Asthma

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A typical inhaler, of Serevent (salmeterol), a long-acting bronchodilator.

Asthma is a chronic disease of the respiratory system in which the airway occasionally constricts, becomes inflamed, and is lined with excessive amounts of mucus, often in response to one or more triggers. This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing, which respond to bronchodilators. A bronchodilator is a medication intended to improve bronchial airflow by acting on β2 receptors in bronchial smooth muscle and bronchial mucus membranes.

These acute episodes may be triggered by such things as exposure to an environmental stimulant (or allergen, a substance causing an allergic reaction), cold air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.[1]

The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes. Between episodes, most patients feel fine. There is no cure for asthma. But human creativity has been applied to develop a myriad of ways to prevent attacks and relieve symptoms, such as tightness of the chest and trouble breathing.

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.[2]

Contents

History

The word asthma is derived from the Greek aazein, meaning "sharp breath." The word first appears in Homer's Iliad;[3] Hippocrates was the first to use it in reference to the medical condition. Hippocrates thought that the spasms associated with asthma were more likely to occur in tailors, anglers, and metalworkers.

Six centuries later, Galen wrote much about asthma, noting that it was caused by partial or complete bronchial obstruction. Moses Maimonides, an influential medieval rabbi, philosopher, and physician, wrote a treatise on asthma, describing its prevention, diagnosis, and treatment.[4] In the seventeenth century, Bernardino Ramazzini noted a connection between asthma and organic dust.

The use of bronchodilators started in 1901, but it was not until the 1960s that the inflammatory component of asthma was recognized, and anti-inflammatory medications were added to the regimen.

Causes

As noted above, there are many possible triggers, including exercise or exertion, emotional stress, and exposure to an allergen or cold air, as well viral illness such as the common cold.[1]

Many studies have linked asthma, bronchitis, and acute respiratory illnesses to air quality experienced by children.[5] One of the largest of these studies is the California Children's Health Study.[6] From the press release[2]

The study showed that children in the high ozone communities who played three or more sports developed asthma at a rate three times higher than those in the low ozone communities. Because participation in some sports can result in a child drawing up to 17 times the “normal” amount of air into the lungs, young athletes are more likely to develop asthma.

Diagnosis

In most 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 (an inflamed skin condition) or other allergic conditions—suggesting a general atopic (allergy-related) 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.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A physician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry, or measuring of breath), and decreased likelihood of family history of atopy.

Pulmonary aspiration (the entry of secretions or foreign material into the trachea and lungs), whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia, which is caused by a bacterial infection or direct chemical insult. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow Test (a test involving X-rays, in which the swallowing mechanism of the patient can be viewed on a video screen) and can be treated with feeding therapy by a qualified speech therapist.

Only a minority of asthma sufferers have an identifiable allergy trigger. The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Occasionally, allergy tests are warranted and, if positive, may help in identifying avoidable symptom triggers.

After pulmonary function has been measured, radiological tests, such as a chest X-ray or computed tomography (CT) scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease (GERD), a disease where improper functioning of the lower esophageal sphincter (LES) allows leakage of stomach contents back into the esophagus. This disease can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine—or, even less commonly, histamine—may be performed.

Asthma is categorized by the United States National Heart, Lung and Blood Institute as mild persistent, moderate persistent, and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent nighttime symptoms and results in limited physical activity, and when lung function as measured by PEV or FEV1 tests is less than 60 percent predicted with PEF variability greater than 30 percent.

Epidemiology

The prevalence of childhood asthma has increased since 1980, especially in younger children.

More than 6 percent of children in the United States have been diagnosed with asthma, a 75 percent increase in recent decades. The rate soars to 40 percent diagnosed with the problem among some populations of urban children. Asthma is usually diagnosed in childhood. The risk factors for asthma include:

  • a personal or family history of asthma or atopy;
  • triggers (see Pathophysiology above);
  • premature birth or low birth weight;
  • viral respiratory infection in early childhood;
  • maternal smoking;
  • being male, for asthma in prepubertal children; and
  • being female, for persistence of asthma into adulthood.

There is a reduced occurrence of asthma in people who were breast-fed as babies.

Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's (CDC) National Health Interview Surveys, some 9 percent of US children below 18 years of age had asthma in 2001, compared with just 3.6 percent in 1980 (see figure). The World Health Organization (WHO) reports that some 8 percent of the Swiss population suffers from asthma today, compared with just 2 percent some 25–30 years ago.[7]

Although asthma is more common in affluent countries, it is by no means a problem restricted to such nations; WHO estimates that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.[7]

On the remote South Atlantic island Tristan da Cunha, 50 percent of the population are asthmatics due to heredity transmission of a mutation in the gene CC16.

Asthma and athletics

Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games showed that 15 percent had been diagnosed with asthma, and that 10 percent were taking asthma medication.[8] These statistics have been questioned on at least two bases. For one, persons with mild asthma may be more likely to be diagnosed with the condition than others because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. Second, it has also been suggested that some professional athletes who do not suffer from asthma claim to in order to obtain special permits to use certain performance-enhancing drugs.

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.[8][9]

In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently or concurrently with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.

Socioeconomic factors

The incidence of asthma is higher among low-income populations within a society (even though it is more common in developed countries than developing countries). In the Western world these are disproportionately minority, and more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighborhoods.[10]

The quality of asthma treatment varies along racial lines, likely because many low-income people cannot afford health insurance and because there is still a correlation between class and race. For example, black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease, they are more likely to have emergency room visits or hospitalization for asthma, and they are three times as likely to die from an asthma attack compared to white Americans. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.[11][12]

Pathophysiology

Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing.

Asthma and gastro-esophageal reflux disease

If gastro-esophageal reflux disease (GERD) is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma. GERD may be common in difficult-to-control asthma, but generally speaking, treating it does not seem to affect the asthma.[13]

Asthma and sleep apnea

It is recognized with increasing frequency that patients who have both obstructive sleep apnea (OSA, a condition where one stops breathing during sleep due to obstruction of the airway) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.[14] Continuous Positive Airway Pressure (CPAP) (a mechanism where air is directly delivered into the airway) is used to treat OSA, but is not effective in patients with nocturnal asthma only.[15]

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells, or T helper cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen.

Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results and chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.

Bronchoconstriction

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.[16]

The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

There are several categories of stimuli:

  • allergenic air pollution, from nature, typically inhaled, which include waste from common household insects, such as the house dust mites and cockroaches, grass pollen, mold spores, and pet epithelial cells;
  • medications, including aspirin[17] and β-adrenergic antagonists (i.e. beta blockers, a class of drugs usually used for the management of cardiac arrhythmias (irregular heart contraction) and cardioprotection after myocardial infarction (i.e. a heart attack);
  • use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog (aka photochemical smog, resulting from the reaction of sunlight with nitrogen oxides and hydrocarbons), nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas;
  • 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;[18]
  • 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) absent at the time of infection. 80 percent of asthma attacks in adults and 60 percent in children are caused by respiratory viruses;
  • exercise, the effects of which differ somewhat from those of the other triggers;
  • (in some countries) - allergenic indoor air pollution from newsprint and other literature such as junk mail leaflets & glossy magazines;
  • emotional stress which is poorly understood as a trigger.

Pathogenesis

(See also: Allergy).

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 (or its origin): the incidence of asthma seems to be increasing worldwide, and asthma is now 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.[19] Szentivanyi's Beta Adrenergic Theory is a citation classic[20] and has been cited more times than any other article in the history of the Journal of Allergy (now the Journal of Allergy and Clinical Immunology).

In 1993, Szentivanyi and colleagues demonstrated that IgE (antibody subclass immunoglobulin E) blocks beta-2 receptors.[21] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of Allergy.[22]

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

One theory of pathogenesis is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria and other antigens soon after birth, "switching on" the TH1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient—as it may be in modern, clean environments—then TH2 cells predominate, and asthma and other allergic diseases may develop. This "hygiene hypothesis" may explain the increase in asthma in affluent populations. The TH2 lymphocytes and eosinophil cells (both types of white blood cells involved in immune response) that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. The Charcot-Leyden crystals are formed when the crystalline material in eosinophils coalesce. These crystals are significant in sputum (e.g. mucus or phlegm) samples of people with asthma. In the developed world, these parasites are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.

Another theory is based on the correlation of air pollution and the incidence of asthma. Although it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proven that air pollution is responsible for the development of asthma. In Western Europe, most atmospheric pollutants have fallen significantly over the last forty years, while the prevalence of asthma has risen.

Finally, it has been postulated that some forms of asthma may be related to infection, in particular by Chlamydia pneumoniae.[23] [24]This issue remains controversial, as the relationship is not borne out by meta-analysis of the research.[25] The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma.[26] One possible explanation is that some asthmatics may have altered immune response that facilitates long-term chlamydia pneumonia infection.[27] The response to targeting with macrolide antibiotics (drugs whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars are attached) has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their antimicrobic action.[25]

Prognosis

The prognosis for asthmatics is good, especially for children with mild disease.

For asthmatics diagnosed during childhood, 54 percent will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes.[16] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids (a type of steroid hormone) prevents or ameliorates decline in lung function as measured by several parameters.[28] For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities. The mortality rate for asthma is low, with around six thousand deaths per year in a population of some ten million patients in the United States.[29] Better control of the condition may help prevent some of these deaths.

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, airborne allergens, and exercise.

Signs of an asthmatic episode or asthma attack are shortness of breath (dyspnea), either stridor (a high-pitched breathing noise caused by obstruction of the airway) or wheezing, rapid breathing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), 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, and the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation).

Although stridor is "often regarded as the sine qua non of asthma,"[29] some victims primarily exhibit 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.

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Severe asthma attacks may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few signs of the disease.

Treatment

The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. Desensitization to allergens has been shown to be a treatment option for certain patients. Desensitization to allergens involves the gradual increase of direct injection of the allergen into the patient, which may cause the immune system to grow less sensitive to the allergen.

As is common with respiratory disease, smoking adversely affects asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications.[30] Asthmatics who smoke typically require additional medications to help control their disease. Furthermore, exposure of both nonsmokers and smokers to secondhand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.[31] Smoking cessation and avoidance of secondhand smoke is strongly encouraged in asthmatics.[32]

The specific medical treatment recommended to patients with asthma depends on the severity of their illness and the frequency of their symptoms. Specific treatments for asthma are broadly classified as relievers, preventers, and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)[32] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[33] are broadly used and supported by many doctors.

Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier (a drug that blocks the body's production of leukotrienes, a compound that contributes to the constriction of airways), a mast-cell stabilizer (which inhibits release of histamine, a compound involved in airway constriction), or theophylline (which relaxes bronchial smooth muscle) may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks.

For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.[29]

Researchers at Harvard Medical School (HMS) have come up with convincing evidence that the answer to what causes asthma lies in a special type of natural "killer" cell. This finding means that physicians may not be treating asthma sufferers with the right kinds of drugs. For example, natural killer T cells seem to be resistant to the corticosteroids in widely used inhalers.[34]

A novel therapeutic target currently under investigation is the A2B receptor, a cell surface G-protein coupled receptor expressed in the lungs and in inflammatory cells expressed in asthma. Several animal models have confirmed the a critical role for A2B antagonists in pulmonary inflammation, fibrosis and airway remodeling.[35]

Alternative and complementary medicine

Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50 percent of asthma patients use some form of unconventional therapy.[36][37] There are little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.[38] A similar review of air ionizers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[39] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, found no evidence to support their use in treating asthma;[40] these maneuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." On the other hand, one meta-analysis (an analysis that uses a combination of results of other studies) found that homeopathy (a treatment that involves treating the sick with extremely diluted agents that, in undiluted doses, produce similar symptoms in the healthy) has a potentially mild benefit in reducing symptom intensity;[41] however, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.[42] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs[43] —"yogasanas, Pranayama, meditation, and kriyas"—to sahaja yoga,[44] a form of meditation.

The Buteyko method, a Russian therapy based on breathing exercises, has been investigated with mixed degrees of effect shown. A randomized, controlled trial of just 39 patients in 1998 suggested that this method may moderately reduce the need for beta-agonists among asthmatics, but found no objective improvement in lung function.[45] A trial in New Zealand in 2003 showed reduced beta-agonist medication by 94 percent and inhaled steroid by 34 percent after just six weeks.[46]

Given that some research has identified a negative association between helminth infection (hookworm) and asthma and hay fever, some have suggested that hookworm infestation, although not medically sanctioned, would cure asthma. There is anecdotal evidence to support this.[47]

Emergency treatment

When an asthma attack is unresponsive to a patient's usual medication, other treatments are available to the physician or hospital:[48]

  • oxygen to alleviate the hypoxia, aka oxygen depletion, (but not the asthma per se) that results from extreme asthma attacks;
  • nebulized salbutamol or terbutaline (short-acting beta-2-agonists), often combined with ipratropium (an anticholinergic);
  • systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone)
  • other bronchodilators that are occasionally effective when the usual drugs fail:
    • nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol);
    • anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine);
    • methylxanthines (theophylline, aminophylline);
    • inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane);
    • the dissociative anaesthetic ketamine, often used in endotracheal tube induction
    • magnesium sulfate, intravenous; and
  • intubation and mechanical ventilation, for patients in or approaching respiratory arrest.

Long-acting β2-agonists

Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer sidechains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required. In November of 2005, the American Food and Drug Administration (FDA) released a health advisory alerting the public to findings that show the use of Long-acting β2-agonists could lead to a worsening of symptoms, and in some cases death.[49]

Currently available long-acting beta2-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, and Seretide in the United Kingdom).

A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a Cornell study. The study goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five U.S. asthma-related deaths per year and should be taken off the market".[50]

Prevention medication

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 brown 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 minimized 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. In more severe cases, hyposensitization ("allergy shots") may be recommended.
  • Omalizumab, an immunoglobulin E (IgE) blocker; this can help patients with severe allergic asthma that do 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 (Gastroesophageal reflux disease, GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.

Relief medication

Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. These are typically provided in pocket-sized, metered-dose inhalers (MDIs).

In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer (see top image) is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.

A nebulizer—which provides a larger, continuous dose—can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapor, which the patient inhales continuously until the full dosage is administered. There is no clear evidence, however, that they are more effective than inhalers used with a spacer. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.

Relievers include:

  • Short-acting, selective beta2-adrenoceptor agonists, such as salbutamol (albuterol United States Adopted Name (USAN)), levalbuterol, terbutaline, and bitolterol, which normally come as blue inhaler devices.
    Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
  • Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, are available over the counter in the US. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[51] [52] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[51] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
  • Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β2-adrenoreceptor agonists.

Notes

  1. 1.0 1.1 J. Zhao, M. Takamura, A. Yamaoka, Y. Odajima, and Y. Iikura. 2002. Altered eosinophil levels as a result of viral infection in asthma exacerbation in childhood. J Pediatr Allergy Immunol 13(1):47-50. PMID 12000498
  2. C. M. Lilly, 2005. Diversity of asthma: Evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol 115(4 Suppl):S526-31. PMID 15806035
  3. S. G. Marketos, and C. N. Ballas. 1982. Bronchial asthma in the medical literature of Greek antiquity. J Asthma 19(4):263-9. PMID 6757243
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