Asthma

Asthma is a chronic condition involving the respiratory system in which the airways occasionally constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more triggers.[1] These episodes may be triggered by such things as exposure to an environmental stimulant such as an allergen, environmental tobacco smoke, cold or warm air, perfume, pet dander, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.[2] This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children.

Signs and symptoms
In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.[4] Although the former is "often regarded as the sine qua non of asthma",[4] some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.[5]

Cause
Asthma is caused by a complex interaction of environmental and genetic factors that researchers do not fully understand yet.[6] These factors can also influence how severe a person’s asthma is and how well they respond to medication.[7] As with other complex diseases, many environmental and genetic factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.

Environmental
Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association:

* Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.[8][9]
* Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.[8]
* Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.[8][10][11]
* Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).[12]
* Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Cesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Cesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).[13]
* Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.[8]

The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.[12][13][14] All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

Genetic
Over 100 genes have been associated with asthma in at least one genetic association study.[15] However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:[15]

* GSTM1
* IL10
* CTLA4
* SPINK5
* LTC4S



* LTA
* GRPA
* NOD1
* CC16
* GSTP1



* STAT6
* NOS1
* CCL5
* TBXA2R
* TGFB1



* IL4
* IL13
* CD14
* ADRB2 (β-2 adrenergic receptor)
* HLA-DRB1



* HLA-DQB1
* TNF
* FCER1B
* IL4R
* ADAM33

Many of these genes are related to the immune system or to modulating inflammation. However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested.[15] This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma.

Stimuli
# Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;[citation needed]
# Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.[citation needed]
# Medications, including aspirin,[18] β-adrenergic antagonists (beta blockers), and penicillin.[citation needed]
# Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.[citation needed]
# Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.[citation needed]
# Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH2Cl), dichloramine (NHCl2) and trichloramine (NCl3)—in the air around them, which are known to induce asthma.[19]
# Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.[citation needed]
# Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. It is known that exercising regularly actually helps to cure asthma.[citation needed]
# Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.[citation needed]
# Emotional stress which is poorly understood as a trigger.[citation needed] Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
# Cold weather can make it harder for asthmatics to breathe.[20] Whether high altitude helps or worsens asthma is debatable and may vary from person to person.

Pathogenesis
The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.[22] Szentivanyi's Beta Adrenergic Theory is a citation classic[23] and has been cited more times than any other article in the history of the Journal of Allergy.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[24] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[25]

The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),[26] Charles Reed (Chief of Allergy at Mayo Medical School),[27] and Craig Venter (Human Genome Project).[28]

John P. McGovern, President of the American Association of Allergy nominated Szentivanyi for The 1968 Nobel Prize in Medicine in recognition of The Beta Adrenergic Theory.

In 2006, Researchers at Harvard Medical School found evidence that asthma is caused by over-proliferation of a special type of natural "killer" cell.

Diagnosis
Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:[33]

* ≥20% difference on at least three days in a week for at least two weeks;
* ≥20% improvement of peak flow following treatment, for example:
o 10 minutes of inhaled β-agonist (e.g., salbutamol);
o six week of inhaled corticosteroid (e.g., beclometasone);
o 14 days of 30mg prednisolone.
* ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).

In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.

Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software.[34] This allows patients to track their peak flow readings and pass information back to their doctor or nurse.[35]

In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,[36] along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.

More recently, exhaled nitric oxide has been studied as a breath test indicative of airway inflammation in asthma.

Prevention
Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.

Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.

Preventive agents include the following.

* Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gain. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.
* Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
* Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
* Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)
* Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.
* Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation.
* Hyposensitization, (also known as immunodesensitisation therapy) may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Depending on the allergen, it can be given orally or by injection.
* Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.
* Methotrexate is occasionally used in some difficult-to-treat patients.
* If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.