In 2015, 358 million people globally had asthma, up from 183 million in 1990. It caused about 397,100 deaths in 2015, most of which occurred in the developing world. Asthma often begins in childhood, and the rates have increased significantly since the 1960s. Asthma was recognized as early as Ancient Egypt. The word "asthma" is from the Greek ἅσθμα, ásthma, which means "panting".
Asthma is characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing.Sputum may be produced from the lung by coughing but is often hard to bring up. During recovery from an asthma attack (exacerbation), it may appear pus-like due to high levels of white blood cells called eosinophils. Symptoms are usually worse at night and in the early morning or in response to exercise or cold air. Some people with asthma rarely experience symptoms, usually in response to triggers, whereas others may react frequently and readily and experience persistent symptoms.
Asthma is caused by a combination of complex and incompletely understood environmental and genetic interactions. These influence both its severity and its responsiveness to treatment. It is believed that the recent increased rates of asthma are due to changing epigenetics (heritable factors other than those related to the DNA sequence) and a changing living environment. Asthma that starts before the age of 12 years old is more likely due to genetic influence, while onset after age 12 is more likely due to environmental influence.
Many environmental factors have been associated with asthma's development and exacerbation, including, allergens, air pollution, and other environmental chemicals.Smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms. Low air quality from environmental factors such as traffic pollution or high ozone levels has been associated with both asthma development and increased asthma severity. Over half of cases in children in the United States occur in areas when air quality is below the EPA standards. Low air quality is more common in low-income and minority communities.
The majority of the evidence does not support a causal role between acetaminophen (paracetamol) or antibiotic use and asthma. A 2014 systematic review found that the association between acetaminophen use and asthma disappeared when respiratory infections were taken into account. Acetaminophen use by a mother during pregnancy is also associated with an increased risk of the child developing asthma. Maternal psychological stress during pregnancy is a risk factor for the child to develop asthma.
Asthma is associated with exposure to indoor allergens. Common indoor allergens include dust mites, cockroaches, animal dander (fragments of fur or feathers), and mold. Efforts to decrease dust mites have been found to be ineffective on symptoms in sensitized subjects. Weak evidence suggests that efforts to decrease mold by repairing buildings may help improve asthma symptoms in adults. Certain viral respiratory infections, such as respiratory syncytial virus and rhinovirus, may increase the risk of developing asthma when acquired as young children. Certain other infections, however, may decrease the risk.
The hygiene hypothesis attempts to explain the increased rates of asthma worldwide as a direct and unintended result of reduced exposure, during childhood, to non-pathogenic bacteria and viruses. It has been proposed that the reduced exposure to bacteria and viruses is due, in part, to increased cleanliness and decreased family size in modern societies. Exposure to bacterial endotoxin in early childhood may prevent the development of asthma, but exposure at an older age may provoke bronchoconstriction. Evidence supporting the hygiene hypothesis includes lower rates of asthma on farms and in households with pets.
Use of antibiotics in early life has been linked to the development of asthma. Also, delivery via caesarean section is associated with an increased risk (estimated at 20–80%) of asthma– this increased risk is attributed to the lack of healthy bacterial colonization that the newborn would have acquired from passage through the birth canal. There is a link between asthma and the degree of affluence which may be related to the hygiene hypothesis as less affluent individuals often have more exposure to bacteria and viruses.
CD14-endotoxin interaction based on CD14 SNP C-159T
Family history is a risk factor for asthma, with many different genes being implicated. If one identical twin is affected, the probability of the other having the disease is approximately 25%. By the end of 2005, 25 genes had been associated with asthma in six or more separate populations, including GSTM1, IL10, CTLA-4, SPINK5, LTC4S, IL4R and ADAM33, among others. Many of these genes are related to the immune system or modulating inflammation. Even among this list of genes supported by highly replicated studies, results have not been consistent among all populations tested. In 2006 over 100 genes were associated with asthma in one genetic association study alone; more continue to be found.
Some genetic variants may only cause asthma when they are combined with specific environmental exposures. An example is a specific single nucleotide polymorphism in the CD14 region and exposure to endotoxin (a bacterial product). Endotoxin exposure can come from several environmental sources including tobacco smoke, dogs, and farms. Risk for asthma, then, is determined by both a person's genetics and the level of endotoxin exposure.
There is a correlation between obesity and the risk of asthma with both having increased in recent years. Several factors may be at play including decreased respiratory function due to a buildup of fat and the fact that adipose tissue leads to a pro-inflammatory state.
Some individuals will have stable asthma for weeks or months and then suddenly develop an episode of acute asthma. Different individuals react to various factors in different ways. Most individuals can develop severe exacerbation from a number of triggering agents.
Home factors that can lead to exacerbation of asthma include dust, animal dander (especially cat and dog hair), cockroach allergens and mold.Perfumes are a common cause of acute attacks in women and children. Both viral and bacterial infections of the upper respiratory tract can worsen the disease. Psychological stress may worsen symptoms– it is thought that stress alters the immune system and thus increases the airway inflammatory response to allergens and irritants.
Asthma exacerbations in school‐aged children peak in autumn, shortly after children return to school. This might reflect a combination of factors, including poor treatment adherence, increased allergen and viral exposure, and altered immune tolerance. There is limited evidence to guide possible approaches to reducing autumn exacerbations, but while costly, seasonal omalizumab treatment from four to six weeks before school return may reduce autumn asthma exacerbations.
While asthma is a well-recognized condition, there is not one universal agreed upon definition. It is defined by the Global Initiative for Asthma as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment".
There is currently no precise test for the diagnosis, which is typically based on the pattern of symptoms and response to therapy over time. A diagnosis of asthma should be suspected if there is a history of recurrent wheezing, coughing or difficulty breathing and these symptoms occur or worsen due to exercise, viral infections, allergens or air pollution.Spirometry is then used to confirm the diagnosis. In children under the age of six the diagnosis is more difficult as they are too young for spirometry.
Spirometry is recommended to aid in diagnosis and management. It is the single best test for asthma. If the FEV1 measured by this technique improves more than 12% and increases by at least 200 milliliters following administration of a bronchodilator such as salbutamol, this is supportive of the diagnosis. It however may be normal in those with a history of mild asthma, not currently acting up. As caffeine is a bronchodilator in people with asthma, the use of caffeine before a lung function test may interfere with the results.Single-breath diffusing capacity can help differentiate asthma from COPD. It is reasonable to perform spirometry every one or two years to follow how well a person's asthma is controlled.
The methacholine challenge involves the inhalation of increasing concentrations of a substance that causes airway narrowing in those predisposed. If negative it means that a person does not have asthma; if positive, however, it is not specific for the disease.
Other supportive evidence includes: a ≥20% difference in peak expiratory flow rate on at least three days in a week for at least two weeks, a ≥20% improvement of peak flow following treatment with either salbutamol, inhaled corticosteroids or prednisone, or a ≥20% decrease in peak flow following exposure to a trigger. Testing peak expiratory flow is more variable than spirometry, however, and thus not recommended for routine diagnosis. It may be useful for daily self-monitoring in those with moderate to severe disease and for checking the effectiveness of new medications. It may also be helpful in guiding treatment in those with acute exacerbations.
Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic), based on whether symptoms are precipitated by allergens (atopic) or not (non-atopic). While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system. Finding ways to identify subgroups that respond well to different types of treatments is a current critical goal of asthma research.
Although asthma is a chronic obstructive condition, it is not considered as a part of chronic obstructive pulmonary disease, as this term refers specifically to combinations of disease that are irreversible such as bronchiectasis and emphysema. Unlike these diseases, the airway obstruction in asthma is usually reversible; however, if left untreated, the chronic inflammation from asthma can lead the lungs to become irreversibly obstructed due to airway remodeling. In contrast to emphysema, asthma affects the bronchi, not the alveoli.
An acute asthma exacerbation is commonly referred to as an asthma attack. The classic symptoms are shortness of breath, wheezing, and chest tightness. The wheezing is most often when breathing out. While these are the primary symptoms of asthma, some people present primarily with coughing, and in severe cases, air motion may be significantly impaired such that no wheezing is heard. In children, chest pain is often present.
In a mild exacerbation the peak expiratory flow rate (PEFR) is ≥200L/min, or ≥50% of the predicted best. Moderate is defined as between 80 and 200L/min, or 25% and 50% of the predicted best, while severe is defined as ≤80 L/min, or ≤25% of the predicted best.
Acute severe asthma, previously known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and corticosteroids. Half of cases are due to infections with others caused by allergen, air pollution, or insufficient or inappropriate medication use.
Brittle asthma is a kind of asthma distinguishable by recurrent, severe attacks. Type 1 brittle asthma is a disease with wide peak flow variability, despite intense medication. Type 2 brittle asthma is background well-controlled asthma with sudden severe exacerbations.
Exercise can trigger bronchoconstriction both in people with or without asthma. It occurs in most people with asthma and up to 20% of people without asthma. Exercise-induced bronchoconstriction is common in professional athletes. The highest rates are among cyclists (up to 45%), swimmers, and cross-country skiers. While it may occur with any weather conditions, it is more common when it is dry and cold. Inhaled beta2-agonists do not appear to improve athletic performance among those without asthma, however, oral doses may improve endurance and strength.
Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupational disease. Many cases, however, are not reported or recognized as such. It is estimated that 5–25% of asthma cases in adults are work-related. A few hundred different agents have been implicated, with the most common being: isocyanates, grain and wood dust, colophony, soldering flux, latex, animals, and aldehydes. The employment associated with the highest risk of problems include: those who spray paint, bakers and those who process food, nurses, chemical workers, those who work with animals, welders, hairdressers and timber workers.
Alcohol may worsen asthmatic symptoms in up to a third of people. This may be even more common in some ethnic groups such as the Japanese and those with aspirin-induced asthma. Other studies have found improvement in asthmatic symptoms from alcohol.
Non-atopic asthma, also known as intrinsic or non-allergic, makes up between 10 and 33% of cases. There is negative skin test to common inhalant allergens and normal serum concentrations of IgE. Often it starts later in life, and women are more commonly affected than men. Usual treatments may not work as well.
Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronic asthma. After the age of 65, most people with obstructive airway disease will have asthma and COPD. In this setting, COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness, and increased smooth muscle in the bronchi. However, this level of investigation is not performed due to COPD and asthma sharing similar principles of management: corticosteroids, long-acting beta-agonists, and smoking cessation. It closely resembles asthma in symptoms, is correlated with more exposure to cigarette smoke, an older age, less symptom reversibility after bronchodilator administration, and decreased likelihood of family history of atopy.
The evidence for the effectiveness of measures to prevent the development of asthma is weak. The World Health Organization recommends decreasing risk factors such as tobacco smoke, air pollution, chemical irritants including perfume, and the number of lower respiratory infections. Other efforts that show promise include: limiting smoke exposure in utero, breastfeeding, and increased exposure to daycare or large families, but none are well supported enough to be recommended for this indication.
Early pet exposure may be useful. Results from exposure to pets at other times are inconclusive and it is only recommended that pets be removed from the home if a person has allergic symptoms to said pet.
Dietary restrictions during pregnancy or when breast feeding have not been found to be effective at preventing asthma in children and are not recommended. Reducing or eliminating compounds known to sensitive people from the work place may be effective. It is not clear if annual influenza vaccinations affects the risk of exacerbations. Immunization, however, is recommended by the World Health Organization. Smoking bans are effective in decreasing exacerbations of asthma.
While there is no cure for asthma, symptoms can typically be improved. A specific, customized plan for proactively monitoring and managing symptoms should be created. This plan should include the reduction of exposure to allergens, testing to assess the severity of symptoms, and the usage of and adjustments to medications. The treatment plan should be written down and advise adjustments to treatment according to changes in symptoms.
The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, or aspirin, and eliminating exposure to them. If trigger avoidance is insufficient, the use of medication is recommended. Pharmaceutical drugs are selected based on, among other things, the severity of illness and the frequency of symptoms. Specific medications for asthma are broadly classified into fast-acting and long-acting categories.
Bronchodilators are recommended for short-term relief of symptoms. In those with occasional attacks, no other medication is needed. If mild persistent disease is present (more than two attacks a week), low-dose inhaled corticosteroids or alternatively, a leukotriene antagonist or a mast cell stabilizer by mouth is recommended. For those who have daily attacks, a higher dose of inhaled corticosteroids is used. In a moderate or severe exacerbation, corticosteroids by mouth are added to these treatments.
Improving people's knowledge about asthma and using a written action plan has been identified as an important component of managing asthma. Providing educational sessions that include information specific to a person's culture is likely effective. More research is necessary to determine if increasing preparedness and knowledge of asthma among school staff and families using home-based and school interventions results in long term improvements in safety for children with asthma. School-based asthma self-management interventions, which attempt to improve knowledge of asthma, its triggers and the importance of regular practitioner review, may reduce hospital admissions and emergency department visits. These interventions may also reduce the number of days children experience asthma symptoms and may lead to small improvements in asthma-related quality of life. More research is necessary to determine if shared-decision-making is helpful for managing adults with asthma or if a personalized asthma action plan is effective and necessary. Some people with asthma use pulse oximeters to monitor their own blood oxygen levels during an asthma attack. However, there is no evidence regarding the use in these instances.
Avoidance of triggers is a key component of improving control and preventing attacks. The most common triggers include allergens, smoke (from tobacco or other sources), air pollution, non selective beta-blockers, and sulfite-containing foods. Cigarette smoking and second-hand smoke (passive smoke) may reduce the effectiveness of medications such as corticosteroids. Laws that limit smoking decrease the number of people hospitalized for asthma. Dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others methods had no effect on asthma symptoms. There is insufficient evidence to suggest that dehumidifiers are helpful for controlling asthma.
Overall, exercise is beneficial in people with stable asthma. Yoga could provide small improvements in quality of life and symptoms in people with asthma. More research is necessary to determine how effective weight loss is on improving quality of life, the usage of health care services, and adverse effects for people of all ages with asthma.
Medications used to treat asthma are divided into two general classes: quick-relief medications used to treat acute symptoms; and long-term control medications used to prevent further exacerbation.Antibiotics are generally not needed for sudden worsening of symptoms or for treating asthma at any time.
Anticholinergic medications, such as ipratropium, provide additional benefit when used in combination with SABA in those with moderate or severe symptoms and may prevent hospitalizations. Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA. If a child requires admission to hospital additional ipratropium does not appear to help over a SABA. For children over 2 years old with acute asthma symptoms, inhaled anticholinergic medications taken alone is safe but is not as effective as inhaled SABA or SABA combined with inhaled anticholinergic medication. Adults who receive combined inhaled medications that includes short-acting anticholinergics and SABA may be at risk for increased adverse effects such as experiencing a tremor, agitation, and heart beat palpitations compared to people who are treated with SABA by itself.
Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy to SABAs. They are however not recommended due to concerns regarding excessive cardiac stimulation.
A short course of corticosteroids after an acute asthma exacerbation may help prevent relapses and reduce hospitalizations. For adults and children who are in the hospital due to acute asthma, systematic (IV) corticosteroids improve symptoms.
Corticosteroids are generally considered the most effective treatment available for long-term control. Inhaled forms such as beclomethasone are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. It is usually recommended that inhaled formulations be used once or twice daily, depending on the severity of symptoms.
Long-acting beta-adrenoceptor agonists (LABA) such as salmeterol and formoterol can improve asthma control, at least in adults, when given in combination with inhaled corticosteroids. In children this benefit is uncertain. When used without steroids they increase the risk of severe side-effects, and with corticosteroids they may slightly increase the risk. Evidence suggests that for children who have persistent asthma, a treatment regime that includes LABA added to inhaled corticosteroids may improve lung function but does not reduce the amount of serious exacerbations. Children who require LABA as part of their asthma treatment may need to go to the hospital more frequently.
Leukotriene receptor antagonists (anti-leukotriene agents such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA. Evidence is insufficient to support use in acute exacerbations. For adults or adolescents who have persistent asthma that is not controlled very well, the addition of anti-leukotriene agents along with daily inhaled corticosteriods improves lung function and reduces the risk of moderate and severe asthma exacerbations. Anti-leukotriene agents may be effective alone for adolescents and adults, however there is no clear research suggesting which people with asthma would benefit from anti-leukotriene receptor alone. In those under five years of age, anti-leukotriene agents were the preferred add-on therapy after inhaled corticosteroids by the British Thoracic Society in 2009. A 2013 Cochrane systematic review concluded that anti-leukotriene agents appear to be of little benefit when added to inhaled steroids for treating children. A similar class of drugs, 5-LOX inhibitors, may be used as an alternative in the chronic treatment of mild to moderate asthma among older children and adults. As of 2013 there is one medication in this family known as zileuton.
Intravenous administration of the drug aminophylline does not provide an improvement in bronchodilation when compared to standard inhaled beta-2 agonist treatment. Aminophylline treatment is associated with more adverse effects compared to inhaled beta-2 agonist treatment.
For children with asthma which is well-controlled on combination therapy of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA), the benefits and harms of stopping LABA and stepping down to ICS-only therapy are uncertain. In adults who have stable asthma while they are taking a combination of LABA and inhaled corticosteroids (ICS), stopping LABA may increase the risk of asthma exacerbations that require treatment with corticosteroids by mouth. Stopping LABA probably makes little or no important difference to asthma control or asthma-related quality of life. Whether or not stopping LABA increases the risk of serious adverse events or exacerbations requiring an emergency department visit or hospitalisation is uncertain.
Anticholinergic medications such as ipratropium bromide have not been shown to be beneficial for treating chronic asthma in children over 2 years old, but is not suggested for routine treatment of chronic asthma in adults.
There is no strong evidence to recommend chloroquine medication as a replacement for taking corticosteroids by mouth (for those who are not able to tolerate inhaled steroids). Methotrexate is not suggested as a replacement for taking corticosteriods by mouth ("steroid sparing") due to the adverse effects associated with taking methotrexate and the minimal relief provided for asthma symptoms.
Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthma spacer or as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, making it easier to receive a full dose of the drug. A nebulizer may also be used. Nebulizers and spacers are equally effective in those with mild to moderate symptoms. However, insufficient evidence is available to determine whether a difference exists in those with severe disease. For delivering short-acting beta-agonists in acute asthma in children, spacers may have advantages compared to nebulisers, but children with life-threatening asthma have not been studied. There is no strong evidence for the use of intravenous LABA for adults or children who have acute asthma. There is insufficient evidence to directly compare the effectiveness of a metered-dose inhaler attached to a homemade spacer compared to commercially available spacer for treating children with asthma.
Long-term use of inhaled corticosteroids at conventional doses carries a minor risk of adverse effects. Risks include thrush, the development of cataracts, and a slightly slowed rate of growth. Rising the mouth after the use of inhaled steroids can decrease the risk of thrush. Higher doses of inhaled steroids may result in lower bone mineral density.
Inflammation in the lungs can be estimated by the level of exhaled nitric oxide. The use of exhaled nitric oxide levels (FeNO) to guide asthma medication dosing may have small benefits for preventing asthma attacks but the potential benefits are not strong enough for this approach to be universally recommended as a method to guide asthma therapy in adults or children.
When asthma is unresponsive to usual medications, other options are available for both emergency management and prevention of flareups. Additional options include:
Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids.
Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults intravenous treatment results in a reduction of hospital admissions. Low levels of evidence suggest that inhaled (nebulised) magnesium sulfate may have a small benefit for treating acute asthma in adults. Overall, high quality evidence do not indicate a large benefit for combining magnesium sulfate with standard inhaled treatments for adults with asthma.
Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases.
Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.
Methylxanthines (such as theophylline) were once widely used, but do not add significantly to the effects of inhaled beta-agonists. Their use in acute exacerbations is controversial.
The dissociative anesthetic ketamine is theoretically useful if intubation and mechanical ventilation is needed in people who are approaching respiratory arrest; however, there is no evidence from clinical trials to support this.
For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs, bronchial thermoplasty may be an option. It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies. While it may increase exacerbation frequency in the first few months it appears to decrease the subsequent rate. Effects beyond one year are unknown.
Monoclonal antibody injections such as mepolizumab,dupilumab, or omalizumab may be useful in those with poorly controlled atopic asthma. However, as of 2019 these medications are expensive and their use is therefore reserved for those with severe symptoms to achieve cost-effectiveness. Monoclonal antibodies targeting interleukin-5 (IL-5) or its receptor (IL-5R), including mepolizumab, reslizumab or benralizumab, in addition to standard care in severe asthma is effective in reducing the rate of asthma exacerbations. There is limited evidence for improved health-related quality of life and lung function.
Many people with asthma, like those with other chronic disorders, use alternative treatments; surveys show that roughly 50% use some form of unconventional therapy. There is little data to support the effectiveness of most of these therapies.
Evidence is insufficient to support the usage of vitamin C or vitamin E for controlling asthma. There is tentative support for use of vitamin C in exercise induced bronchospasm.Fish oil dietary supplements (marine n-3 fatty acids) and reducing dietary sodium do not appear to help improve asthma control. In people with mild to moderate asthma, treatment with vitamin D supplementation may reduce the risk of asthma exacerbations, however, it is not clear if this is only helpful for people who have low vitamin D levels to begin with (low baseline vitamin D). There is no strong evidence to suggest that vitamin D supplements improve day-to-day asthma symptoms or a person's lung function. There is no strong evidence to suggest that adults with asthma should avoid foods that contain monosodium glutamate (MSG). There have not been enough high-quality studies performed to determine if children with asthma should avoid eating food that contains MSG.
Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use.Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators. Manual therapies, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma. The Buteyko breathing technique for controlling hyperventilation may result in a reduction in medication use; however, the technique does not have any effect on lung function. Thus an expert panel felt that evidence was insufficient to support its use. There is no clear evidence that breathing exercises are effective for treating children with asthma.
The prognosis for asthma is generally good, especially for children with mild disease. Mortality has decreased over the last few decades due to better recognition and improvement in care. In 2010 the death rate was 170 per million for males and 90 per million for females. Rates vary between countries by 100 fold.
Globally it causes moderate or severe disability in 19.4million people as of 2004 (16million of which are in low and middle income countries). Of asthma diagnosed during childhood, half of cases will no longer carry the diagnosis after a decade. Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes. Early treatment with corticosteroids seems to prevent or ameliorates a decline in lung function. Asthma in children also has negative effects on quality of life of their parents.
As of 2011, 235–330 million people worldwide are affected by asthma, and approximately 250,000–345,000 people die per year from the disease. Rates vary between countries with prevalences between 1 and 18%. It is more common in developed than developing countries. One thus sees lower rates in Asia, Eastern Europe and Africa. Within developed countries it is more common in those who are economically disadvantaged while in contrast in developing countries it is more common in the affluent. The reason for these differences is not well known. Low and middle income countries make up more than 80% of the mortality.
While asthma is twice as common in boys as girls, severe asthma occurs at equal rates. In contrast adult women have a higher rate of asthma than men and it is more common in the young than the old. In children, asthma was the most common reason for admission to the hospital following an emergency department visit in the US in 2011.
Global rates of asthma have increased significantly between the 1960s and 2008 with it being recognized as a major public health problem since the 1970s. Rates of asthma have plateaued in the developed world since the mid-1990s with recent increases primarily in the developing world. Asthma affects approximately 7% of the population of the United States and 5% of people in the United Kingdom. Canada, Australia and New Zealand have rates of about 14–15%.
The average death rate from 2011 to 2015 from asthma in the UK was about 50% higher than the average for the European Union and had increased by about 5% in that time. Child are more likely see a physician due to asthma symptoms after school starts in September.
From 2000 to 2010, the average cost per asthma-related hospital stay in the United States for children remained relatively stable at about $3,600, whereas the average cost per asthma-related hospital stay for adults increased from $5,200 to $6,600. In 2010, Medicaid was the most frequent primary payer among children and adults aged 18–44 years in the United States; private insurance was the second most frequent payer. Among both children and adults in the lowest income communities in the United States there is a higher rate of hospital stays for asthma in 2010 than those in the highest income communities.
Asthma was recognized in ancient Egypt and was treated by drinking an incense mixture known as kyphi. It was officially named as a specific respiratory problem by Hippocrates circa 450 BC, with the Greek word for "panting" forming the basis of our modern name. In 200 BC it was believed to be at least partly related to the emotions. In the 12th century the Jewish physician-philosopher Maimonides wrote a treatise on asthma in Arabic, based partly on Arabic sources, in which he discussed the symptoms, proposed various dietary and other means of treatment, and emphasized the importance of climate and clean air.
In 1873, one of the first papers in modern medicine on the subject tried to explain the pathophysiology of the disease while one in 1872, concluded that asthma can be cured by rubbing the chest with chloroform liniment.Medical treatment in 1880 included the use of intravenous doses of a drug called pilocarpine. In 1886, F. H. Bosworth theorized a connection between asthma and hay fever.Epinephrine was first referred to in the treatment of asthma in 1905. Oral corticosteroids began to be used for this condition in the 1950s while inhaled corticosteroids and selective short acting beta agonist came into wide use in the 1960s.
A notable and well-documented case in the 19th century was that of young Theodore Roosevelt (1858–1919). At that time there was no effective treatment. Roosevelt's youth was in large part shaped by his poor health partly related to his asthma. He experienced recurring nighttime asthma attacks that caused the experience of being smothered to death, terrifying the boy and his parents.
During the 1930s to 1950s, asthma was known as one of the "holy seven" psychosomatic illnesses. Its cause was considered to be psychological, with treatment often based on psychoanalysis and other talking cures. As these psychoanalysts interpreted the asthmatic wheeze as the suppressed cry of the child for its mother, they considered the treatment of depression to be especially important for individuals with asthma.
Related Research Articles
Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms. Common symptoms include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, headaches, a poor sense of smell, sore throat, and a cough. The cough is often worse at night. Serious complications are rare. It is defined as acute sinusitis if it lasts fewer than 4 weeks, and as chronic sinusitis if it lasts for more than 12 weeks.
Pneumonia is an inflammatory condition of the lung affecting primarily the small air sacs known as alveoli. Typically symptoms include some combination of productive or dry cough, chest pain, fever, and trouble breathing. Severity is variable.
The common cold, also known simply as a cold, is a viral infectious disease of the upper respiratory tract that primarily affects the nose. The throat, sinuses, and larynx may also be affected. Signs and symptoms may appear less than two days after exposure to the virus. These may include coughing, sore throat, runny nose, sneezing, headache, and fever. People usually recover in seven to ten days, but some symptoms may last up to three weeks. Occasionally those with other health problems may develop pneumonia.
A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.
Otitis media is a group of inflammatory diseases of the middle ear. The two main types are acute otitis media (AOM) and otitis media with effusion (OME). AOM is an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, increased crying, and poor sleep. Decreased eating and a fever may also be present. OME is typically not associated with symptoms. Occasionally a feeling of fullness is described. It is defined as the presence of non-infectious fluid in the middle ear for more than three months. Chronic suppurative otitis media (CSOM) is middle ear inflammation that results in discharge from the ear for more than three months. It may be a complication of acute otitis media. Pain is rarely present. All three types of otitis media may be associated with hearing loss. The hearing loss in OME, due to its chronic nature, may affect a child's ability to learn.
Cold medicines are medications used by people with the common cold, cough, or related conditions. There is, however, no good evidence that cough medications reduce coughing.
Acute bronchitis, also known as a chest cold, is short-term bronchitis – inflammation of the bronchi of the lungs. The most common symptom is a cough. Other symptoms include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. The infection may last from a few to ten days. The cough may persist for several weeks afterward with the total duration of symptoms usually around three weeks. Some have symptoms for up to six weeks.
Sore throat, also known as throat pain, is pain or irritation of the throat. It is usually caused by pharyngitis or tonsillitis. It can also result from trauma.
Bronchiolitis is blockage of the small airways in the lungs due to a viral infection. It usually only occurs in children less than two years of age. Symptoms may include fever, cough, runny nose, wheezing, and breathing problems. More severe cases may be associated with nasal flaring, grunting, or the skin between the ribs pulling in with breathing. If the child has not been able to feed properly, signs of dehydration may be present.
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland or organ function depending on which nerves are affected; in other words, neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.
An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, or larynx. This commonly includes nasal obstruction, sore throat, tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold. Most infections are viral in nature, and in other instances, the cause is bacterial. URTIs can also be fungal or helminthic in origin, but these are less common.
Lower respiratory tract infection (LRTI) is a term often used as a synonym for pneumonia, but can also be applied to other types of infection including lung abscess and acute bronchitis. Symptoms include shortness of breath, weakness, fever, coughing and fatigue. A routine chest x-ray is not always necessary for people who have symptoms of a lower respiratory tract infection.
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.
Long-acting β adrenoceptor agonists are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β2 agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β2 agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to continuously bind and unbind at β2 receptors in the smooth muscle in the lungs.
Bronchitis is inflammation of the bronchi in the lungs that causes coughing. Symptoms include coughing up sputum, wheezing, shortness of breath, and chest pain. Bronchitis can be acute or chronic.
Alternative treatments used for the common cold include numerous home remedies and alternative medicines. Scientific research regarding the efficacy of each treatment is generally nonexistent or inconclusive. Current best evidence indicates prevention, including hand washing and neatness, and management of symptoms.
An acute exacerbation of chronic obstructive pulmonary disease (COPD), is a sudden worsening of COPD symptoms including that typically lasts for several days. It may be triggered by an infection with bacteria or viruses or by environmental pollutants. Typically, infections cause 75% or more of the exacerbations; bacteria can roughly be found in 25% of cases, viruses in another 25%, and both viruses and bacteria in another 25%. Airway inflammation is increased during the exacerbation resulting in increased hyperinflation, reduced expiratory air flow and decreased gas exchange.
Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long-term breathing problems and poor airflow. The main symptoms include shortness of breath and cough with sputum production. COPD is a progressive disease, meaning it typically worsens over time. Eventually, everyday activities such as walking or getting dressed become difficult. Chronic bronchitis and emphysema are older terms used for different types of COPD. The term "chronic bronchitis" is still used to define a productive cough that is present for at least three months each year for two years. Those with such a cough are at a greater risk of developing COPD. The term "emphysema" is also used for the abnormal presence of air or other gas within tissues.
Fluticasone furoate/vilanterol (FF/VI), sold under the trade names Breo Ellipta among others, is a combination medication for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. It contains fluticasone furoate, an inhaled corticosteroid, and vilanterol, an ultra-long-acting β2 agonist (ultra-LABA).
Chronic cough is long-term coughing, sometimes defined as more than several weeks or months. The term can be used to describe the different causes related to coughing, the 3 main ones being; upper airway cough syndrome, asthma and gastroesophageal reflux disease. It occurs in the upper airway of the respiratory system. Generally, a cough lasts around 1–2 weeks, however, chronic cough can persist for an extended period of time defined as 6 weeks or longer. People with chronic cough often experience more than one cause present. Due to the nature of the syndrome the treatments that are used are similar however there is a subsequent number of treatments available.
1 2 Manniche L. (1999). Sacred luxuries: fragrance, aromatherapy, and cosmetics in ancient Egypt. Cornell University Press. pp.49. ISBN978-0-8014-3720-5.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Murray, John F. (2010). "Ch. 38 Asthma". In Mason, Robert J.; Murray, John F.; Broaddus, V. Courtney; Nadel, Jay A.; Martin, Thomas R.; King, Jr., Talmadge E.; Schraufnagel, Dean E. (eds.). Murray and Nadel's textbook of respiratory medicine (5th ed.). Elsevier. ISBN978-1-4160-4710-0.
↑ Tan DJ, Walters EH, Perret JL, Lodge CJ, Lowe AJ, Matheson MC, Dharmage SC (February 2015). "Age-of-asthma onset as a determinant of different asthma phenotypes in adults: a systematic review and meta-analysis of the literature". Expert Review of Respiratory Medicine. 9 (1): 109–23. doi:10.1586/17476348.2015.1000311. PMID25584929.
↑ Brooks, Nancy; Sethi, Rajiv (February 1997). "The Distribution of Pollution: Community Characteristics and Exposure to Air Toxics". Journal of Environmental Economics and Management. 32 (2): 233–50. doi:10.1006/jeem.1996.0967.
↑ Mamane A, Baldi I, Tessier JF, Raherison C, Bouvier G (June 2015). "Occupational exposure to pesticides and respiratory health". European Respiratory Review. 24 (136): 306–19. doi:10.1183/16000617.00006014. PMID26028642.
↑ Mamane A, Raherison C, Tessier JF, Baldi I, Bouvier G (September 2015). "Environmental exposure to pesticides and respiratory health". European Respiratory Review. 24 (137): 462–73. doi:10.1183/16000617.00006114. PMID26324808.
↑ Cheelo M, Lodge CJ, Dharmage SC, Simpson JA, Matheson M, Heinrich J, Lowe AJ (January 2015). "Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis". Archives of Disease in Childhood. 100 (1): 81–9. doi:10.1136/archdischild-2012-303043. PMID25429049.
↑ Eyers S, Weatherall M, Jefferies S, Beasley R (April 2011). "Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis". Clinical and Experimental Allergy. 41 (4): 482–9. doi:10.1111/j.1365-2222.2010.03691.x. PMID21338428.
↑ van de Loo KF, van Gelder MM, Roukema J, Roeleveld N, Merkus PJ, Verhaak CM (January 2016). "Prenatal maternal psychological stress and childhood asthma and wheezing: a meta-analysis". The European Respiratory Journal. 47 (1): 133–46. doi:10.1183/13993003.00299-2015. PMID26541526.
↑ Custovic A, Simpson A (2012). "The role of inhalant allergens in allergic airways disease". Journal of Investigational Allergology & Clinical Immunology. 22 (6): 393–401, qiuz follow 401. PMID23101182.
↑ Calderón MA, Linneberg A, Kleine-Tebbe J, De Blay F, Hernandez Fernandez de Rojas D, Virchow JC, Demoly P (July 2015). "Respiratory allergy caused by house dust mites: What do we really know?". The Journal of Allergy and Clinical Immunology. 136 (1): 38–48. doi:10.1016/j.jaci.2014.10.012. PMID25457152.
↑ Lai T, Wu M, Liu J, Luo M, He L, Wang X, et al. (February 2018). "Acid-Suppressive Drug Use During Pregnancy and the Risk of Childhood Asthma: A Meta-analysis". Pediatrics. 141 (2): e20170889. doi:10.1542/peds.2017-0889. PMID29326337.
↑ Sharpe RA, Bearman N, Thornton CR, Husk K, Osborne NJ (January 2015). "Indoor fungal diversity and asthma: a meta-analysis and systematic review of risk factors". The Journal of Allergy and Clinical Immunology. 135 (1): 110–22. doi:10.1016/j.jaci.2014.07.002. PMID25159468.
1 2 Self, Timothy; Chrisman, Cary; Finch, Christopher (2009). "22. Asthma". In Mary Anne Koda-Kimble, Brian K. Alldredge; et al. (eds.). Applied therapeutics: the clinical use of drugs (9th ed.). Philadelphia: Lippincott Williams & Wilkins. OCLC230848069.
↑ Barnes, P. J. (2008). "Asthma". In Fauci, Anthony S.; Braunwald, E.; Kasper, D. L. (eds.). Harrison's Principles of Internal Medicine (17th ed.). New York: McGraw-Hill. pp.1596–607. ISBN978-0-07-146633-2.
↑ Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, et al. (May 2008). European Respiratory, Society; European Academy of Allergy and Clinical, Immunology; GA(2)LEN. "Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN". Allergy. 63 (5): 492–505. doi:10.1111/j.1398-9995.2008.01663.x. PMID18394123.
1 2 3 Baur X, Aasen TB, Burge PS, Heederik D, Henneberger PK, Maestrelli P, et al. (June 2012). ERS Task Force on the Management of Work-related, Asthma. "The management of work-related asthma guidelines: a broader perspective". European Respiratory Review. 21 (124): 125–39. doi:10.1183/09059180.00004711. PMID22654084.
↑ Frew AJ (2008). "Chapter 42: Occupational Asthma". In Castro M, Kraft M (eds.). Clinical Asthma. Philadelphia: Mosby / Elsevier. ISBN978-0-323-07081-2.
↑ Chang JE, White A, Simon RA, Stevenson DD (2012). "Aspirin-exacerbated respiratory disease: burden of disease". Allergy and Asthma Proceedings. 33 (2): 117–21. doi:10.2500/aap.2012.33.3541. PMID22525387.
↑ Chen CM, Tischer C, Schnappinger M, Heinrich J (January 2010). "The role of cats and dogs in asthma and allergy—a systematic review". International Journal of Hygiene and Environmental Health. 213 (1): 1–31. doi:10.1016/j.ijheh.2009.12.003. PMID20053584.
1 2 Prescott SL, Tang ML (May 2005). Australasian Society of Clinical Immunology and, Allergy. "The Australasian Society of Clinical Immunology and Allergy position statement: Summary of allergy prevention in children". The Medical Journal of Australia. 182 (9): 464–7. doi:10.5694/j.1326-5377.2005.tb06787.x. PMID15865590.
↑ "Strategic Advisory Group of Experts on Immunization - report of the extraordinary meeting on the influenza A (H1N1) 2009 pandemic, 7 July 2009". Releve Epidemiologique Hebdomadaire. 84 (30): 301–4. July 2009. PMID19630186.
↑ Gibson, P. G.; Powell, H.; Coughlan, J.; Wilson, A. J.; Abramson, M.; Haywood, P.; Bauman, A.; Hensley, M. J.; Walters, E. H. (2003). "Self-management education and regular practitioner review for adults with asthma". The Cochrane Database of Systematic Reviews (1): CD001117. doi:10.1002/14651858.CD001117. ISSN1469-493X. PMID12535399.
↑ Welsh EJ, Carr R (September 2015). Cochrane Airways Group (ed.). "Pulse oximeters to self monitor oxygen saturation levels as part of a personalised asthma action plan for people with asthma". The Cochrane Database of Systematic Reviews (9): CD011584. doi:10.1002/14651858.CD011584.pub2. PMID26410043.
↑ Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, et al. (May 2013). "An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction". American Journal of Respiratory and Critical Care Medicine. 187 (9): 1016–27. doi:10.1164/rccm.201303-0437ST. PMID23634861.
1 2 Griffiths B, Ducharme FM (August 2013). "Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children". The Cochrane Database of Systematic Reviews (8): CD000060. doi:10.1002/14651858.CD000060.pub2. PMID23966133.
↑ Vézina K, Chauhan BF, Ducharme FM (July 2014). "Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital". The Cochrane Database of Systematic Reviews. 7 (7): CD010283. doi:10.1002/14651858.CD010283.pub2. PMID25080126.
↑ Rodrigo GJ, Nannini LJ (March 2006). "Comparison between nebulized adrenaline and beta2 agonists for the treatment of acute asthma. A meta-analysis of randomized trials". The American Journal of Emergency Medicine. 24 (2): 217–22. doi:10.1016/j.ajem.2005.10.008. PMID16490653.
↑ Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW (July 2007). "Corticosteroids for preventing relapse following acute exacerbations of asthma". The Cochrane Database of Systematic Reviews (3): CD000195. doi:10.1002/14651858.CD000195.pub2. PMID17636617.
↑ Smith M, Iqbal S, Elliott TM, Everard M, Rowe BH (2003). "Corticosteroids for hospitalised children with acute asthma". The Cochrane Database of Systematic Reviews (2): CD002886. doi:10.1002/14651858.CD002886. PMID12804441.
↑ Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW (2001). "Early emergency department treatment of acute asthma with systemic corticosteroids". The Cochrane Database of Systematic Reviews (1): CD002178. doi:10.1002/14651858.CD002178. PMID11279756.
↑ Ducharme F, Schwartz Z, Hicks G, Kakuma R (2004). "Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma". The Cochrane Database of Systematic Reviews (2): CD003133. doi:10.1002/14651858.CD003133.pub2. PMID15106191.
↑ Watts K, Chavasse RJ (May 2012). Watts K (ed.). "Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and children". The Cochrane Database of Systematic Reviews. 5 (5): CD006100. doi:10.1002/14651858.CD006100.pub2. PMID22592708.
↑ "Zyflo (Zileuton tablets)"(PDF). United States Food and Drug Administration. Cornerstone Therapeutics Inc. June 2012. p.1. Archived(PDF) from the original on 13 December 2014. Retrieved 12 December 2014.
1 2 Nair P, Milan SJ, Rowe BH (December 2012). "Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma". The Cochrane Database of Systematic Reviews. 12: CD002742. doi:10.1002/14651858.CD002742.pub2. PMID23235591.
↑ McDonald NJ, Bara AI (2003). "Anticholinergic therapy for chronic asthma in children over two years of age". The Cochrane Database of Systematic Reviews (3): CD003535. doi:10.1002/14651858.CD003535. PMID12917970.
↑ Dean T, Dewey A, Bara A, Lasserson TJ, Walters EH (2003). "Chloroquine as a steroid sparing agent for asthma". The Cochrane Database of Systematic Reviews (4): CD003275. doi:10.1002/14651858.CD003275. PMID14583965.
↑ Cates CJ, Welsh EJ, Rowe BH (September 2013). Cochrane Airways Group (ed.). "Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma". The Cochrane Database of Systematic Reviews (9): CD000052. doi:10.1002/14651858.CD000052.pub3. PMID24037768.
↑ Travers AH, Milan SJ, Jones AP, Camargo CA, Rowe BH (December 2012). "Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma". The Cochrane Database of Systematic Reviews. 12: CD010179. doi:10.1002/14651858.CD010179. PMID23235685.
1 2 Castro M, Musani AI, Mayse ML, Shargill NS (April 2010). "Bronchial thermoplasty: a novel technique in the treatment of severe asthma". Therapeutic Advances in Respiratory Disease. 4 (2): 101–16. doi:10.1177/1753465810367505. PMID20435668.
↑ Sastre J, Dávila I (June 2018). "Dupilumab: A New Paradigm for the Treatment of Allergic Diseases". Journal of Investigational Allergology & Clinical Immunology. 28 (3): 139–150. doi:10.18176/jiaci.0254. PMID29939132.
↑ Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, et al. (March 2013). "Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review". JAMA. 309 (12): 1278–88. doi:10.1001/jama.2013.2049. PMID23532243.
↑ Blanc PD, Trupin L, Earnest G, Katz PP, Yelin EH, Eisner MD (November 2001). "Alternative therapies among adults with a reported diagnosis of asthma or rhinosinusitis: data from a population-based survey". Chest. 120 (5): 1461–7. doi:10.1378/chest.120.5.1461. PMID11713120.
↑ Sergel, Michelle J.; Cydulka, Rita K. (September 2009). "Ch. 75: Asthma". In Wolfson, Allan B.; Harwood-Nuss, Ann (eds.). Harwood-Nuss' Clinical Practice of Emergency Medicine (5th ed.). Lippincott Williams & Wilkins. pp.432–. ISBN978-0-7817-8943-1.
↑ Silva N, Carona C, Crespo C, Canavarro MC (June 2015). "Quality of life in pediatric asthma patients and their parents: a meta-analysis on 20 years of research". Expert Review of Pharmacoeconomics & Outcomes Research. 15 (3): 499–519. doi:10.1586/14737167.2015.1008459. hdl:10316/45410. PMID25651982.
↑ Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. (December 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. hdl:10536/DRO/DU:30050819. PMID23245604.