Asthma is a chronic inflammation of the lungs in which the airways (bronchi) are reversibly narrowed. Asthma affects 7% of the population, or 20 million Americans,[1][2] and 300 million worldwide.[3] During attacks (exacerbations), the smooth muscle cells in the bronchi constrict, and the airways become inflamed and swollen. Breathing becomes difficult, and asthma causes 4,000 deaths a year in the U.S. Attacks can be prevented by avoiding triggering factors and by drug treatment. Drugs are used for acute attacks, commonly inhaled β2-agonists. In more serious cases, drugs are used for long-term prevention, starting with inhaled corticosteroids, and then long-acting β2-agonists if necessary. Leukotriene antagonists are less effective than corticosteroids but have no side effects. Monoclonal antibodies such as mepolizumab and omalizumab are sometimes effective. Prognosis is good with treatment.
In contrast to chronic obstructive pulmonary disease and chronic bronchitis, the inflammation of asthma is reversable. In contrast to emphysema, asthma affects the bronchi, not the alveoli.
The National Heart, Lung and Blood Institute defines asthma as a common chronic disorder of the airways characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness (bronchospasm), and an underlying inflammation.[4]
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.[5]
Classification
Asthma is classified according to the frequency of symptoms, FEV1 and peak expiratory flow rate.[6]
Classification of asthma severity[6]
| Severity |
Symptom frequency |
Nighttime symptoms |
Peak expiratory flow rate or FEV1 of predicted |
Variability of peak expiratory flow rate or FEV1 |
| Intermittent |
< once a week |
≤ twice per month |
≥ 80% predicted |
< 20% |
| Mild persistent |
> once per week but < once per day |
> twice per month |
≥ 80% predicted |
20–30% |
| Moderate persistent |
Daily |
> once per week |
60–80% predicted |
> 30% |
| Severe persistent |
Daily |
Frequent |
< 60% predicted |
> 30% |
Signs and symptoms
Because of the spectrum of severity within asthma, some asthmatics only rarely experience symptoms, usually in response to triggers, where as other more severe asthmatics may have marked airflow obstruction at all times.
Asthma exists in two states: the steady-state of chronic asthma, and the acute state of an acute asthma exacerbation. The symptoms are different depending on what state the asthmatic is in.
Common symptoms of asthma in a steady-state include: nighttime coughing, shortness of breath with exertion but no dyspnea at rest, a chronic 'throat-clearing' type cough, and complaints of a tight feeling in the chest. Severity often correlates to an increase in symptoms. Symptoms can worsen gradually and rather insidiously, up to the point of an acute exacerbation of asthma. It is a common misconception that all asthmatics wheeze—some asthmatics never wheeze, and their disease may be confused with another Chronic obstructive pulmonary disease such as emphysema or chronic bronchitis.
An acute exacerbation of asthma is commonly referred to as an asthma attack. The cardinal symptoms of an attack are shortness of breath (dyspnea), wheezing and chest tightness.[7] Although the former is "often regarded as the sine qua non of asthma.[8] 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.[9].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). It is important to note inspiratory stridor without expiratory wheeze however, as an upper airway obstruction may manifest with symptoms similar to an acute exacerbation of asthma, with stridor instead of wheezing, and will remain unresponsive to bronchodilators.
Severity of asthma attack [9]
| Sign/Symptom |
Mild |
Moderate |
Severe |
Imminent respiratory arrest |
| Alertness |
May show agitation |
Agitated |
Agitated |
Confused/Drowsy |
| Breathlessness |
On walking |
On talking |
Even at rest |
|
| Talks in |
Sentences |
Phrases |
Words |
|
| Wheeze |
Moderate |
Loud |
Loud |
Absent |
| Accessory muscle |
Usually,not used |
Used |
Used |
|
| Respiratory rate (/min) |
Increased |
Increased |
Often >30 |
|
| Pulse rate (/min) |
100 |
100-120 |
>120 |
<60 (Bradycardia) |
| PaO2 |
Normal |
>60 |
<60 ,possible cyanosis |
|
| PaCO2 |
<45 |
<45 |
>45 |
|
Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), and rhonchous lung sounds (audible through a stethoscope). 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 there may be the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest.
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 cold. Severe asthma attacks which are not responsive to standard treatments, called status asthmaticus, are life-threatening and may lead to respiratory arrest and death.
Though symptoms may be very severe during an acute exacerbation, between attacks an asthmatic may show few or even no signs of the disease.[10]
Cause
Asthma is caused by environmental and genetic factors,[11] which can influence how severe asthma is and how well it responds to medication.[12] Some environmental and genetic factors have been confirmed by further research, while others have not been.
Environmental
Many environmental risk factors have been associated with asthma development and morbidity in children, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association.
Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.[13] 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.[13][14]
Recent studies show a relationship between exposure to air pollutants (e.g. from traffic) and childhood asthma [15]. This research finds that both the occurrence of the disease and exacerbation of childhood asthma are affected by outdoor air pollutants.
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 Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).[16]
Psychological stress has long been suspected of being an asthma trigger, but only in recent decades has convincing scientific evidence substantiated this hypothesis. Rather than stress directly causing the asthma symptoms, it is thought that stress modulates the immune system to increase the magnitude of the airway inflammatory response to allergens and irritants.[13][17]
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.[13][18][19]
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).[20] The hygiene hypothesis is a hypothesis 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.[16][20][21] 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.
Recently scientists connected the rise in prevalence of asthma, to the rise in use of acetaminophen, suggesting the possibility that acetaminophen can cause asthma.[22]
Genetic
Over 100 genes have been associated with asthma in at least one genetic association study.[23] However, such studies must be repeated to ensure the findings are not due to chance. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:[23]
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.[23] 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. One theory is that asthma is a collection of several diseases, and that genes might have a role in only subsets of asthma. For example, one group of genetic differences (single nucleotide polymorphisms in 17q21) was associated with asthma that develops in childhood.[24]
Gene–environment interactions
Research suggests that some genetic variants may only cause asthma when they are combined with specific environmental exposures, and otherwise may not be risk factors for asthma.[11]
The genetic trait, CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) are a well-replicated example of a gene-environment interaction that is associated with asthma. Endotoxin exposure varies from person to person and can come from several environmental sources, including environmental tobacco smoke, dogs, and farms. Researchers have found that risk for asthma changes based on a person’s genotype at CD14 C-159T and level of endotoxin exposure.[25]
CD14-endotoxin interaction based on CD14 SNP C-159T[25]
| Endotoxin levels |
CC genotype |
TT genotype |
| High exposure |
Low risk |
High risk |
| Low exposure |
High risk |
Low risk |
Risk factors
Studying the prevalence of asthma and related diseases such as eczema and hay fever have yielded important clues about some key risk factors. The strongest risk factor for developing asthma is a family history of atopic disease; [26] this increases one's risk of hay fever by up to 5x and the risk of asthma by 3-4x. [27] In children between the ages of 3-14, a positive skin test for allergies and an increase in immunoglobulin E increases the chance of having asthma. [28] In adults, the more allergens one reacts positively to in a skin test, the higher the odds of having asthma.[29]
Because much allergic asthma is associated with sensitivity to indoor allergens and because Western styles of housing favor greater exposure to indoor allergens, much attention has focused on increased exposure to these allergens in infancy and early childhood as a primary cause of the rise in asthma. [30][31] Primary prevention studies aimed at the aggressive reduction of airborne allergens in a home with infants have shown mixed findings. Strict reduction of dust mite allergens, for example, reduces the risk of allergic sensitization to dust mites, and modestly reduces the risk of developing asthma up until the age of 8 years old. [32][33][34][35] However, studies also showed that the effects of exposure to cat and dog allergens worked in the converse fashion; exposure during the first year of life was found to reduce the risk of allergic sensitization and of developing asthma later in life.[36][37][38]
The inconsistency of this data has inspired research into other facets of Western society and their impact upon the prevalence of asthma. One subject that appears to show a strong correlation is the development of asthma and obesity. In the United Kingdom and United States, the rise in asthma prevalence has echoed an almost epidemic rise in the prevalence of obesity. [39][40] In Taiwan, symptoms of allergies and airway hyperreactivity increased in correlation with each 20% increase in body-mass index.[41]
Hygiene hypothesis
One theory for the cause of the increase in asthma prevalence worldwide is the so-called "hygiene hypothesis" — that the rise in the prevalence of allergies and asthma is a direct and unintended result of the success of modern hygienic practices in preventing childhood infections. Studies have shown repeatedly that children coming from environments one would expect to be less hygienic (East Germany vs. West Germany,[42] families with many children,[43][44][45] day care environments,[46][47]) tended to result in lower incidences of asthma and allergic diseases. This seems to run counter to the logic that viruses are often causative agents in exacerbation of asthma [48][49][50] Additionally, other studies have shown that viral infections of the lower airway may in some cases induce asthma, as a history of bronchiolitis or croup in early childhood is a predictor of asthma risk in later life. [51] Studies which show that upper respiratory tract infections are protective against asthma risk also tend to show that lower respiratory tract infections conversely tend to increase the risk of asthma. [52]
Population disparities
Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.[13] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos and Native Hawaiians, and lowest in Mexicans and Koreans.[53][54][55] Mortality rates follow similar trends, and response to Ventolin is lower in Puerto Ricans than in African Americans or Mexicans.[56][57] As with worldwide asthma disparities, differences in asthma prevalence, mortality, and drug response in the US may be explained by differences in genetic, social and environmental risk factors.
Asthma prevalence also differs between populations of the same ethnicity who are born and live in different places.[58] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US.[59] This probably reflects differences in social and environmental risk factors associated with acculturation to the US.[citation needed]
Asthma prevalence and asthma deaths also differ by gender. Males are more likely to be diagnosed with asthma as children, but asthma is more likely to persist into adulthood in females.[60] Sixty five percent more adult women than men will die from asthma.[citation needed] This difference may be attributable to hormonal differences, among other things. In support of this, girls who reach puberty before age 12 were found to have a later diagnosis of asthma more than twice as much as girls who reach puberty after age 12.[citation needed] Asthma is also the number one cause of missed days from school.[citation needed]
Socioeconomic factors
The incidence of asthma is highest among low-income populations (asthma deaths are most common in low to middle income countries [2]), which in the western world are disproportionately ethnic minorities[61] and are 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.
Asthma incidence and quality of treatment varies among different racial groups, though this may be due to correlations with income (and thus affordability of health care) and geography. For example, African Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.[62][63]
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, in Atlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication.[64]
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.[64][65]
Occupational asthma
Asthma as a result of (or worsened by) workplace exposures is the world's most commonly reported occupational respiratory disease. Still most cases of occupational asthma are not reported or are not recognized as such. Estimates by the American Thoracic Society (2004) suggest that 15–23% of new-onset asthma cases in adults are work related.[66] In one study monitoring workplace asthma by occupation, the highest percentage of cases occurred among operators, fabricators, and laborers (32.9%), followed by managerial and professional specialists (20.2%), and in technical, sales, and administrative support jobs (19.2%). Most cases were associated with the manufacturing (41.4%) and services (34.2%) industries.[66] Animal proteins, enzymes, flour, natural rubber latex, and certain reactive chemicals are commonly associated with work-related asthma. When recognized, these hazards can be mitigated, dropping the risk of disease.[67]
Pathophysiology
Asthma is an airway disease that can be classified physiologically as a variable and partially reversible obstruction to air flow, and pathologically with overdeveloped mucus glands, airway thickening due to scarring and inflammation, and bronchoconstriction, the narrowing of the airways in the lungs due to the tightening of surrounding smooth muscle. Bronchial inflammation also causes narrowing due to edema and swelling caused by an immune response to allergens.
Bronchoconstriction
Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing.
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.[68]
The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). (It is usually classified as type I hypersensitivity.)[69][70] 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. Bronchospasm may resolve spontaneously in 1–2 hours, or in about 50% of subjects, may become part of a 'late' response, where this initial insult is followed 3–12 hours later with further bronchoconstriction and inflammation.[71]
The normal caliber of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal center, then down the vagal efferent pathway to again reach the bronchial small airways. Acetylcholine is released from the efferent nerve endings. This acetylcholine results in the excessive formation of inositol 1,4,5-trisphosphate (IP3) in bronchial smooth muscle cells which leads to muscle shortening and this initiates bronchoconstriction.
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) "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: chemicals are produced that cause the wall of the airway to thicken, cells which produce scarring to proliferate and contribute to further 'airway remodeling', causes mucus producing cells to grow larger and produce more and thicker mucus, and the cell-mediated arm of the immune system is activated. Inflamed airways are more hyper-reactive, and will be more prone to bronchospasm.
The "hygiene hypothesis" postulates that an imbalance in the regulation of these TH cell types in early life leads to a long-term domination of the cells involved in allergic responses over those involved in fighting infection. The suggestion is that for a child being exposed to microbes early in life, taking fewer antibiotics, living in a large family, and growing up in the country stimulate the TH1 response and reduce the odds of developing asthma. [72]
Stimuli
- Allergens from nature, typically inhaled, which include waste from common household pests, the house dust mite and cockroach, as well as grass pollen, mold spores, and pet epithelial cells;[73]
- 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. [7][73]
- Medications, including aspirin,[74] β-adrenergic antagonists (beta blockers),[75] and penicillin.[76]
- 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.[77]
- 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.[7]
- 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.[78]
- Early childhood infections, especially viral upper respiratory tract infections. Children who suffer from frequent respiratory infections prior to the age of six are at higher [79] risk of developing asthma, particularly if they have a parent with the condition. 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. [7] In children, the most common triggers are viral illnesses such as those that cause the common cold.[80]
- Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. They are thought to be primarily in response to the exposure of the airway epithelium to cold, dry air.
- 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.[7]
- Psychological stress. There is growing evidence that psychological stress is a trigger. It can modulate the immune system, causing an increased inflammatory response to allergens and pollutants.[17]
- Cold weather can make it harder for asthmatics to breathe.[81] Whether high altitude helps or worsens asthma is debatable and may vary from person to person.[82]
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.[83] Szentivanyi's Beta Adrenergic Theory is a citation classic[84] using the Science Citation Index and has been cited more times than any other article in the history of the Journal of Allergy and Clinical Immunology.
In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[85] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[86]
Asthma and sleep apnea
It is recognized with increasing frequency that patients who have both obstructive sleep apnea and asthma often improve tremendously when the sleep apnea is diagnosed and treated.[87] CPAP is not effective in patients with nocturnal asthma only.[88]
Asthma and gastro-esophageal reflux disease
If gastro-esophageal reflux disease (GERD) is present, the patient may have repetitive episodes of acid aspiration. GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma.[89]
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:[90]
- ≥20% difference on at least three days in a week for at least two weeks;
- ≥20% improvement of peak flow following treatment, for example:
- ≥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.
In children, the key to asthma diagnosis is the sound of wheezing or a high-pitched sound upon exhalation. Other clues are recurrent wheezing, breathing difficulty, or chest tightness, or a history of coughing that is worse at night. The doctor should also know if the child's symptoms are worse with exercise, colds,or exposure to certain irritants such as smoke, emotional stress, or changes in the weather. [72]
Other information important to diagnosis is the age at which symptoms began and how they progressed, the timing and pattern of wheezing, when and how often a child had to visit a clinic or hospital emergency department because of symptoms, whether the child ever took bronchodilator medication for the symptoms and the nature of the response to medication. [72]
Although pediatricians may tend to ask parents for information about their children's symptoms, studies suggest that children themselves are reliable sources as early as age 7 and perhaps even as early as age 6.[91]
In adults and older children, diagnosis can be made with spirometry or a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication. The latest guidelines from the U.S. National Asthma Education and Prevention Program (NAEPP) recommend spirometry at the time of initial diagnosis, after treatment is initiated and symptoms are stabilized, whenever control of symptoms deteriorates, and every 1 or 2 years on a regular basis.[92]
The NAEPP guidelines do not recommend testing peak expiratory flow as a regular screening method, because it is more variable than spirometry. However, testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. It may also be useful for daily self-monitoring and for checking the effects of new medications.[92] Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software. This allows patients to track their peak flow readings and pass information back to their doctor or nurse.[93]
In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,[94] along with pulse oximetry which shows the percentage of hemoglobin that is carrying oxygen, 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.
Differential diagnosis
Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician 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). Among elderly patients, the presenting symptom may be fatigue, cough, or difficulty breathing, all of which may be erroneously attributed to COPD, congestive heart failure, or simple aging.[95]
After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. Occasionally, a bronchial challenge test may be performed using methacholine or histamine to assess bronchial hyperresponsiveness.
Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.[96]
Pulmonary aspiration, 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. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.
In some people, asthma-like symptoms may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids.
A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.[97]
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. Allergy tests can help identify avoidable symptom triggers.
Asthma is categorized by the United States National Heart, Lung, and Blood Institute as falling into one of four categories: intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.
Prevention and Control
Prevention of the development of asthma is different from prevention of asthma episodes. Aggressive treatment of mild allergy with immunotherapy has been shown to reduce the likelihood of asthma development. In controlling symptoms, the crucial first step in treatment is for patient and doctor to collaborate in establishing a specific plan of action to prevent episodes of asthma by avoiding triggers and allergens, regularly testing for lung function, and using preventive medications (see especially "Control of Environmental Factors" @ http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.)
Current treatment protocols recommend controller 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 controller drugs are added until almost all asthma symptoms are prevented. With the proper use of control drugs, asthmatics can avoid the complications that result from overuse of rescue medications.
Asthmatics sometimes stop taking their controller medication when they feel fine and have no problems breathing. This often results in further attacks after a time, and no long-term improvement.
The only preventive agent known is allergen immunotherapy. Controller medications include the following:
- Inhaled glucocorticoids are the most widely used 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. High doses of steroids may cause osteoporosis. These side effects are generally not seen with the inhaled steroids when used in conventional doses for control of asthma due to the smaller dose which is targeted to the lungs, unlike the higher doses of oral or injected preparations. Patients on the highest doses of inhaled steroids should take prophylactic treatment (usually Calcium and exercise, but sometimes Fosamax or similar) to prevent osteoporosis. Deposition of steroids in the mouth may result in oral thrush. Deposition near the vocal cords can cause hoarse voice. These may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer. Spacers also generally increase the amount of drug that reaches the lungs. A new agent, ciclesonide, is inactive until activated in the lung. For this reason changing to ciclesonide can relieve dysphonia in some patients.
- Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton) provide both anti-spasm and anti-inflammatory effects. In general they are weaker than inhaled corticosteroids, but the do not have any steroid side-effects and the benefit is additive with inhaled steroid.
- Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil). These medications are believed to prevent the initiation of the allergy reaction, by stabilizing the mast cell. They are not effective once the reaction has already begun, and typically must be used 4 times a day for maximal effect. But they do truly prevent asthma symptoms and are nearly free of side-effects.
- Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium). These agents both relieve spasm and reduce formation of mucous. They are more effective in patients with empysema or 'smokers lung.' They are rarely effective in asthma and are not true asthma controller medications.
- Methylxanthines (theophylline and aminophylline). These agents are bronchodilators with minimal anti-inflammatory effect. At one time they were the only effective asthma medications available. They are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoid, leukotriene modifier, and long-acting β-agonist combintaions.
- Antihistamines are often used to treat the nasal allergies which can accompany asthma. Older agents are too drying and can result in thick mucous so should be avoided. Newer antihistamines which do not have this effect can safely be used by asthmatics.
- Allergy Desensitization, also known as allergy immunotherapy, may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Allergy shots are dangerous in severe asthma and in uncontrolled asthma. However if allergy immunotherapy is started early in the disease there is a good chance that a remission of asthma can be induced (aka "asthma cure"). Typically the need for medication is reduced by about half with injection allergy immunotherapy, when done correctly. If a patient is only allergic to one or two items, oral allergy immunotherapy can be used. This is safe, much easier in young children, and is about half as effective. Unfortunately if a patient is allergic to more than 2 or 3 items then oral therapy cannot be given in a dose which is proven safe and effective.
- Omalizumab, an IgE blocker, can help patients with severe allergic asthma that is not well controlled with other drugs. It is expensive, but not compared with hospitalization(s). It requires regular injections.
- 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.
- Chronic sinus disease may be a contributing factor in difficult to control asthma, and should be evaluated.
Trigger avoidance
As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways, including an increased severity of symptoms (likely due to increased inflammation[98]), a more rapid decline of lung function, and decreased response to preventive medications.[99] Automobile emissions are considered an even more significant cause and aggravating factor.[citation needed] Asthmatics who smoke or who live near traffic[citation needed] typically require additional medications to help control their disease. Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.[100] Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.[101] Air filters and room air cleaners may help prevent some asthma symptoms.[102] Ozone is also considered as a major factor in increasing asthma.[103]
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.[8]
Diet and Supplements
Eating a healthy balanced diet with plenty of fruits and vegetables is important to staying healthy, particularly for people with asthma. Recent clinical studies have shown that people with asthma tend to eat fewer fruits and vegetables and are often deficient in nutrients such as Vitamin C, Magnesium and Selenium[citation needed]. In addition, increased intake of Omega 3 Fatty Acids has been shown to decrease inflammation[citation needed].
Vitamin C is a key vitamin antioxidant present in the extracellular fluid lining the lungs. Low intake of Vitamin C has been related to pulmonary dysfunction and several studies have shown that increasing Vitamin C intake may improve lung function in people with asthma and provide a protective effect against exercise-induced asthma.[104] While results have been positive, it is unlikely that Vitamin C alone will attenuate the effects of asthma. Larger and methodologically stronger studies are necessary before Vitamin C can be recommended for people with asthma.[105]
Magnesium is an essential mineral that has been shown to provide bronchodilating effects in people with asthma[citation needed]. In addition, clinical studies have shown that people with asthma may be deficient in Magnesium and that this mineral may play a role in asthma[citation needed]. However, it has not yet been unequivocally established that all asthmatics are deficient in this important mineral, because it is difficult to measure. More studies are needed to determine the role of Magnesium supplementation in the treatment for asthma. It is proven, however, that Magnesium sulfate intravenous treatment greatly improves pulmonary function when used in addition to conventional treatment in severe acute asthma attacks.[106]
Selenium is a trace mineral that is essential to good health. It is thought that deficiency of selenium may play some role in the development of asthma[citation needed]. Because selenium is important to the production of antioxidants, it is said that selenium deficiency may increase oxidative stress on the body, which may be a factor in chronic diseases such as asthma[citation needed]. Some clinical studies suggest that selenium supplementation for people with chronic asthma may help to improve symptoms[citation needed], however more research is needed to confirm these results.[107]
Treatment
Perhaps the most important step in controlling asthma is establishing a partnership between doctor and patient (whether child or adult) to create a specific, customized plan for proactively monitoring and managing symptoms. It is essential to be certain that someone who has asthma understands (and takes an active part in deciding) what needs to be accomplished, including reducing exposure to allergens, taking medical tests to assess the severity of symptoms, and possibly using medications. The treatment plan should be written down, consulted at every visit, and adjusted according to changes in symptoms.[108]
The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. If trigger avoidance is insufficient, medical treatment is available. Desensitization has been suggested as a possible cure.[109] Additionally, some trial subjects were able to remove their symptoms by retraining their breathing habits with the Buteyko method.[110]
Other forms of treatment include relief medication, prevention medication, long-acting β2-agonists, and emergency treatment.
Medical
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)[101] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[111] are broadly used and supported by many doctors.
The Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma of the U.S. National Asthma Education and Prevention Program, released in 2007, presented a focused 6-step approach to asthma management, based on four principles that act as a blueprint to guide individualized treatment:
- Frequent and regular assessment of symptoms
- Patient education
- Control of environmental triggers
- Systematic evaluation of the effectiveness and safety of medications.
The 2007 revised NAEPP guidelines differ from the earlier version in an increased focus on asthma control and individualized treatment, reorganizing the goals of treatment to differentiate risk from impairment. They specify defined measures that should prompt a decision to "step up" or "step down" the intensity of treatment, and they emphasize education and integrated decision-making to encourage patient self-management. [112]
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 mast-cell stabilizer, or theophylline 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.
Pharmaceutical agents
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 vapour, 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 USAN), levalbuterol, terbutaline and bitolterol.
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. 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, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[113] [114] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[113] 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.
- Inhaled glucocorticoids are usually considered preventive medications while oral glucocorticoids are often used to supplement treatment of a severe attack. They should be used twice daily in children with mild to moderate persistent asthma.[115] A randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.[116]
Long-acting β2-agonists
Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer side chains 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 2005, the American 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.[117] In December 2008, members of the FDA's drug-safety office recommended withdrawing approval for these medications in children. Discussion is ongoing about their use in adults.[118]
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). Another combination is budesonide/formoterol which is commercially known as Symbicort.
A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. The study, published in the Annals of Internal Medicine in 2006, found that long-acting beta-agonists increased the risk for asthma hospitalizations and asthma deaths 2- to 4-fold, compared with placebo.[119] "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 press release after the publication of the study. The release goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".[120] This assertion is viewed by many asthma specialists as being inaccurate. Dr. Hal Nelson, in a recent letter to the Annals of Internal Medicine, points out the following:
- "Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts."
Dr. Shelley Salpeter, in a letter to the Annals of Internal Medicine, responds to the comments of Dr. Nelson, as follows:
- "It is true that the asthma death rate increased after salmeterol was introduced, then peaked and is now starting to decline despite continued use of the long-acting beta-agonists. This trend in death rates can best be explained by examining the ratio of beta-agonist use to inhaled corticosteroids... In the recent past, inhaled corticosteroid use has increased steadily while long-acting beta-agonist use has begun to stabilize and short-acting beta-agonist use has declined... Using this estimate, we can imagine that if long-acting beta-agonists were withdrawn from the market while maintaining high inhaled corticosteroid use, the death rate in the United States could be reduced significantly..."
Emergency
When an asthma attack is unresponsive to a patient's usual medication, other treatment options available for emergency management include:[121]
- Oxygen to alleviate the hypoxia that results from extreme asthma attacks (but not the asthma attack itself).
- 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). Some research has looked into an alternative inhaled route.[122]
- Other bronchodilators that are occasionally effective when the usual drugs fail:
- Intravenous salbutamol
- Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
- Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
- 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
- Intubation and mechanical ventilation, for patients in or approaching respiratory arrest.
- Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a more laminar flow than ambient air and moves more easily through constricted airways.
Non-medical treatments
Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.[123][124] There is little data to support the effectiveness of most of these therapies. However, the Buteyko method of controlling hyperventilation hypocapnia has shown in five randomized controlled trials to result in a significant reduction in need for medications without an effect on bronchial hyperreactivity or lung function.[125][126][127][128][129] In May 2008 the updated British Guidelines for the Management of Asthma endorsed Buteyko Technique.[130] A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.[131] A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[132] Another systematic study reviewed a range of dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others. Overall these methods had no effect on asthma symptoms .[133] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvres, found there is insufficient evidence to support or refute their use in treating asthma;[134] these manoeuvers 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." One meta-analysis finds that homeopathy may have a potentially mild benefit in reducing the intensity of symptoms.[135] However, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.[136] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs,[137] yogasanas, Pranayama, meditation, and kriyas, to Sahaja yoga,[138] a form of 'new religious' meditation.[139] A study, performed by scientists at Egypt's Tanta University, has found that a combination of omega-3, vitamin C and zinc may improve the symptoms of asthma.
Treatment controversies
In November 2007 The New York Times reported a review of more than 500 studies finding that independently backed studies on inhaled corticosteroids are up to four times more likely to find adverse effects than studies paid for by drug companies.[140][141]
Prognosis
The prognosis for asthmatics is good, especially for children with mild disease.[72] Of asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes.[68] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters.[142] 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 6,000 deaths per year in a population of some 10 million patients in the United States.[8] Better control of the condition may help prevent some of these deaths.
Epidemiology
The
prevalence of childhood asthma has increased since 1980, especially in younger children.
Tracking the epidemiology of asthma is confounded by changes in how asthma has been described and defined over the decades. Most epidemiological studies use questionnaires, self-reports of asthma symptoms, and reports of physician diagnosis of asthma.[71] This information may or may not be accompanied by objective pulmonary function data.[143] All factors considered, even studies that maintain a constant definition of "asthma" throughout time show worldwide increases in asthma prevalence since the 1960s.[144]
The International Study of Asthma and Allergies in Childhood (ISAAC), a monumental study which involved 155 centers in 56 countries was one of the first to reliably compare the prevalence of asthma worldwide.[145] Surveying nearly half a million children 13–14 years of age, this study found great disparities (as high as a 20 to 60-fold difference) in asthma prevalence across the world, with a trend toward more developed and westernized countries having higher asthma prevalence. Rote westernization however does not explain the entire difference in asthma prevalence between countries, and the disparities may also be affected by differences in genetic, social and environmental risk factors.[13] There are also worldwide disparities in asthma mortality, which is most common in low to middle income countries.[146] Asthma symptoms were most prevalent (as much as 20%) in the United Kingdom, Australia, New Zealand, and Republic of Ireland; they were lowest (as low as 2–3%) in Eastern Europe, Indonesia, Greece, Uzbekistan, India, and Ethiopia.[145]
Current research therefore suggests that the prevalence of childhood asthma has been increasing, and this increased prevalence is greater than that in adults. [147] According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980 (see figure). The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago.[148]
Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate 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. Striking increases in asthma prevalence have been observed in populations migrating from a rural environment to an urban one, [149] or from a third-world country to Westernized one.[150]
History
Asthma was long considered a psychosomatic disease, and
- ... during the 1930s–50s, was even known as one of the 'holy seven' psychosomatic illnesses. At that time, psychoanalytic theories described the aetiology of asthma as psychological, with treatment often primarily involving psychoanalysis and other 'talking cures'. As the asthmatic wheeze was interpreted as the child's suppressed cry for his or her mother, psychoanalysts viewed the treatment of depression as especially important for individuals with asthma.[151]
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