Asthma
is a common long-term inflammatory disease of the airways of the lungs.[3] It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms.[10][11] Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath.[2] These may occur a few times a day or a few times per week.[3] Depending on the person, asthma symptoms may become worse at night or with exercise.[3]
Asthma is thought to be caused by a combination of genetic and environmental factors.[4] Environmental factors include exposure to air pollution and allergens.[3] Other potential triggers include medications such as aspirin and beta blockers.[3] Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry lung function testing.[5] Asthma is classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate.[12] It may also be classified as atopic or non-atopic, where atopy refers to a predisposition toward developing a type 1 hypersensitivity reaction.[13][14]
There is no cure for asthma.[3] Symptoms can be prevented by avoiding triggers, such as allergens and irritants, and by the use of inhaled corticosteroids.[6][15] Long-acting beta agonists (LABA) or antileukotriene agents may be used in addition to inhaled corticosteroids if asthma symptoms remain uncontrolled.[16][17] Treatment of rapidly worsening symptoms is usually with an inhaled short-acting beta-2 agonist such as salbutamol and corticosteroids taken by mouth.[7] In very severe cases, intravenous corticosteroids, magnesium sulfate, and hospitalization may be required.[18]
In 2015, 358 million people globally had asthma, up from 183 million in 1990.[8][19] It caused about 397,100 deaths in 2015,[9] most of which occurred in the developing world.[3] Asthma often begins in childhood,[3] and the rates have increased significantly since the 1960s.[20] Asthma was recognized as early as Ancient Egypt.[21] 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.[23] Sputum may be produced from the lung by coughing but is often hard to bring up.[24] During recovery from an asthma attack (exacerbation), it may appear pus-like due to high levels of white blood cells called eosinophils.[25] Symptoms are usually worse at night and in the early morning or in response to exercise or cold air.[26] Some people with asthma rarely experience symptoms, usually in response to triggers, whereas others may react frequently and readily and experience persistent symptoms.[27]
Associated conditions
A number of other health conditions occur more frequently in people with asthma, including gastro-esophageal reflux disease (GERD), rhinosinusitis, and obstructive sleep apnea.[28] Psychological disorders are also more common,[29] with anxiety disorders occurring in between 16–52% and mood disorders in 14–41%.[30] It is not known whether asthma causes psychological problems or psychological problems lead to asthma.[31] Those with asthma, especially if it is poorly controlled, are at increased risk for radiocontrast reactions.[32]
Cavities occur more often in people with asthma.[33] This may be related to the effect of beta 2 agonists decreasing saliva.[34] These medications may also increase the risk of dental erosions.[34]
Causes
Asthma is caused by a combination of complex and incompletely understood environmental and genetic interactions.[4][35] These influence both its severity and its responsiveness to treatment.[36] 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.[37] 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.[38]
Environmental
Many environmental factors have been associated with asthma's development and exacerbation, including, allergens, air pollution, and other environmental chemicals.[39] Smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms.[40] Low air quality from environmental factors such as traffic pollution or high ozone levels[41] has been associated with both asthma development and increased asthma severity.[42] Over half of cases in children in the United States occur in areas when air quality is below the EPA standards.[43] Low air quality is more common in low-income and minority communities.[44]
Exposure to indoor volatile organic compounds may be a trigger for asthma; formaldehyde exposure, for example, has a positive association.[45] Phthalates in certain types of PVC are associated with asthma in both children and adults.[46][47] While exposure to pesticides is linked to the development of asthma, a cause and effect relationship has yet to be established.[48][49]
The majority of the evidence does not support a causal role between acetaminophen (paracetamol) or antibiotic use and asthma.[50][51] A 2014 systematic review found that the association between acetaminophen use and asthma disappeared when respiratory infections were taken into account.[52] Acetaminophen use by a mother during pregnancy is also associated with an increased risk of the child developing asthma.[53] Maternal psychological stress during pregnancy is a risk factor for the child to develop asthma.[54]
Asthma is associated with exposure to indoor allergens.[55] Common indoor allergens include dust mites, cockroaches, animal dander (fragments of fur or feathers), and mold.[56][57] Efforts to decrease dust mites have been found to be ineffective on symptoms in sensitized subjects.[58][59] Weak evidence suggests that efforts to decrease mold by repairing buildings may help improve asthma symptoms in adults.[60] Certain viral respiratory infections, such as respiratory syncytial virus and rhinovirus,[22] may increase the risk of developing asthma when acquired as young children.[61] Certain other infections, however, may decrease the risk.[22]
Hygiene hypothesis
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.[62][63] 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.[64] Exposure to bacterial endotoxin in early childhood may prevent the development of asthma, but exposure at an older age may provoke bronchoconstriction.[65] Evidence supporting the hygiene hypothesis includes lower rates of asthma on farms and in households with pets.[64]
Use of antibiotics in early life has been linked to the development of asthma.[66] 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.[67][68] 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.[69]
Genetic
Family history is a risk factor for asthma, with many different genes being implicated.[71] If one identical twin is affected, the probability of the other having the disease is approximately 25%.[71] 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.[72] 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.[72] In 2006 over 100 genes were associated with asthma in one genetic association study alone;[72] more continue to be found.[73]
Some genetic variants may only cause asthma when they are combined with specific environmental exposures.[4] 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.[70]
Medical conditions
A triad of atopic eczema, allergic rhinitis and asthma is called atopy.[74] The strongest risk factor for developing asthma is a history of atopic disease;[61] with asthma occurring at a much greater rate in those who have either eczema or hay fever.[75] Asthma has been associated with eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome), an autoimmune disease and vasculitis.[76] Individuals with certain types of urticaria may also experience symptoms of asthma.[74]
There is a correlation between obesity and the risk of asthma with both having increased in recent years.[77][78] 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.[79]
Beta blocker medications such as propranolol can trigger asthma in those who are susceptible.[80] Cardioselective beta-blockers, however, appear safe in those with mild or moderate disease.[81][82] Other medications that can cause problems in asthmatics are angiotensin-converting enzyme inhibitors, aspirin, and NSAIDs.[83] Use of acid suppressing medication (proton pump inhibitors and H2 blockers) during pregnancy is associated with an increased risk of asthma in the child.[84]
Exacerbation
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.[85] Most individuals can develop severe exacerbation from a number of triggering agents.[85]
Home factors that can lead to exacerbation of asthma include dust, animal dander (especially cat and dog hair), cockroach allergens and mold.[85][86] 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.[85] 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.[42][87]
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.[88]
Pathophysiology
Asthma is the result of chronic inflammation of the conducting zone of the airways (most especially the bronchi and bronchioles), which subsequently results in increased contractability of the surrounding smooth muscles. This among other factors leads to bouts of narrowing of the airway and the classic symptoms of wheezing. The narrowing is typically reversible with or without treatment. Occasionally the airways themselves change.[23] Typical changes in the airways include an increase in eosinophils and thickening of the lamina reticularis. Chronically the airways' smooth muscle may increase in size along with an increase in the numbers of mucous glands. Other cell types involved include: T lymphocytes, macrophages, and neutrophils. There may also be involvement of other components of the immune system including: cytokines, chemokines, histamine, and leukotrienes among others.
Diagnosis
While asthma is a well-recognized condition, there is not one universal agreed upon definition.[22] 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".[23]
There is currently no precise test for the diagnosis, which is typically based on the pattern of symptoms and response to therapy over time.[5][22] 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.[89] Spirometry is then used to confirm the diagnosis.[89] In children under the age of six the diagnosis is more difficult as they are too young for spirometry.[90]
Spirometry
Spirometry is recommended to aid in diagnosis and management.[91][92] 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.[22] As caffeine is a bronchodilator in people with asthma, the use of caffeine before a lung function test may interfere with the results.[93] Single-breath diffusing capacity can help differentiate asthma from COPD.[22] It is reasonable to perform spirometry every one or two years to follow how well a person's asthma is controlled.[94]
Others
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.[22]
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.[95] 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.[96]
Classification
Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate.[12] 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).[13] While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system.[97] Finding ways to identify subgroups that respond well to different types of treatments is a current critical goal of asthma research.[97]
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.[98] 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.[99] In contrast to emphysema, asthma affects the bronchi, not the alveoli.[100]
Asthma exacerbation
An acute asthma exacerbation is commonly referred to as an asthma attack. The classic symptoms are shortness of breath, wheezing, and chest tightness.[22] The wheezing is most often when breathing out.[102] While these are the primary symptoms of asthma,[103] some people present primarily with coughing, and in severe cases, air motion may be significantly impaired such that no wheezing is heard.[101] In children, chest pain is often present.[104]
Signs occurring during an asthma attack include the use of accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck), there may be a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest.[105] A blue color of the skin and nails may occur from lack of oxygen.[106]
In a mild exacerbation the peak expiratory flow rate (PEFR) is ≥200 L/min, or ≥50% of the predicted best.[107] Moderate is defined as between 80 and 200 L/min, or 25% and 50% of the predicted best, while severe is defined as ≤ 80 L/min, or ≤25% of the predicted best.[107]
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.[108] Half of cases are due to infections with others caused by allergen, air pollution, or insufficient or inappropriate medication use.[108]
Brittle asthma is a kind of asthma distinguishable by recurrent, severe attacks.[101] 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.[101]
Exercise-induced
Exercise can trigger bronchoconstriction both in people with or without asthma.[109] It occurs in most people with asthma and up to 20% of people without asthma.[109] Exercise-induced bronchoconstriction is common in professional athletes. The highest rates are among cyclists (up to 45%), swimmers, and cross-country skiers.[110] While it may occur with any weather conditions, it is more common when it is dry and cold.[111] Inhaled beta2-agonists do not appear to improve athletic performance among those without asthma,[112] however, oral doses may improve endurance and strength.[113][114]
Occupational
Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupational disease.[115] Many cases, however, are not reported or recognized as such.[116][117] 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.[115]
Aspirin-induced asthma
Aspirin-exacerbated respiratory disease (AERD), also known as aspirin-induced asthma, affects up to 9% of asthmatics.[118] AERD consists of asthma, nasal polyps, sinus disease, and respiratory reactions to aspirin and other NSAID medications (such as ibuprofen and naproxen).[119] People often also develop loss of smell and most experience respiratory reactions to alcohol.[120]
Alcohol-induced asthma
Alcohol may worsen asthmatic symptoms in up to a third of people.[121] This may be even more common in some ethnic groups such as the Japanese and those with aspirin-induced asthma.[121] Other studies have found improvement in asthmatic symptoms from alcohol.[121]
Non-atopic asthma
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.[122]
Differential diagnosis
Many other conditions can cause symptoms similar to those of asthma. In children, other upper airway diseases such as allergic rhinitis and sinusitis should be considered as well as other causes of airway obstruction including foreign body aspiration, tracheal stenosis, laryngotracheomalacia, vascular rings, enlarged lymph nodes or neck masses.[123] Bronchiolitis and other viral infections may also produce wheezing.[124] In adults, COPD, congestive heart failure, airway masses, as well as drug-induced coughing due to ACE inhibitors should be considered. In both populations vocal cord dysfunction may present similarly.[123]
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.[125] 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
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