levels in respiratory failure at rest (a partial pressure of oxygen less than 50–55 mmHg or oxygen saturations of less than 88%). When taking into account complications including cor pulmonale and pulmonary hypertension, the levels involved are 56–59 mmHg. Oxygen therapy is to be used for between 15 and 18 hours per day and is said to decrease the risk of heart failure and death. During acute exacerbations, many require oxygen therapy; the use of high concentrations of oxygen without taking into account a person's oxygen saturations may lead to increased levels of carbon dioxide and worsened outcomes. In those at high risk of high carbon dioxide levels, oxygen saturations of 88–92% are recommended, while for those without this risk, recommended levels are 94–98%. Rehabilitation Pulmonary rehabilitation is a program of exercise, disease management and counseling, coordinated to benefit the individual. A severe exacerbation leads to hospital admission, high mortality and a decline in the ability to carry out daily activities. Following a hospital admission, pulmonary rehabilitation has been shown to significantly reduce future hospital admissions, mortality and improve quality of life. The optimal exercise routine, use of noninvasive ventilation during exercise and intensity of exercise suggested for people with COPD, is unknown. Performing endurance arm exercises improves arm movement for people with COPD and may result in a small improvement in breathlessness. Pursed-lip breathing exercises may be useful. Inspiratory and expiratory muscle training (IMT, EMT) have been suggested and may provide some improvements when compared to no treatment. A combination of IMT and walking exercises at home may help limit breathlessness in cases of severe COPD. Additionally, the use of low amplitude high velocity joint mobilization together with exercise improves lung function and exercise capacity. The goal of spinal manipulation therapy is to improve thoracic mobility in an effort to reduce the work on the lungs during respiration, however, the evidence supporting manual therapy for people with COPD is very weak. Airway clearance techniques (ACTs), such as postural drainage, percussion/vibration, autogenic drainage, hand-held positive expiratory pressure (PEP) devices and other mechanical devices, may reduce the need for increased ventilatory assistance, the duration of ventilatory assistance and the length of hospital stay in people with acute COPD. In people with stable COPD, ACTs may lead to short-term improvements in health-related quality of life and a reduced long-term need for hospitalizations related to respiratory issues. Management of exacerbations People with COPD can experience exacerbations (flare-ups) that commonly start with respiratory tract infections. The symptoms that worsen are not specific to COPD and differential diagnoses need to be considered. Acute exacerbations are typically treated by increasing the use of short-acting bronchodilators, including a combination of a short-acting inhaled beta agonist and short-acting anticholinergic. These medications can be given either via a metered-dose inhaler with a spacer or via a nebulizer, with both appearing to be equally effective. Nebulization may be easier for those who are more unwell. Oxygen supplementation can be useful.