User:IntentionallyDense/Asthma

Due to the diversity in onset, symptoms, outcomes, and response to treatment, asthma is often considered a syndrome — a collection of signs and symptoms — rather than one single condition.^{[1] [2]} Historically asthma was classified as caused by external factors such as allergens (extrinsic) or by internal factors, unrelated to allergies (intrinsic).^[2] Currently asthma is most commonly classified according to severity, control of symptoms, phenotypes and endotypes.^{[2] [3]}

Asthma and chronic obstructive pulmonary disease (COPD) cause airway restriction and have a wide range of overlapping mechanisms and symptoms. The main difference between the two disorders is that in asthma expiratory airflow fluctuates over time while in COPD airflow obstruction is chronic and can increase in severity over time.^{[4] : 131–133}

Asthma severity is determined on the basis of how much medication is required to control symptoms and exacerbations while asthma control is the burden of asthma on an individual such as symptoms and inflammation.^{[4] : 35 [3]} Classification of asthma control does not depend on medication usage like severity does, however they often assess similar factors.^[3]

Asthma control is assessed on the basis of how well the symptoms are being control and the risk of any future consequences of the disorder.^{[4] : 36} The frequency and severity of symptoms, impairment caused by symptoms, use of rescue inhalers, questionnaires, healthcare usage, and objective tests such as spirometry, FeNO, sputum eosinophils, and hyperresponsiveness studies are used to evaluate asthma control.^[3]

Asthma severity is is measured based on how difficult the disorder is to treat. Severity can only be measured once the disorder is under control. Those with mild asthma may only require as needed medication to treat the disease while those with severe asthma require high doses of medication to gain control over the disorder or may be unable to get their symptoms under control even with medications.^{[4] : 44}

A phenotype is the way in which a condition presents itself, such as when the disease first starts to affect a person and what symptoms an individual displays. An endotype is the mechanisms that underlie the condition.^[5] Asthma is most commonly divided into two endotypes, T2-high and T2-low (non-T2). Within the two main endotypes there are subpopulations (phenotypes), some of which overlap or can be categorized under both of the two endotypes.^[1]

The two endotypes are distinguished based on the type of inflammation present with the type-2 high endotype involving the type 2 immune system response and type-2 low involving type 1 immune system response. Type-2 high is characterized by increased eosinophils, increased Fractional exhaled nitric oxide (FeNO), or allergens. Type-2 low asthma is the absence of these inflammatory markers and the mechanisms are not well researched. The phenotypes included under the type-2 high endotype include early-onset allergic asthma, late-onset eosinophilic asthma, and Aspirin-exacerbated respiratory disease. Type-2 low asthma phenotypes include asthma associated with obesity, neutrophilic asthma, asthma associated with cigarette smoke, and paucigranulocytic asthma.^[5] Occupational asthma can be further split into separate phenotypes, irritant-induced asthma — caused by exposure to airway irritants such as cleaning products and dust — and sensitizer-induced occupational asthma — developed hypersensitivity. Irritant-induced asthma is a type-2 low phenotype while sensitizer-induced occupational asthma is a type-2 high phenotype.^{[1] [5]} Asthma-COPD overlap (ACO) currently lacks a consistent definition making it hard to categorize it into either endotype.^[1]

Asthma is caused by a mixture of genetic and external factors. The disease manifests when those with a genetic susceptibility to asthma are exposed to specific environmental factors.^[6] Environmental factors can also trigger asthma symptoms.^[7]

Factors during pregnancy that have been linked to the development of asthma include weight gain or obesity in the mother, stressful pregnancy, smoking while pregnant, the use of certain medications while pregnant and caesarean section. Early childhood exposure to secondhand smoke, high levels of stress in parents, respiratory infections, and indoor mold or fungi have also been associated with asthma development.^[8]

Respiratory tract infections, especially during early childhood or if they are severe and recurring can lead to decreased lung function and subsequent asthma.^{[7] [9]} Conversely, there has been research suggesting that certain infections during childhood may lessen the risk of developing asthma. This theory is known as the "hygiene hypothesis".^[7]

Prenatal or childhood exposure to cigarette smoke increases the likelihood of a child developing asthma. Children whose maternal grandmother smoked during pregnancy are also more likely to develop asthma, regardless of if their mothers developed asthma or smoked. Nicotine is believed to be the cause of these effects and nicotine is linked to changes in DNA.^[9]

Chronic exposure to air pollution increases the risk of developing asthma. Outdoor air pollution includes nitrogen dioxide and traffic pollution while indoor air pollution includes biomass, pesticides, building materials such as asbestos and formaldehyde, mold, dust mites, cockroaches, and endotoxins.^{[9] [7]}

Asthma is more commonly seen in urban environments than in rural environments. This is believed to be due to the higher presence of certain risk factors for asthma such as traffic pollution, secondhand smoke, social inequality, and industrialization in urban settings as well as protective factors such as less air pollution, exposure to allergens and bacteria and higher levels of physical activity associated with rural environments.^[8]

In those who are affected by allergies, exposure to allergens can trigger asthma symptoms. ^[9] However, some research has suggested that early exposure to allergens in childhood may help desensitize individuals from allergies. Other studies have shown that early exposure may increase risk of allergies and the development of allergies is multifactorial. Allergens also play a role in the development of adult-onset asthma.^[8]

Adult-onset asthma is caused by relations between genetics, lifestyle factors such as obesity and smoking, and environmental factors such as an urban or rural environment, occupational exposures, and air pollution.^[8] Unlike childhood asthma, which is more prevalent in males, in adults asthma is more prevalent in females.^[7] Over 400 occupational exposure have been linked to asthma. Exposure to asthmagens, allergens and substances that are known to cause asthma; the amount and length of time that an individual was exposed to the substance; genetics; allergies; and smoking can affect the development of occupational asthma.^[9]

The mechanisms underlying asthma and asthma symptoms include spasms in the bronchial muscles, inflammation in the airways, hypersensitive airways, and excessive secretion of mucus in the airways.^[10] Asthma mainly affects medium-sized airways, however small or large airways may also be affected as the condition progresses. Airway inflammation is consistent across everyone with asthma, regardless of symptoms.^[7] The cells involved in the inflammation seen in asthma include eosinophils, neutrophils, CD4 T lymphocytes, mast cells, basophils, macrophages, respiratory epithelium, endothelial, and smooth muscle cells.^{[7] [10]} Airway inflammation leads to structural changes in the airways, including thickening of the airway smooth muscle and the tissue beneath the lining. There is increased tissue and matrix buildup in the airway wall, along with more small blood vessels and nerve fibers. The glands that produce mucus also increase in size.^{[7] [11]}

In asthma, the airways contract more than what is normal in response to both internal and external triggers. This hyperresponsiveness alongside inflammation affects the nerves in the airways — making them more sensitive — and causes the body to produce too much mucus. ^[7] Contraction of airway smooth muscle, swelling (edema), thickening of the airway wall due to remodelling, increased mucus production, and mucus plugs contribute to narrowing of the airways. Airway hyperresponsiveness is excessive narrowing of the airways in response to stimuli that are normally harmless. This narrowing leads to variable airflow restriction and asthma symptoms. Airway hyperresponsiveness is somewhat reversible with treatment.^{[7] [11] [10]}

Diagnostic guidelines for asthma vary in regards to what testing should be done to confirm the diagnosis, when to test, and what criteria should be used for the diagnosis.^{[12] [13]} The diagnosis cannot be made based on a single test and is instead made based on a combination of symptoms and respiratory function testing.^{[12] [4] : 22} Asthma guidelines advise using objective tests to confirm asthma in people with suggestive symptoms. Respiratory tests such as spirometry, bronchodilator reversibility (BDR) testing, and measuring changes in breathing flow over time (peak flow variability) are included in all major asthma guidelines.^[13]

Symptoms of wheezing, shortness of breath, chest tightness, and coughing that fluctuate according to time of day and exposure to triggers are characteristic of asthma. Personal or family history of allergic conditions can also help identify people with asthma. Asthma rarely presents with physical findings on examination unless the person is symptomatic.^{[14] : 8 [15]} If someone is medically unwell or displays a high amount of symptoms before the diagnosis is confirmed, medical guidelines recommend treating the person before performing respiratory testing.^{[14] : 9}

Global Initiative for Asthma (GINA) guidelines for children above five years of age and adults suggest confirming variable expiratory airflow in those who have symptoms suggestive of asthma. Variable expiratory airflow in asthma refers to fluctuations in lung function over time. ^{[4] : 25–27} Variation in lung function can be shown by spirometry testing, peak expiratory flow, or bronchial provocation testing. ^{[4] : 25}

The most accurate measurement of lung function is spirometry, which tests how much air a person can forcefully breathe out in one second (FEV1), FEV1 is then compared to the total amount of air exhaled after taking a deep breath (FEV1/FVC ratio). When testing for asthma, spirometry is performed twice; the first measurements are taken when the patient is not using any asthma medication and the second is taken after the administration of medication. An increase of FEV1 after taking asthma medication is indicative of asthma. If spirometry is not available then peak expiratory flow can be used to show variable lung function. GINA guidelines recommend testing how fast a person can breathe out (peak expiratory flow) twice a day for two weeks. Daily changes greater than 10% may suggest asthma.^{[4] : 25, 28}

Bronchial provocation testing measures how sensitive and reactive the airways are. During the test, substances such as inhaled methacholine, histamine, or inhaled mannitol as well as exercise and controlled rapid breathing are used to try to trigger airway narrowing. These tests can help identify asthma but are not specific, because airway sensitivity can also occur in other conditions like allergic rhinitis, cystic fibrosis, bronchopulmonary dysplasia, and COPD. A negative test result in someone not using inhaled corticosteroids (ICS) can help rule out asthma. However, a positive result does not always confirm asthma, so symptoms and other clinical findings must also be considered.^{[4] : 31}

For adults, NICE guidelines recommend testing fractional exhaled nitric oxide (FeNO) and blood eosinophils as a first step. If FeNo or eosinophils are not elevated then they recommend testing bronchodilator reversibility (BDR) with spirometry or peak expiratory flow (PEF) if spirometry is not available. Finally, if testing remains inconclusive, bronchial challenge tests are recommended.^{[14] : 10} Guidelines for children ages five to sixteen are similar to the adult guidelines aside from recommendations surrounding blood eosinophil count.^{[14] : 10–11} For children ages five to sixteen NICE guidelines do not recommend blood eosinophil count as an initial test, but instead they recommend measuring blood eosinophil count, skin prick testing for dust mites, or total IgE levels if respiratory testing is inconclusive.^{[14] : 11}

According to NICE guidelines, children younger than five should be treated for asthma if they have symptoms suggestive of the condition instead of undergoing testing.^{[14] : 13} GINA has proposed a set of diagnostic criteria for asthma in those under the age of five. All three of the following criteria must be met:^{[4] : 182}

1. More than two acute episodes of asthma symptoms or at least one episode of wheezing with asthma symptoms in between episodes. Wheezing must be confirmed in at least one episode.
2. Lack of alternative explanation for symptoms.
3. Response to asthma medication during acute wheezing episodes.

The goal of asthma management is to reduce symptoms minimize the risk of complication such as exacerbations, reduced lung functioning, and medication side effects.^{[4] : 50} This is done by evaluating asthma control and the risk of exacerbation, providing education and guidance on how to manage the disease, finding triggers and ways to minimize them, and medication.^{[16] [15]} Asthma control should be reviewed during doctors appointments so that treatment can be adjusted accordingly.^{[14] : 63 [4] : 52–53}

After a diagnosis of asthma is made the person receiving the diagnosis and their family should receive education about the disease and a plan for management.^{[15] [16]} Education includes information about avoiding triggers, self monitoring of symptoms or peak expiratory flow, an asthma action plan, asthma control and treatment options.^{[14] : 28–30 [4] : 114} Asthma action plans include management options to prevent and treat exacerbations as well as how to modify treatment based on symptoms or seek additional medical care.^{[16] [4] : 115} School based education programs on how to manage asthma decrease hospitalizations for asthma in school-aged children.^{[4] : 116}

Medications for asthma are generally divided into three categories, controllers — taken daily to control symptoms, reduce exacerbations and decrease inflammation — relievers — taken as needed for severe symptoms or exacerbations — and additional medications added on to manage more severe asthma.^{[15] [4] : 69} Medications are prescribed at the lowest dose possible while still treating symptoms and preventing exacerbations.^[16]

The choice of medication used for asthma management depends on symptom control, risk factors, availability, adherence, ability to use the medication, cost and environmental impact.^{[4] : 72} It typically takes one or two weeks for symptoms to improve after starting inhaled corticosteroids (ICS) and the response to medication is monitored whenever it is adjusted.^{[16] [4] : 73} If asthma symptoms and exacerbations remain well controlled after two or three months, the dosage of medication can be gradually reduced to achieve symptom control at the lowest possible dose of medication.^{[4] : 73} If asthma symptoms and exacerbations persist despite two to three months of treatment with ICS factors such as inhaler technique, adherence, exposure to triggers, comorbidities, and alternative diagnoses are assessed before medication dosage is increased.^{[16] [4] : 73}

The first line treatment of asthma for children are ICS, for teenagers and adults guidelines recommend a combined ICS and long-acting beta₂ agonist (LABA) inhaler.^[15] After a diagnosis of asthma is confirmed, ICS are started as soon as possible. Guidelines also recommend that everyone diagnosed with asthma have access to a reliever inhaler in case of symptom flare ups.^{[4] : 72 [16]} In children younger than five, higher doses of ICS are used to treat persistent symptoms while older individuals may be treated with an additional medication. Medical guidelines recommend referring people who have persistent symptoms despite adequate treatment to an asthma specialist (usually a respirologist or allergist).^[15]

Historically, asthma was treated with short-acting β2 agonists (SABA) as needed and ICS were only used if symptoms persisted. Due to research suggesting that management with SABA over ICS was insufficient to prevent exacerbations, guidelines now prefer ICS over SABA.^{[10] [14] : 20}

For those over the age of twelve, if asthma isn’t well controlled with an ICS/formoterol inhaler then guidelines recommend that medications be taken daily instead of on an as needed basis and gradually increased until symptoms are controlled.^{[14] : 18–19} If higher doses of ICS/formoterol aren’t enough to control symptoms then there are several different medications that may be added in to help manage asthma. These include the leukotriene receptor antagonists (LTRA) montelukast, a mist inhaler containing the LAMA tiotropium, and azithromycin.^{[14] : 19 [4] : 92 [15]} In those with sensitization to aeroallergens, allergen-specific immunotherapy can increase tolerance to allergens by slowly introducing the allergen to an effected person. This is done through two different methods; subcutaneous immunotherapy — injections — and sublingual immunotherapy — under the tongue.^{[15] [4] : 104–105} Biologics can be used to reduce inflammation that may play a role in asthma symptoms.^[15] Finally, oral corticosteroids or bronchial thermoplasty may be used as last resorts for severe asthma.^{[4] : 93, 106–107}

In children under the age of five who have comorbid atopic disorders and intermittent asthma symptoms or severe flare-ups a 8-12 week trial of low dose ICS as maintenance treatment and a SABA for flare-ups is recommended by NICE guidelines. If symptoms clear up during the trial then medication can be stopped and symptoms are monitored in the following months to watch for returning symptoms or exacerbation, in which case ICS and SABA can be started again. Persistent symptoms are treated with increasing doses of ICS and an LTRA.^{[14] : 24–25}

Low doses of ICS for maintenance and SABA as needed are used to manage asthma in children ages six to eleven, with ICS used whenever SABA are needed to treat flare-ups. If symptoms persist then the dose of ICS may be gradually increased, a LTRA can be added on top of inhalers or a low-dose ICS-LABA or ICS-formoterol can be used instead of ICS.^{[14] : 22–23 [4] : 97–98}

Treatment of asthma exacerbations involves several doses of bronchodilators, oral corticosteroids, and oxygen supplementation. Salbutamol (albuterol) is commonly used for treating exacerbations with several doses being administered every couple of hours until symptoms lessen. When exacerbations are severe or don’t subside with inhaled medications, oral corticosteroids are used and continued for a week after the exacerbation. Oxygen therapy is also used to maintain a healthy oxygen saturation.^{[4] : 169–170} Ipratropium, a short-acting anticholinergic, can also be used alongside other treatments to manage exacerbations in those experiencing moderate or severe symptoms. Both intravenous magnesium sulfate and helium–oxygen therapy are not recommended by clinical guidelines for the management of exacerbations, however they may be used in those whose symptoms do not react to other first-line treatment options.^{[4] : 175–176, 207}

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