Section of a lung showingcentrilobular emphysema, with enlarged airspaces in the centre of alobule usually caused by smoking and a major feature of COPD
The main symptoms of COPD include shortness of breath and acough, which may or may not producemucus.[4] COPDprogressively worsens, witheveryday activities such as walking or dressing becoming difficult.[3] While COPD is incurable, it is preventable and treatable. The two most common types of COPD areemphysema andchronic bronchitis, and have been the two classic COPDphenotypes. However, this basic dogma has been challenged as varying degrees of co-existing emphysema, chronic bronchitis, and potentially significant vascular diseases have all been acknowledged in those with COPD, giving rise to the classification of other phenotypes or subtypes.[11]
Emphysema is defined as enlarged airspaces (alveoli) whosewalls have broken down, resulting in permanent damage to thelung tissue. Chronic bronchitis is defined as a productive cough that is present for at least three months each year for two years. Both of these conditions can exist without airflow limitations when they are not classed as COPD. Emphysema is just one of the structural abnormalities that can limit airflow and can exist without airflow limitation in a significant number of people.[12][13] Chronic bronchitis does not always result in airflow limitation. However, in young adults with chronic bronchitis who smoke, the risk of developing COPD is high.[14] Many definitions of COPD in the past included emphysema and chronic bronchitis, but these have never been included inGOLD report definitions.[9] Emphysema and chronic bronchitis remain the predominant phenotypes of COPD, but there is often overlap between them, and several other phenotypes have also been described.[11][15] COPD andasthma may coexist and converge in some individuals.[16] COPD is associated with low-grade systemic inflammation.[17]
As of 2021, COPD affected about 213 million people (2.7% of the global population).[7] It typically occurs in males and females over the age of 35–40.[1][3] In 2021, COPD caused 3.65 million deaths.[8] Almost 90% of COPD deaths in those under 70 years of age occur inlow and middle income countries.[3] In 2021, it was the fourth biggest cause of death, responsible for approximately 5% of total deaths.[3] The number of deaths is projected to increase further because of continued exposure to risk factors and an aging population.[9] In the United States, costs of the disease were estimated in 2010 at $50 billion, most of which is due to exacerbation.[9]
Acardinal symptom of COPD is the chronic and progressiveshortness of breath which is most characteristic of the condition. Shortness of breath (breathlessness) is often the most distressing symptom, responsible for the associated anxiety and level of disability experienced.[4] Symptoms ofwheezing and chest tightness associated with breathlessness can be variable over the course of a day or between days and are not always present. Chest tightness often follows exertion.[4] Many people with more advanced COPDbreathe through pursed lips, which can improve shortness of breath.[24] Shortness of breath is often responsible for reduced physical activity, and low levels of physical activity are associated with worse outcomes.[25][26] In severe and very severe cases there may beconstant tiredness, weight loss, muscle loss andanorexia. People with COPD often have increased breathlessness and frequentcolds before seeking treatment.[4]
The most often first symptom of COPD is a chronic cough, which may or may not be productive ofmucus asphlegm. Phlegm coughed up assputum can be intermittent and may be swallowed or spat out depending on social or cultural factors, and is therefore not always easy to evaluate. However, an accompanying productive cough is only seen in up to 30% of cases. Sometimes, limited airflow may develop in the absence of a cough.[4] Symptoms are usually worse in the morning.[27]
A chronicproductive cough is the result ofmucus hypersecretion, and when it persists for more than three months each year for at least two years, it is defined aschronic bronchitis.[14] Chronic bronchitis can occur before the restricted airflow diagnostic of COPD.[9] Some people with COPD attribute the symptoms to the consequences of smoking. In severe COPD, vigorous coughing may lead torib fractures or toa brief loss of consciousness.[4]
Anacute exacerbation is a sudden worsening ofsigns and symptoms that lasts for several days. The key symptom is increased breathlessness; other more pronounced symptoms are of excessive mucus, increased cough and wheeze. A commonly found sign isair trapping, giving difficulty in completeexhalation.[28]The usual cause of an exacerbation is aviral infection, most often thecommon cold.[14] The common cold is usually associated with the winter months but can occur at any time.[29] Otherrespiratory infections may be bacterial or in combination sometimes secondary to a viral infection.[30] The most common bacterial infection is caused byHaemophilus influenzae.[31] Other risks include exposure to tobacco smoke (active andpassive) and environmentalpollutants – both indoor and outdoor.[32] During theCOVID-19 pandemic, hospital admissions for COPD exacerbations sharply decreased which may be attributable to reduction of emissions and cleaner air.[33] There has also been a marked decrease in the number of cold and flu infections during this time.[34]
Smoke from wildfires is proving an increasing risk in many parts of the world, and government agencies have published protective advice on their websites. In the US theEPA advises that the use ofdust masks does not give protection from the fine particles inwildfires and instead advises the use of well-fittingparticulate masks.[35] This same advice is offered in Canada and Australia to the effects of their forest fires.[36][37]
The number of exacerbations is not seen to relate to any stage of the disease; those with two or more a year are classed asfrequent exacerbators and these lead to a worsening in the disease progression.[28]Frailty in ageing increases exacerbations and hospitalization.[38]
Acute exacerbations in COPD are often unexplained and thought to have many causes other than infections. A study has emphasized the possibility of apulmonary embolism as sometimes being responsible in these cases. Signs can includepleuriticchest pain andheart failure without signs of infection. Such emboli could respond toanticoagulants.[39]
COPD often occurs along with several other conditions (comorbidities) due in part to shared risk factors. Common comorbidities includecardiovascular disease,skeletal muscle dysfunction,metabolic syndrome,osteoporosis,depression,anxiety,asthma andlung cancer.[40]Alpha-1 antitrypsin deficiency (A1AD) is an important risk factor for COPD.[41] It is advised that everybody with COPD be screened for A1AD.[40]Metabolic syndrome has been seen to affect up to fifty percent of those with COPD and significantly affects the outcomes.[42] When comorbid with COPD there is more systemic inflammation.[42] It is not known if it co-exists with COPD or develops as a consequence of the pathology. Metabolic syndrome on its own has a high rate of morbidity and mortality, and this rate is amplified when comorbid with COPD.Tuberculosis is a risk factor for the development of COPD, and is also a potential comorbidity.[14] Most people with COPD die from comorbidities and not from respiratory problems.[43]
Along with these complications, there is an associated risk of developingpulmonary hypertension. The estimated prevalence of pulmonary hypertension complicating COPD was reported at 39% in a meta-analysis.[45] Of the people with COPD listed for lung transplantation, 82% were documented as having pulmonary hypertension via right heart catheterization, noting a mean pulmonary arterial pressure greater than 20mm Hg.[45] Despite pulmonary hypertension being relatively rare in people with COPD, mild elevations of pulmonary arterial pressure can lead to worse outcomes, including risk of death.[45]
Cognitive impairment is common in those with COPD, as it is for other lung conditions that affect airflow. Cognitive impairment is associated with the declining ability to cope with the basicactivities of daily living.[46]
It is unclear if those with COPD are at greater risk of contractingCOVID-19, though if infected, they are at risk of hospitalization and developing severe COVID-19. However, laboratory and clinical studies are showing a possibility of certaininhaled corticosteroids for COPD providing a protective role against COVID-19.[47] Differentiating COVID-19 symptoms from an exacerbation is difficult; mildprodromal symptoms may delay its recognition, and where they include loss of taste or smell, COVID-19 is to be suspected.[33]
Many definitions of COPD in the past have included chronic bronchitis andemphysema, but these have never been included inGOLD report definitions.[9] Emphysema is defined as enlarged airspaces (alveoli) whose walls break down resulting in permanent damage to thelung tissue and is just one of the structural abnormalities that can limit airflow. The condition can exist without airflow limitation, but commonly it does.[12] Chronic bronchitis is defined as aproductive cough that is present for at least three months each year for two years, but does not always result in airflow limitation, although the risk of developing COPD is great.[14] These older definitions grouped the two types astype A andtype B. Type A were emphysema types known aspink puffers due to their pink complexion, fast breathing rate and pursed lips. Type B were chronic bronchitic types referred to asblue bloaters due to low oxygen levels causing abluish color to the skin and lips and swollen ankles.[48] These differences were suggested to be due to the presence or not ofcollateral ventilation, evident in emphysema and lacking in chronic bronchitis.[49] This terminology was no longer accepted as useful, as most people with COPD have a combination of both emphysema and airway disease.[48] These are now recognized as the two major phenotypes of COPD — the emphysematous phenotype and the chronic bronchitic phenotype.[11]
It has since been recognized that COPD is more complex, with a diverse group of disorders of differing risk factors and clinical courses that have resulted in several subtypes or phenotypes of COPD being accepted and proposed.[50][51] The two classic emphysematous and chronic bronchiticphenotypes are fundamentally different conditions with unique underlying mechanisms.[11] Another subtype of COPD, categorized by some as a separate clinical entity, isasthma-COPD overlap, which is a condition sharing clinical features of bothasthma and COPD.[52][53] Spirometry measures are inadequate for defining phenotypes and chest X-ray, CT and MRI scans have been mostly employed. Most cases of COPD are diagnosed at a late stage, and the use of imaging methods would allow earlier detection and treatment.[11]
The identification and recognition of different phenotypes can guide appropriate treatment approaches. For example, thePDE4 inhibitorroflumilast is targeted at the chronic-bronchitic phenotype.[54]
Two inflammatory phenotypes show a phenotype stability: theneutrophilic inflammatory phenotype and theeosinophilic inflammatory phenotype.[55]Mepolizumab, amonoclonal antibody, has been shown to have benefit in treating the eosinophilic inflammatory type rather than the use of oral corticosteroids, but further studies have been called for.[56]
Another recognized phenotype is the frequent exacerbator.[57] The frequent exacerbator has two or more exacerbations a year, has a poor prognosis, and is described as a moderately stable phenotype.[28]
A pulmonary vascular COPD phenotype has been described due to cardiovascular dysfunction.[58] A molecular phenotype ofCFTR dysfunction is shared withcystic fibrosis.[15] A combined phenotype of chronic bronchitis andbronchiectasis has been described, with a difficulty noted in determining the best treatment.[59]
The most common cause of the development of COPD is the exposure to harmfulparticles or gases, includingtobacco smoke, that irritate the lung, causing inflammation that interacts with several host factors. Such exposure needs to be significant or long-term.[9] The greatest risk factor for the development of COPD is tobacco smoke.[18] However, less than 50 percent of heavy smokers develop COPD, so other factors need to be considered, including exposure to indoor and outdoor pollutants, allergens, occupational exposure, and host factors.[27][14] One of the known causes of COPD is exposure toconstruction dust. The three main types of construction dust aresilica dust, non-silica dust (e.g., dust from gypsum, cement, limestone, marble and dolomite) andwood dust.[61] Host factors include a genetic susceptibility,factors associated with poverty, aging and physical inactivity.Asthma andtuberculosis are also recognized as risk factors, as the comorbidity of COPD is reported to be 12 times higher in patients with asthma after adjusting for smoking history.[14] In Europe,airway hyperresponsiveness is rated as the second most important risk factor after smoking.[14]
A host factor of anairway branching variation, arising duringdevelopment, has been described.[62] Therespiratory tree is a filter for harmful substances, and any variant has the potential to disrupt this. A variation is associated with the development of chronic bronchitis, and another with the development of emphysema. A branch variant in the central airway is specifically associated with an increased susceptibility for the later development of COPD. A genetic association for the variants has been sometimes found withFGF10.[62][63]
Alcohol abuse can lead toalcoholic lung disease and is seen to be an independent risk factor for COPD.[64]Mucociliary clearance is disrupted by chronic exposure to alcohol;macrophage activity is diminished and an inflammatory response promoted.[65][66] The damage leads to a susceptibility for infection, includingCOVID-19,[67] more so when combined with smoking; smoking induces the upregulation of the expression ofACE2, a receptor for theSARS-CoV-2 virus.[64]
The primary risk factor for COPD globally istobacco smoking, with an increased rate of developing COPD shown in smokers and ex-smokers.[9][18] Of those who smoke, about 20% will get COPD,[68] increasing to less than 50% in heavy smokers.[9] In the United States and United Kingdom, of those with COPD, 80–95% are either current or previous smokers.[68][69][70] Several studies indicate that women are more susceptible than men to the harmful effects of tobacco smoke.[71] For the same amount of cigarette smoking, women have a higher risk of COPD than men.[72] Women who smoke duringpregnancy, and during the early life of the child is a risk factor for the later development of COPD in their child.[73] Epigenetic studies support this link, showing thatACSF3 is differentiallymethylated in smoke-exposedfetal lungs, and an integrative study identified it as a key regulator of COPD.[74]
Inhaled smoke triggers the release of excessiveproteases in lungs, which then degradeselastin, the major component of alveoli.[18] Smoke also impairs the action ofcilia, inhibitingmucociliary clearance that clears the bronchi of mucus, cellular debris and unwanted fluid.[18]
Other types of tobacco smoke, such as from cigar,pipe,water-pipe andhookah use, also confer a risk.[14] Water-pipe or hookah smoke appears to be as harmful or even more harmful than smoking cigarettes.[75]
Marijuana is the second most commonly smoked substance, but evidence linking its use to COPD is very limited. Limited evidence shows that marijuana does not accelerate lung function decline.[76] A low use of marijuana gives a bronchodilatory effect rather than the bronchoconstrictive effect from tobacco use, but it is often smoked in combination with tobacco or on its own by tobacco smokers. Higher use however has shown a decline in theFEV1.[77] There is evidence of it causing some respiratory problems and its use in combination may have a cumulative toxic effect, suggesting it as a risk factor for spontaneous pneumothorax,bullous emphysema, COPD and lung cancer.[76][78] A noted difference between marijuana use and tobacco was that respiratory problems were resolved with stopping usage unlike the continued decline with stopping tobacco smoking.[76] Respiratory symptoms reported with marijuana use included chronic cough, increased sputum production and wheezing, but not shortness of breath. Also, these symptoms were typically reported ten years ahead of their onset in tobacco smokers.[76] Another study found that chronic marijuana smokers even with the additional use of tobacco developed similar respiratory problems, but did not seem to develop airflow limitation and COPD.[79]
Exposure toparticulates can bring about the development of COPD or its exacerbations. Those with COPD are more susceptible to the harmful effects of particulate exposure that can cause acute exacerbations brought about by infections.[42]Black carbon also known assoot, is anair pollutant associated with an increased risk of hospitalization due to the exacerbations caused. Long-term exposure is indicated as an increased rate of mortality in COPD.[42] Studies have shown that people who live in large cities have a higher rate of COPD compared to people who live in rural areas.[81] Areas with poor outdoor air quality, including that fromexhaust gas, generally have higher rates of COPD.[82] Urban air pollution significantly affects the developing lung and its maturation, and contributes a potential risk factor for the later development of COPD. The overall effect in relation to smoking is believed to be small.[14]
Poorly ventilated fires used for cooking and heating, are often fueled by coal orbiomass such as wood anddry dung, leading toindoor air pollution and are one of the most common causes of COPD indeveloping countries. Women are affected more as they have a greater exposure.[14] These fuels are used as the main source of energy in 80% of homes inIndia,China andsub-Saharan Africa.[82]
Intense and prolonged exposure to workplacedusts, chemicals and fumes increases the risk of COPD in smokers, nonsmokers and never-smokers. Substances implicated in occupational exposure and listed in the UK, includeorganic andinorganic dusts such ascadmium,silica, dust fromgrains andflour and fumes from cadmium andwelding that promote respiratory symptoms.[19][14] Workplace exposure is believed to be the cause in 10–20% of cases and in the United States, it is believed to be related to around 30% of cases among never smokers and probably represents a greater risk in countries without sufficient regulations.[14][83] The negative effects of dust exposure and cigarette smoke exposure appear to be cumulative.[84]
Genetics plays a role in the development of COPD. It is more common among relatives of those with COPD who smoke than among unrelated smokers.[14] The most well known genetic risk factor isalpha-1 antitrypsin deficiency (AATD) and this is the onlygenotype (genetic subtype) with a specific treatment.[60] This risk is particularly high if someone deficient inalpha-1 antitrypsin (AAT) also smokes.[85] It is responsible for about 1–5% of cases[85][86] and the condition is present in about three to four in 10,000 people.[87]
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 theInternational COPD Genetics Consortium has identified more than 80 genome regions associated with COPD, and further studies in these regions have been called for.Whole genome sequencing is an ongoingcollaboration (2019) with theNational Heart, Lung and Blood Institute (NHLBI) to identify rare genetic determinants.[89]
Normallungs shown in upper diagram. Lungs damaged by COPD in the lower diagram with an inset showing a cross-section ofbronchioles blocked bymucus and damagedalveoli.
COPD is a progressivelung disease in which chronic, incompletely reversible poor airflow (airflow limitation) and an inability to breathe out fully (air trapping) exist.[90] The poor airflow is the result of small airways disease and emphysema (the breakdown oflung tissue).[91] The relative contributions of these two factors vary between people.[9] Air trapping precedes lung hyperinflation.[92]
COPD develops as a significant and chronic inflammatory response to inhaled irritants which ultimately leads to bronchial and alveolar remodelling in the lung known assmall airways disease.[93][94][95] Thus, airway remodelling with narrowing of peripheral airway and emphysema are responsible for the alteration of lung function.[55]Mucociliary clearance is particularly altered with a dysregulation ofcilia andmucus production.[96] Small airway disease sometimes calledchronic bronchiolitis, appears to be the precursor for the development of emphysema.[97]The inflammatory cells involved includeneutrophils andmacrophages, two types of white blood cells. Those who smoke additionally havecytotoxic T cell involvement, and some people with COPD haveeosinophil involvement similar to that in asthma. Part of this cell response is brought on by inflammatory mediators such aschemotactic factors. Other processes involved with lung damage includeoxidative stress produced by high concentrations offree radicals in tobacco smoke and released by inflammatory cells and breakdown of theconnective tissue of the lungs byproteases (particularlyelastase) that are insufficiently inhibited byprotease 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.[14]
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.[98] 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 byhyperinflation.[98][99][92] Hyperinflation from exercise is linked to shortness of breath in COPD, as breathing in is less comfortable when the lungs are already partly filled.[100] Hyperinflation may also worsen during an exacerbation.[101] There may also be a degree ofairway hyperresponsiveness to irritants similar to those found in asthma.[87]
Low oxygen levels and eventually,high carbon dioxide levels in the blood, can occur from poorgas exchange due to decreased ventilation from airway obstruction, hyperinflation and a reduced desire to breathe.[14] 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 innarrowing of the arteries in the lungs, while emphysema leads to the breakdown of capillaries in the lungs. Both of these conditions may result inpulmonary heart disease also classically known ascor pulmonale.[44]
A person blowing into aspirometer. Smaller handheld devices are available for office use.
The diagnosis of COPD should be considered in anyone over the age of 35 to 40 who hasshortness of breath, a chronic cough, sputum production, or frequent winter colds and a history of exposure to risk factors for the disease.Spirometry is then used to confirm the diagnosis.[4][102]
Spirometry measures the amount of airflow obstruction present and is generally carried out after the use of abronchodilator, a medication to open up the airways.[103] Two main components are measured to make the diagnosis, theforced 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 theforced vital capacity (FVC), which is the greatest volume of air that can be breathed out in a single large breath.[104] Normally, 75–80% of the FVC comes out in the first second[104] and aFEV1/FVC ratio less than 70% in someone with symptoms of COPD defines a person as having the disease.[103] Based on these measurements, spirometry would lead to over-diagnosis of COPD in the elderly.[103] TheNational Institute for Health and Care Excellence criteria additionally require a FEV1 less than 80% of predicted.[105] People with COPD also exhibit a decrease indiffusing capacity of the lung for carbon monoxide due to decreased surface area in the alveoli, as well as damage to the capillary bed.[106] Testing thepeak expiratory flow (the maximum speed of expiration), commonly used in asthma diagnosis, is not sufficient for the diagnosis of COPD.[105]
Screening using spirometry in those without symptoms has uncertain effects and is generally not recommended; however, it is recommended for those without symptoms but with a known risk factor.[40]
A number of methods can be used to assess the effects and severity of COPD.[102][40] TheMRC breathlessness scale or the COPD assessment test (CAT) are simple questionnaires that may be used.[107][102]GOLD refers to a modified MRC scale that if used, needs to include other tests since it is simply a test of breathlessness experienced.[40][108] Scores on CAT range from 0–40 with the higher the score, the more severe the disease.[109] Spirometry may help to determine the severity of airflow limitation.[4] This is typically based on the FEV1 expressed as a percentage of the predicted "normal" for the person's age, gender, height and weight.[4] Guidelines published in 2011 by American and European medical societies recommend partly basing treatment recommendations on the FEV1.[103] TheGOLD guidelines group people into four categories based on symptoms assessment, degree of airflow limitation and history of exacerbations.[108] Weight loss, muscle loss and fatigue are seen in severe and very severe cases.[40]
Use of screening questionnaires, such as the COPD diagnostic questionnaire (CDQ), alone or in combination with hand-held flow meters, is appropriate for screening of COPD in primary care.[110]
Achest X-ray is not useful to establish a diagnosis of COPD, but it is of use in either excluding other conditions or including comorbidities such aspulmonary fibrosis andbronchiectasis. Characteristic signs of COPD on X-ray include hyperinflation (shown by a flattened diaphragm and an increased retrosternal air space) and lung hyperlucency.[5] Asaber-sheath trachea may also be shown that isindicative of COPD.[111]
ACT scan is not routinely used except for the exclusion of bronchiectasis.[5]Pulse oximetry measurement of peripheral oxygen saturation is recommended in people with clinical signs of respiratory failure or right heart failure.[5] Ananalysis of arterial blood is recommended in those with a peripheral oxygen saturation of 92% or less to determine actual blood oxygen level and assess forhigh levels of carbon dioxide in the blood, which may have therapeutic implications such as need fornon-invasive ventilation or oxygen supplementation.[10]WHO recommends that all those diagnosed with COPD be screened foralpha-1 antitrypsin deficiency.[40]
Chest X-ray demonstrating severe COPD, displaying small heart size in comparison to the lungs
A lateral chest X-ray of a person with emphysema, displayingbarrel chest and flat diaphragm
Lung bulla as seen on chest X-ray in a person with severe COPD
A severe case of bullous emphysema
Axial CT image of the lung of a person with end-stage bullous emphysema
Very severe emphysema with lung cancer on the left (CT scan)
Thepolicies of governments, public health agencies and antismoking organizations can reduce smoking rates by discouraging people from starting and encouraging people to stop smoking.[113]Smoking bans in public areas and places of work are important measures to decrease exposure to secondhand smoke, and while many places have instituted bans, more are recommended.[82]
In those who smoke,stopping smoking is the only measure shown to slow down the worsening of COPD.[114][115] 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.[116] Often, several attempts are required before long-term abstinence is achieved.[113] Attempts over 5 years lead to success in nearly 40% of people.[117]
Some smokers can achieve long-term smoking cessation through willpower alone. Smoking, however, is highly addictive, and many smokers need further support.[118] The chance of quitting is improved with social support, engagement in a smoking cessation program and the use of medications such asnicotine replacement therapy,bupropion, orvarenicline.[113][115][117] 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.[119]
Several measures have been taken to reduce the likelihood that workers in at-risk industries—such as coal mining, construction and stonemasonry—will develop COPD.[82] Examples of these measures include the creation of public policy,[82] education of workers and management about the risks, promoting smoking cessation,checking workers for early signs of COPD, use ofrespirators and dust control.[120][121] Effective dust control can be achieved by improving ventilation, using water sprays and by using mining techniques that minimize dust generation.[122] If a worker develops COPD, further lung damage can be reduced by avoiding ongoing dust exposure, for example by changing their work role.[123]
Both indoor and outdoor air quality can be improved, which may prevent COPD or slow the worsening of existing disease.[82] This may be achieved by public policy efforts, cultural changes and personal involvement.[21] Many developed countries have successfully improved outdoor air quality through regulations, which has resulted in improvements in the lung function of their populations.[82] Individuals are also advised to avoid irritants of indoor and outdoor pollution.[21]
In developing countries, one key effort is to reduce exposure to smoke from cooking and heating fuels through improved ventilation of homes and better stoves and chimneys.[21] Proper stoves may improveindoor air quality by 85%. Using alternative energy sources such assolar cooking and electrical heating is also effective. Using fuels such as kerosene or coal might produce less household particulate matter than traditional biomass such as wood or dung, but whether this is better health wise is unclear.[82]
COPD currently has no cure,[124] but the symptoms are treatable and its progression can be delayed, particularly bystopping smoking.[1][6] The major goals of management are 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.[1] Other recommendations includepneumococcal vaccination and yearlyinfluenza vaccination to help reduce the risk of exacerbations; as of 2024 CDC and GOLD also recommendRSV vaccine for individuals above 60 years.[125][10] Guidance is also advised as to managing breathlessness and stress.[6]
Other illnesses are also being managed. An action plan is drawn up and is to be reviewed.[21] Providing people with a personalized action plan, an educational session and support for use of their action plan in the event of an exacerbation, reduces the number of hospital visits and encourages early treatment of exacerbations.[126] 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.[127] In those with COPD who aremalnourished, supplementation withvitamin C,vitamin E,zinc andselenium can improve weight, strength ofrespiratory muscles and health-related quality of life.[22] Significantvitamin 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.[28][128]
In those with a severe exacerbation, antibiotics improve outcomes.[129] Several different antibiotics may be used, includingamoxicillin,doxycycline andazithromycin; whether one is better than the others is unclear.[130] There is no clear evidence of improved outcomes for those with less severe cases.[129] The FDA recommends against the use offluoroquinolones when other options are available due to higher risks of serious side effects.[131]In treatingacute hypercapnic respiratory failure (acutely raised levels of carbon dioxide),bilevel positive airway pressure (BPAP) can decrease mortality and the need ofintensive care.[132]
Inhaled short-actingbronchodilators are the primary medications used on anas needed basis; their use regularly is not recommended.[6] The two major types arebeta2-adrenergic agonists andanticholinergics; either in long-acting or short-acting forms. Beta2–adrenergic agonists targetreceptors in thesmooth muscle cells inbronchioles causing them to relax and allow improved airflow. They reduce shortness of breath, tend to reducedynamic hyperinflation and improve exercise tolerance.[6][135] 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.[6] An inhaled corticosteroid used with a long-acting beta-2 agonist is more effective than either one on its own.[136]
Which type of long-acting agent,long-acting muscarinic antagonist (LAMA) such astiotropium orlong-acting beta agonist (LABA), is better is unclear, and trying each and continuing with the one that works best may be advisable.[137] Both types of agent appear to reduce the risk of acute exacerbations by 15–25%.[132] The combination of LABA/LAMA may reduce COPD exacerbations and improve quality-of-life compared to long-acting bronchodilators alone.[138] 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.[139]
Several short-acting β2 agonists are available, includingsalbutamol (albuterol) andterbutaline.[6] They provide relief of symptoms for four to six hours.[6] Along-acting beta agonist (LABA) such assalmeterol,formoterol andindacaterol are often used as maintenance therapy, with a duration of action of 12 to 24 hours.[6] Some feel the evidence of benefits is limited,[140] while others view the evidence of benefit as established.[141][142][143] Long-term use of LABAs appears safe in COPD,[144] with adverse effects includeshakiness andheart palpitations.[132] When used with inhaled steroids they increase the risk of pneumonia.[132] While steroids and LABAs may work better together,[140] it is unclear if this slight benefit outweighs the increased risks.[145] There is some evidence that combined treatment of LABAs with long-actingmuscarinic antagonists (LAMA), an anticholinergic, and LABA +ICS (inhaled corticosteroid) may be similar in benefits in terms of fewer exacerbation's and quality of life measures for moderate to severe COPD, but LAMA+LABA offers better improvements in forced expiratory volume (FEV1%) and a lower risk of pneumonia.[146] All three together, LABA, LAMA and ICS, have some evidence of benefits.[147] 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.[143]
The two main anticholinergics used in COPD areipratropium andtiotropium. Ipratropium is ashort-acting muscarinic antagonist (SAMA), while tiotropium islong-acting muscarinic antagonist (LAMA). Tiotropium is associated with a decrease in exacerbations and improved quality of life,[148] and tiotropium provides those benefits better than ipratropium.[149] Tiotropium does not appear to affect mortality or the overall hospitalization rate.[148] Anticholinergics can cause dry mouth and urinary tract symptoms.[132] They are also associated with increased risk of heart disease andstroke.[150]Aclidinium, another long-acting agent, reduces hospitalizations associated with COPD and improves quality of life.[151][152][153] The LAMAumeclidinium bromide is another anticholinergic alternative.[154] When compared to tiotropium, the LAMAs aclidinium, glycopyrronium, and umeclidinium appear to have a similar level of efficacy, with all four being more effective thanplacebo.[155] Further research is needed comparing aclidinium to tiotropium.[153]
Inhaledcorticosteroids are anti-inflammatories that are recommended byGOLD as a first-line maintenance treatment in COPD cases with repeated exacerbations.[156][157] Their regular use increases the risk of pneumonia in severe cases.[28] Studies have shown that the risk of pneumonia is associated with all types of corticosteroids; is related to the disease severity and a dose-response relationship has been noted.[156] Oralglucocorticoids can be effective in treating an acute exacerbation.[136] They appear to have fewer side effects than those given intravenously.[158] Five days of steroids work as well as ten or fourteen days.[159]
The use of corticosteroids is associated with a decrease in the number of lymphoid follicles (in thebronchial lymphoid tissue).[97] 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.[160][136] NICE guidelines recommend the use of ICSs in people with asthmatic features or features suggesting steroid responsiveness.[139]
Phosphodiesterase-4 inhibitors (PDE4 inhibitors) are anti-inflammatories that improve lung function and reduce exacerbations in moderate to severe illness.Roflumilast is a PDE4 inhibitor used orally once daily to reduce inflammation; it has no direct bronchodilatory effects. It is essentially used in treating those with chronic bronchitis along with systemic corticosteroids.[56] Reported adverse effects of roflumilast appear early in treatment, become less with continued treatment and are reversible. One effect is dramatic weight loss, and its use is to be avoided in underweight people. It is also advised to be used with caution in those who have depression.[56]
Methylxanthines such astheophylline are widely used. Theophylline is seen to have a mild bronchodilatory effect in stable COPD. Inspiratory muscle function is seen to be improved, but the causal effect is unclear. Theophylline is seen to improve breathlessness when used as an add-on tosalmeterol. All instances of improvement have been reported using sustained-release preparations.[6] Methylxanthines are not recommended for use in exacerbations due to adverse effects.[28]
Mucolytics may help to reduce exacerbations in some people with chronic bronchitis, as noticed by fewer hospitalizations and fewer days of disability in one month.[164]Erdosteine is recommended by NICE.[165] 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.[56] Erdosteine has been shown to significantly reduce the risk of exacerbations, shorten their duration and hospital stays.[166]
Cough medicines are not recommended.[167]Beta blockers are not contraindicated for those with COPD and should only be used where there is concomitant cardiovascular disease.[56]
Recent studies show that metformin plays a role in reducing systemic inflammation by reducing biomarker levels that are increased during COPD exacerbations.[168]
Supplemental oxygen is recommended for those withlow oxygen levels inrespiratory failure at rest (apartial pressure of oxygen less than 50–55 mmHg oroxygen saturations of less than 88%).[22] When taking into account complications includingcor pulmonale and pulmonary hypertension, the levels involved are 56–59 mmHg.[169] Oxygen therapy is to be used for between 15 and 18 hours per day and is said to decrease the risk ofheart failure and death.[169] In those with normal or mildly low oxygen levels, oxygen supplementation (ambulatory) may improve shortness of breath when given during exercise, but may not improve breathlessness during normal daily activities or affect the quality of life.[170] 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.[171][172] 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%.[172] Once prescribed long-term oxygen therapy, patients should be re-assessed after 60 to 90 days, to determine whether supplemental oxygen is still indicated and if prescribed supplemental oxygen is effective.[10][173]
Pulmonary rehabilitation is a program of exercise, disease management and counseling, coordinated to benefit the individual.[174] 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.[54]
The optimal exercise routine, use of noninvasive ventilation during exercise and intensity of exercise suggested for people with COPD, is unknown.[175][176] Performing endurance arm exercises improves arm movement for people with COPD and may result in a small improvement in breathlessness.[177] Performing arm exercises alone does not appear to improve quality of life.[177]Pursed-lip breathing exercises may be useful.[24]Tai chi exercises appear to be safe to practice for people with COPD and may be beneficial for pulmonary function and pulmonary capacity when compared to a regular treatment program.[178] Tai Chi was not found to be more effective than other exercise intervention programs.[178] Inspiratory and expiratory muscle training (IMT, EMT) have been suggested and may provide some improvements when compared to no treatment.[179] A combination of IMT and walking exercises at home may help limit breathlessness in cases of severe COPD.[180] Additionally, the use of low amplitude high velocity joint mobilization together with exercise improves lung function and exercise capacity.[181] 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.[181][182]
Airway clearance techniques (ACTs), such aspostural drainage, percussion/vibration,autogenic drainage, hand-heldpositive 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.[183] 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.[183]
Being either underweight or overweight can affect the symptoms, degree of disability and prognosis of COPD. People with COPD who are underweight can improve their breathing muscle strength by increasing their calorie intake. When combined with regular exercise or a pulmonary rehabilitation program, this can lead to improvements in COPD symptoms. Supplemental nutrition may be useful in those who aremalnourished.[22][184]
People with COPD can experienceexacerbations (flare-ups) that are commonly caused byrespiratory tract infections. The symptoms that worsen are not specific to COPD and differential diagnoses need to be considered.[28] 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.[28] These medications can be given either via ametered-dose inhaler with aspacer or via anebulizer, with both appearing to be equally effective.[56][185] Nebulization may be easier for those who are more unwell.[56]Oxygen supplementation can be useful. Excessive oxygen; however, can result inincreased CO2 levels and a decreased level of consciousness.[186] Corticosteroidsgiven orally can improve lung function and shorten hospital stays but their use is recommended for only five to seven days; longer courses increase the risk of pneumonia and death.[28]
Maintainingroom temperature of at least 21 °C (70 °F) for a minimum of nine hours a day was associated with better health in those with COPD, especially for smokers.[187] The World Health Organization (WHO) recommends indoor temperatures of a slightly higher range between 18 and 24 °C (64 and 75 °F).[188]
For people with COPD, the ideal indoor humidity levels are 30–50% RH. Maintaining indoor humidity can be difficult in the winter, especially in cold climates where the heating system is constantly running.[189]
Keeping the indoor relative humidity above 40% RH significantly reduces the infectivity of aerosolized viruses.[190]
For severe emphysema that has proved unresponsive to other therapieslung volume reduction surgery (LVRS) may be an option.[191][192] LVRS involves the removal of damaged tissue, which improves lung function by allowing the rest of the lungs to expand.[132] It is considered when the emphysema is in the upper lobes and when there are no comorbidities.[193]
Minimally invasive bronchoscopic procedures may be carried out to reduce lung volume. These include the use of valves, coils, or thermal ablation.[22][194]Endobronchial valves are one-way valves that may be used in those with severe hyperinflation resulting from advanced emphysema; a suitable target lobe and nocollateral ventilation are required for this procedure. The placement of one or more valves in the lobe induces a partialcollapse of the lobe that ensures a reduction in residual volume that improves lung function, the capacity for exercise and quality of life.[195]
The placement ofnitinol coils instead of valves is recommended where there is collateral ventilation that would prevent the use of valves.[196] Nitinol is abiocompatible alloy.
Both of these techniques are associated with adverse effects, including persistent air leaks and cardiovascular complications. Thermal vapor ablation has an improved profile. Heated water vapor is used to target lobe regions, which leads to permanent fibrosis and volume reduction. The procedure can target individual lobe segments, can be carried out regardless of collateral ventilation, and can be repeated with the natural advance of emphysema.[197]
In very severe cases,lung transplantation might be considered.[191] A CT scan may be useful in surgery considerations.[87]Ventilation/perfusion scintigraphy is another imaging method that may be used to evaluate cases for surgical interventions and also to evaluate post-surgery responses.[198] Abullectomy may be carried out when a giantbulla occupies more than a third of a hemithorax.[193]
COPD is progressive and can lead to premature death. It is estimated that 3% ofall disability is related to COPD.[200] The proportion of disability from COPD globally has decreased from 1990 to 2010 due to improved indoor air quality primarily in Asia.[200] The overall number of years lived with disability from COPD, however, has increased.[201]
There are many variables affecting the long-term outcome in COPD and GOLD recommends the use of a composite test (BODE) that includes the main variables ofbody-mass index, obstruction of airways,dyspnea (breathlessness) and exercise and not just spirometry results.[40] NICE recommends against the use of BODE for the prognosis assessment in stable COPD; factors such as exacerbations andfrailty need to be considered.[194] Other factors that contribute to a poor outcome include older age,comorbidities such as lung cancer and cardiovascular disease and the number and severity of exacerbations needing hospital admission.[28]
Estimates of prevalence have considerable variation due to differences in analytical and surveying approach and the choice of diagnostic criteria.[202] An estimated 213 million people had COPD in 2021, corresponding to a global prevalence of 2.7%,[7] whereas epidemiological studies indicated an estimation of 384 million having COPD in 2010, corresponding to a global prevalence of 12%.[9] The disease affects men and women.[3] The increase in the developing world between 1970 and the 2000s is believed to be related to increasing rates of smoking in this region, an increasing population and an aging population due to fewer deaths from other causes such as infectious diseases.[132] Some developed countries have seen increased rates, some have remained stable and some have seen a decrease in COPD prevalence.[132]
Around three million people die of COPD each year.[9] In some countries, mortality has decreased in men but increased in women.[203] This is most likely due to rates of smoking in women and men becoming more similar.[87] A higher rate of COPD is found in those over 40 years and this increases greatly with advancing age with the highest rate found in those over 60 years.[9] Sex differences in the anatomy of the respiratory system include smaller airway lumens and thicker airway walls in women, which contribute to a greater severity of COPD symptoms like dyspnea and frequency of COPD exacerbation.[204]
In the UK, three million people are reported to be affected by COPD – two million of these being undiagnosed. On average, the number of COPD-related deaths between 2007 and 2016 was 28,600. The estimated number of deaths due to occupational exposure was estimated to be about 15% at around 4,000.[202] In the United States in 2018, almost 15.7 million people had been diagnosed with COPD and it is estimated that millions more have not been diagnosed.[205]
In 2011, there were approximately 730,000 hospitalizations in the United States for COPD.[206] Globally, COPD in 2019 was the third-leading cause of death. In low-income countries, COPD does not appear in the Top 10 causes of death; in other income groups, it is in the Top 5.[207]
The namechronic obstructive pulmonary disease is believed to have first been used in 1965.[208] Previously it has been known by a number of different names, includingchronic obstructive bronchopulmonary disease,chronic airflow obstruction,chronic obstructive lung disease,nonspecific chronic pulmonary disease, anddiffuse obstructive pulmonary syndrome.[208]
The termsemphysema andchronic bronchitis were formally defined as components of COPD in 1959 at theCIBA guest symposium and in 1962 at theAmerican Thoracic Society Committee meeting on Diagnostic Standards.[208]
Early descriptions of probable emphysema began in 1679 by T. Bonet of a condition of "voluminous lungs" and in 1769 byGiovanni Morgagni of lungs which were "turgid particularly from air".[208][209] In 1721 the first drawings of emphysema were made by Ruysh.[209]René Laennec, used the termemphysema in his bookA Treatise on the Diseases of the Chest and of Mediate Auscultation (1837) to describe lungs that did not collapse when he opened the chest during an autopsy. He noted that they did not collapse as usual because they were full of air and the airways were filled with mucus.[208] In 1842,John Hutchinson invented thespirometer, which allowed the measurement ofvital capacity of the lungs. However, his spirometer could only measure volume, not airflow. Tiffeneau and Pinelli in 1947 described the principles of measuring airflow.[208]
Air pollution and the increase in cigarette smoking in Great Britain at the start of the 20th century led to high rates of chronic lung disease, though it received little attention until theGreat Smog of London in December 1952. This spurred epidemiological research in the United Kingdom, Holland and elsewhere.[210] In 1953, George L. Waldbott, an American allergist, first described a new disease he namedsmoker's respiratory syndrome in the 1953Journal of the American Medical Association. This was the first association between tobacco smoking and chronic respiratory disease.[211]
Modern treatments were developed during the second half of the 20th century. Evidence supporting the use ofsteroids in COPD was published in the late 1950s.Bronchodilators came into use in the 1960s following a promising trial ofisoprenaline. Further bronchodilators, such as short-actingsalbutamol, were developed in the 1970s and the use oflong-acting bronchodilators began in the mid-1990s.[212]
It is generally accepted that COPD is widely underdiagnosed and many people remain untreated. In the US theNIH has promoted November asCOPD Awareness Month to be an annual focus on increasing awareness of the condition.[213]
Globally, as of 2010, COPD is estimated to result in economic costs of $2.1 trillion, half of which occurring in the developing world.[214] Of this total an estimated $1.9 trillion are direct costs such as medical care, while $0.2 trillion are indirect costs such as missed work.[215] This is expected to more than double by 2030.[214] In Europe, COPD represents 3% of healthcare spending.[9] In the United States, costs of the disease were estimated at $50 billion in 2010, most of which is due to exacerbation.[9] In the United Kingdom this cost was in 2021 estimated at £3.8 billion annually.[216]
The effectiveness ofalpha-1 antitrypsin augmentation treatment for people who have alpha-1 antitrypsin deficiency is unclear.[218]
Metabolomic approaches to diagnosing and differentiating subtypes of COPD are being studied.[219][220][221]
Research continues into the use oftelehealthcare to treat people with COPD when they experience episodes of shortness of breath; treating people remotely may reduce the number of emergency-room visits and improve the person's quality of life.[222]
American people with COPD and their caregivers consider the following COPD-related research areas as the most important: family/social/community research, well-being of people with COPD, curative research, biomedical therapies, policy, and holistic therapies.[223]
Chronic obstructive pulmonary disease may occur in a number of other animals and may be caused by exposure to tobacco smoke.[224] Most cases of the disease, however, are relatively mild.[225] Inhorses it is known asrecurrent airway obstruction (RAO) orheaves. RAO can be quite severe and most often is linked to exposure to common allergens.[226] COPD is also commonly found in old dogs.[227]
^Torres-Duque CA, García-Rodriguez MC, González-García M (August 2016). "Is Chronic Obstructive Pulmonary Disease Caused by Wood Smoke a Different Phenotype or a Different Entity?".Archivos de Bronconeumologia.52 (8):425–31.doi:10.1016/j.arbres.2016.04.004.PMID27207325.
^abcdefgGold Report 2021, pp. 60–65, Chapter 3: Evidence supporting prevention and maintenance therapy.
^Dobler CC, Morrow AS, Beuschel B, Farah MH, Majzoub AM, Wilson ME, et al. (March 2020). "Pharmacologic Therapies in Patients With Exacerbation of Chronic Obstructive Pulmonary Disease: A Systematic Review With Meta-analysis".Annals of Internal Medicine.172 (6):413–422.doi:10.7326/M19-3007.hdl:1959.4/unsworks_66204.PMID32092762.S2CID211476101.
^abMayer AF, Karloh M, Dos Santos K, de Araujo CL, Gulart AA (March 2018). "Effects of acute use of pursed-lips breathing during exercise in patients with COPD: a systematic review and meta-analysis".Physiotherapy.104 (1):9–17.doi:10.1016/j.physio.2017.08.007.PMID28969859.
^Aleva FE, Voets LW, Simons SO, de Mast Q, van der Ven AJ, Heijdra YF (March 2017). "Prevalence and Localization of Pulmonary Embolism in Unexplained Acute Exacerbations of COPD: A Systematic Review and Meta-analysis".Chest.151 (3):544–554.doi:10.1016/j.chest.2016.07.034.PMID27522956.S2CID7181799.
^Postma DS, Rabe KF (24 September 2015). "The Asthma–COPD Overlap Syndrome".New England Journal of Medicine.373 (13):1241–1249.doi:10.1056/NEJMra1411863.PMID26398072.
^abcdChatkin JM, Zabert G, Zabert I, Chatkin G, Jiménez-Ruiz CA, de Granda-Orive JI, et al. (September 2017). "Lung Disease Associated With Marijuana Use".Arch Bronconeumol.53 (9):510–515.doi:10.1016/j.arbres.2017.03.019.PMID28483343.
^Underner M, Urban T, Perriot J, Peiffer G, Harika-Germaneau G, Jaafari N (December 2018). "[Spontaneous pneumothorax and lung emphysema in cannabis users]".Rev Pneumol Clin (in French).74 (6):400–415.doi:10.1016/j.pneumo.2018.06.003.PMID30420278.S2CID59233744.
^Knox-Brown B, Patel J, Potts J, Ahmed R, Aquart-Stewart A, Cherkaski H, et al. (January 2023). "Small airways obstruction and its risk factors in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study".Lancet Glob Health.11 (1):e69 –e82.doi:10.1016/S2214-109X(22)00456-9.hdl:10044/1/100800.PMID36521955.S2CID254665705.
^O'Donnell DE (April 2006). "Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease".Proceedings of the American Thoracic Society.3 (2):180–4.doi:10.1513/pats.200508-093DO.PMID16565429.S2CID20644418.
^Cooper CB (October 2006). "The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function".The American Journal of Medicine.119 (10 Suppl 1):21–31.doi:10.1016/j.amjmed.2006.08.004.PMID16996896.
^abcdQaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, et al. (August 2011). "Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society".Annals of Internal Medicine.155 (3):179–191.doi:10.7326/0003-4819-155-3-201108020-00008.PMID21810710.S2CID18830625.
^Mackay AJ, Hurst JR (July 2012). "COPD exacerbations: causes, prevention, and treatment".The Medical Clinics of North America.96 (4):789–809.doi:10.1016/j.mcna.2012.02.008.PMID22793945.
^abCave AC, Hurst MM (May 2011). "The use of long acting β₂-agonists, alone or in combination with inhaled corticosteroids, in chronic obstructive pulmonary disease (COPD): a risk-benefit analysis".Pharmacology & Therapeutics.130 (2):114–143.doi:10.1016/j.pharmthera.2010.12.008.PMID21276815.
^Jones P (April 2013). "Aclidinium bromide twice daily for the treatment of chronic obstructive pulmonary disease: a review".Advances in Therapy.30 (4):354–68.doi:10.1007/s12325-013-0019-2.PMID23553509.S2CID3530290.
^Cazzola M, Page CP, Matera MG (June 2013). "Aclidinium bromide for the treatment of chronic obstructive pulmonary disease".Expert Opinion on Pharmacotherapy.14 (9):1205–14.doi:10.1517/14656566.2013.789021.PMID23566013.S2CID24973904.
^Chinet T, Dumoulin J, Honore I, Braun JM, Couderc LJ, Febvre M, et al. (December 2016). "[The place of inhaled corticosteroids in COPD]".Revue des Maladies Respiratoires.33 (10):877–891.doi:10.1016/j.rmr.2015.11.009.PMID26831345.
^Mammen MJ, Sethi S (2012). "Macrolide therapy for the prevention of acute exacerbations in chronic obstructive pulmonary disease".Polskie Archiwum Medycyny Wewnetrznej.122 (1–2):54–9.doi:10.20452/pamw.1134.PMID22353707.S2CID35183033.
^Thomas MJ, Simpson J, Riley R, Grant E (June 2010). "The impact of home-based physiotherapy interventions on breathlessness during activities of daily living in severe COPD: a systematic review".Physiotherapy.96 (2):108–19.doi:10.1016/j.physio.2009.09.006.PMID20420957.
^abMurray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. (December 2012). "Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010".Lancet.380 (9859):2197–2223.doi:10.1016/S0140-6736(12)61689-4.PMID23245608.S2CID205967479.
^Fishman AP (May 2005). "One hundred years of chronic obstructive pulmonary disease".American Journal of Respiratory and Critical Care Medicine.171 (9):941–8.doi:10.1164/rccm.200412-1685OE.PMID15849329.
^Dasgupta S, Ghosh N, Bhattacharyya P, Roy Chowdhury S, Chaudhury K (2023-02-17). "Metabolomics of asthma, COPD, and asthma-COPD overlap: an overview".Critical Reviews in Clinical Laboratory Sciences.60 (2):153–170.doi:10.1080/10408363.2022.2140329.ISSN1040-8363.PMID36420874.
^Zeng X, Lan Y, Xiao J, Hu L, Tan L, Liang M, Wang X, Lu S, Peng T, Long F (2022-12-02). "Advances in phosphoproteomics and its application to COPD".Expert Review of Proteomics.19 (7–12):311–324.doi:10.1080/14789450.2023.2176756.ISSN1478-9450.PMID36730079.
^Churg A, Wright JL (2007). "Animal models of cigarette smoke-induced chronic obstructive lung disease".Models of Exacerbations in Asthma and COPD. Contributions to Microbiology. Vol. 14. pp. 113–25.doi:10.1159/000107058.ISBN978-3-8055-8332-9.PMID17684336.
^Miller MS, Tilley LP, Smith FW (January 1989). "Cardiopulmonary disease in the geriatric dog and cat".The Veterinary Clinics of North America. Small Animal Practice.19 (1):87–102.doi:10.1016/S0195-5616(89)50007-X.PMID2646821.
