Pa Tho Physiology of Asthma

8/2/2019 Pa Tho Physiology of Asthma

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Pathophysiology of asthmaFrom Wikipedia, the free encyclopedia

Inflamed airways and bronchoconstriction in asthma results in airways narrowing and thuswheezing.

Asthma is an airway disease that can be classified physiologically as a variable and partially reversibleobstruction to air flow, and pathologically with overdeveloped mucus glands, airway thickening due toscarring and inflammation, and bronchoconstriction, the narrowing of the airways in the lungs due to thetightening of surrounding smooth muscle. Bronchial inflammation also causes narrowing due to edema andswelling caused by an immune response to allergens.

Bronchoconstriction

Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basementmembrane thickening and severe inflammation of bronchiole.

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 theresult of an immune response in the bronchial airways.

[1]

The airways of asthma patients are "hypersensitive" to certain triggers, also known as stimuli(see below). (Itis usually classified as type I hypersensitivity.)

[2][3]In response to exposure to these triggers,

the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to afurther narrowing of the airways and excessivemucus production, which leads to coughing and otherbreathing difficulties. Bronchospasm may resolve spontaneously in 12 hours, or in about 50% of subjects,may become part of a 'late' response, where this initial insult is followed 312 hours later with furtherbronchoconstriction and inflammation.

[4]

The normal caliber of the bronchus is maintained by a balanced functioning of these systems, which bothoperate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate underthe 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 pathwayto again reach the bronchial small airways. Acetylcholine is released from the efferent nerve endings. Thisacetylcholine results in the excessive formation of inositol 1,4,5-trisphosphate (IP3) in bronchial smoothmuscle cells which leads to muscle shortening and this initiates bronchoconstriction.

Bronchial inflammation

The mechanisms behind allergic asthmai.e., asthma resulting from an immune response toinhaled allergensare the best understood of the causal factors. In both people with asthma and peoplewho are free of the disease, inhaled allergens that find their way to the innerairways are ingested by a type


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of cell known as antigen-presenting cells, or APCs. APCs then "present" pieces of the allergen tootherimmune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignorethe allergen molecules. In asthma patients, 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 immunesystem. The humoral immune system produces antibodiesagainst the inhaled allergen. Later, when a patient

inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammationresults: chemicals are produced that cause the wall of the airway to thicken, cells which produce scarring toproliferate and contribute to further 'airway remodeling', causes mucus producing cells to grow larger andproduce more and thicker mucus, and the cell-mediated arm of the immune system is activated. Inflamedairways 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 lifeleads to a long-term domination of the cells involved in allergic responses over those involved in fightinginfection. 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 T H1 response and reduce the odds ofdeveloping asthma.

[5]

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;

[6]

Indoorair pollution from volatile organic compounds, including perfumes and perfumed products.Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, papertowels, 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-basedpaint.

[6][7]

Medications, including aspirin,[8]-adrenergic antagonists (beta blockers),[9] and penicillin.[10] 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[11]

Sulfite sensitivity Asthma can occur in reaction to ingestion or inhalation of sulfites, which are

added to foods and wine as preservatives.[12]

Salicylate sensitivity Salicylates can trigger asthma in sensitive individuals. Salicylates occur

naturally in many healthy foods. Aspirin is also a salicylate.[13]

Use offossil fuel related allergenicair pollution, such as ozone, smog, summer smog, nitrogendioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence ofasthma in urban areas.

[7]

Various industrial compounds (e.g. toluene diisocyanate[14]) and other chemicals,notably sulfites; chlorinated swimming pools generate chloraminesmonochloramine (NH2Cl),dichloramine (NHCl2) and trichloramine (NCl3)in the air around them, which are known to induceasthma.

[15]

Early childhood infections, especially viralupper respiratory tract infections. Children who sufferfrom frequent respiratory infections prior to the age of six are at higher risk of developingasthma,

[16]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 befrom another category (e.g. pollen) and absent at the time of infection. In many cases, significantasthma may not even occur until the respiratory infection is in its waning stage, and the person isseemingly improving.

[7]In children, the most common triggers are viral illnesses such as those that

cause the common cold.[17]

Exercise or intense use of respiratory systemthe 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 ofthe airway epithelium to cold, dry air.

Hormonal changes in adolescent girls and adult women associated with theirmenstrual cycle canlead to a worsening of asthma. Some women also experience a worsening of their asthmaduring pregnancy whereas others find no significant changes, and in other women their asthmaimproves during their pregnancy.

[7]

Psychological stress. There is growing evidence that psychological stress is a trigger. It canmodulate the immune system, causing an increased inflammatory response to allergens andpollutants.

[18]


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Cold weather can make it harder for patients to breathe. [19] Whether high altitude helps or worsensasthma is debatable and may vary from person to person.

[20]

Pathogenesis

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

In 1968Andor Szentivanyi first described The Beta AdrenergicTheory of Asthma; in which blockage of theBeta-2 receptors of pulmonary smooth muscle cells causes asthma.

[21]Szentivanyi's Beta Adrenergic

Theory is a citation classic[22]

using the Science Citation Index and has been cited more times than any otherarticle in the history of the Journal of Allergy and Clinical Immunology.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[23]

Since overproductionof IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.

[24]

Asthma and sleep apnea

It is recognized with increasing frequency that patients who have both obstructive sleep apnea and asthmaoften improve tremendously when the sleep apnea is diagnosed and treated.

[25]CPAP is not effective in

patients with nocturnal asthma only.[26]

Asthma and gastro-esophageal reflux disease

Ifgastro-esophageal reflux disease (GERD) is present, the patient may have repetitive episodes of acidaspiration. GERD may be common in difficult-to-control asthma, but according to one study, treating it doesnot seem to affect the asthma.

[27]When there is a clinical suspicion for GERD as the cause of the asthma,

anEsophageal pH Monitoring is required to confirm the diagnosis and establish the relationship betweenGERD and asthma.

AsthmaFrom Wikipedia, the free encyclopedia

Asthma (from the Greek , sthma, "panting") is the common chronicinflammatory disease ofthe airways characterized by variable and recurring symptoms, reversible airflow obstruction,and bronchospasm.

[1]Symptoms includewheezing, coughing, chest tightness, and shortness of

breath.[2]

Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in1 second (FEV1), and peak expiratory flow rate.

[3]Asthma may also be classified asatopic (extrinsic) or non-

atopic (intrinsic).[4]

It is thought to be caused by a combination of genetic and environmental factors.[5]

Treatment of acutesymptoms is usually with an inhaled short-acting beta-2 agonist(such as salbutamol).

[6]Symptoms can be

prevented by avoiding triggers, such asallergens[7]

and irritants, and byinhaling corticosteroids.

[8]Leukotriene antagonistsare less effective than corticosteroids and thus less

preferred.[9]

Its diagnosis is usually made based on the pattern of symptoms and/or response to therapy overtime.

[10]The prevalence of asthma has increased significantly since the 1970s. As of 2010, 300 million

people were affected worldwide.[11]

In 2009 asthma caused 250,000 deaths globally.[12]

Despite this, withproper control of asthma with step down therapy, prognosis is generally good.

[13]

Classification

Asthma is defined by the Global Initiative for Asthma as "a chronic inflammatory disorder of the airways inwhich many cells and cellular elements play a role. The chronic inflammation is associated with airway


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hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness andcoughing particularly at night or in the early morning. These episodes are usually associated withwidespread, but variable airflow obstruction within the lung that is often reversible either spontaneously orwith treatment".

[14]

Clinical classification of severity[3]

Severity inpatients 12 years ofage

[15]

Symptomfrequency

Night timesymptoms

%FEV1 ofpredicted

FEV1Variability

Use of short-actingbeta2agonistfor symptomcontrol (notforprevention ofEIB)

Intermittent 2 per week2 permonth

80% 2 per weekbut not daily

34 permonth

80% 2030%>2 days/weekbut not daily

Moderatepersistent

Daily>1 per weekbut notnightly

6080% >30% Daily

Severepersistent

Throughoutthe day

Frequent(often7/week)

30%Several timesper day

Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second(FEV1), and peak expiratory flow rate.

[3]Asthma may also be classified as atopic (extrinsic) or non-atopic

(intrinsic), based on whether symptoms are precipitated by allergens (atopic) or not (non-atopic).[4]

While asthma is classified based on severity, at the moment there is no clear method for classifying differentsubgroups of asthma beyond this system.

[16]Within the classifications described above, although the cases

of asthma respond to the same treatment differs, thus it is clear that the cases within a classification havesignificant differences.

[16]Finding ways to identify subgroups that respond well to different types of

treatments is a current critical goal of asthma research.[16]

Although asthma is achronicobstructive condition, it is not considered as a part ofchronic obstructivepulmonary disease as this term refers specifically to combinations of disease that are irreversible suchas bronchiectasis, chronic bronchitis, and emphysema.

[15]Unlike these diseases, the airway obstruction in

asthma is usually reversible; however, if left untreated, the chronic inflammation of the lungs during asthmacan become irreversible obstruction due to airway remodeling.

[17]In contrast to emphysema, asthma affects

the bronchi, not the alveoli.[18]


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Brittle asthma

Main article: Brittle asthma

Brittle asthma is a term used to describe two types of asthma, distinguishable by recurrent, severeattacks.

[19]Type 1 brittle asthma refers to disease with wide peak flow variability, despite intense medication.

Type 2 brittle asthma describes background well-controlled asthma, with sudden severe exacerbations.[19]

Asthma attack

An acute asthma exacerbation is commonly referred to as anasthma attack. The classic symptomsare shortness of breath, wheezing, and chest tightness.

[20]While these are the primary symptoms of

asthma,[21]

some people present primarily with coughing, and in severe cases, air motion may besignificantly impaired such that no wheezing is heard.

[19]

Signs which occur during an asthma attack include the use of accessory muscles of respiration(sternocleidomastoid and scalene muscles of the neck), there may be a paradoxical pulse (a pulse that isweaker during inhalation and stronger during exhalation), and over-inflation of the chest.

[22]A blue colorof

the skin and nails may occur from lack of oxygen.[23]

In a mild exacerbation the peak expiratory flow rate (PEFR) is 200 L/min or 50% of the predicted

best.[24]

Moderate is defined as between 80 and 200 L/min or 25% and 50% of the predicted best whilesevere is defined as 80 L/min or 25% of the predicted best.

[24]

Insufficient levels of vitamin D are linked with severe asthma attacks.[25]

Status asthmaticus

Main article: Statusasthmaticus

Status asthmaticus is an acute exacerbation of asthma that does not respond to standard treatments ofbronchodilators and steroids. Nonselective beta blockers (such as Timolol) have caused fatal statusasthmaticus.

[26]

Exercise induced

Main article: Exercise-inducedasthma

A diagnosis of asthma is common among top athletes. One survey of participants in the 1996SummerOlympic Games, inAtlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that10% were on asthma medication.

[27]

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, andlong-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much ofthese disparities are from the effects of training in the sport.

[27][28]

Exercise induced asthma can be treated with the use of a short-acting beta2 agonist.[15]

Occupational

Main article: Occupationalasthma

Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupationalrespiratory 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 1523% of new-onset asthma cases inadults are work related.

[29]In one study monitoring workplace asthma by occupation, the highest percentage

of cases occurred among operators, fabricators, and laborers (32.9%), followed by managerial andprofessional specialists (20.2%), and in technical, sales, and administrative support jobs (19.2%). Mostcases were associated with themanufacturing (41.4%) and services (34.2%) industries.

[29]Animal


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proteins, enzymes, flour, natural rubberlatex, and certain reactive chemicals are commonly associated withwork-related asthma. When recognized, these hazards can be mitigated, dropping the risk of disease.

[30]

Signs and symptoms

Common symptoms of asthma include wheezing, shortness of breath, chest tightness and coughing, anduse of accessory muscle. Symptoms are often worse at night or in the early morning, or in response toexercise or cold air.[31] Some people with asthma only rarely experience symptoms, usually in response totriggers, whereas other may have marked persistent airflow obstruction.

[32]

Gastro-esophageal reflux disease

Gastro-esophageal reflux disease coexists with asthma in 80% of people with asthma, with similarsymptoms. Various theories say that asthma could facilitate GERD and/or viceversa. The first case could bedue to the effect of change in thoracic pressures, use of antiasthma drugs, could facilitate the passage of thegastric content back into the oesophagus by increasing abdominal pressure or decreasing the loweresophageal sphincter. The second by promoting bronchoconstriction and irritation by chronic acid aspiration,vagally mediated reflexes and others factors that increase bronchial responsiveness and irritation.

[33]

Sleep disorders

Due to altered anatomy of the respiratory tract: increased upper airway adipose deposition, altered pharynxskeletal morphology, and extension of the pharyngeal airway; leading to upper airway collapse.

[34]

Causes

Asthma is caused by environmental and genetic factors.[5]

These factors influence how severe asthma isand how well it responds to medication.

[35]The interaction is complex and not fully understood.

[36]

Studying the prevalence of asthma and related diseases such as eczema and hay feverhave yieldedimportant clues about some key risk factors.

[37]The strongest risk factor for developing asthma is a history

ofatopic disease;[38]

this increases one's risk of hay fever by up to 5 and the risk of asthma by 34.[39]

Inchildren between the ages of 314, a positive skin test forallergies and an increase in immunoglobulinE increases the chance of having asthma.

[40]In adults, the more allergens one reacts positively to in a skin

test, the higher the odds of having asthma. [41]

Because much allergic asthma is associated with sensitivity to indoor allergens and because Western stylesof housing favor greater exposure to indoor allergens, much attention has focused on increased exposure tothese allergens in infancy and early childhood as a primary cause of the rise in asthma.

[42][43]Primary

prevention studies aimed at the aggressive reduction of airborne allergens in a home with infants haveshown mixed findings. Strict reduction of dust mite allergens, for example, reduces the risk of allergicsensitization to dust mites, and modestly reduces the risk of developing asthma up until the age of 8 yearsold.

[44][45][46][47]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 allergicsensitization and of developing asthma later in life.

[48][49][50]

The inconsistency of this data has inspired research into other facets of Western society and their impactupon 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 analmost epidemic rise in the prevalence of obesity.

[51][52][53][54]In Taiwan, symptoms of allergies and airway

hyper-reactivity increased in correlation with each 20% increase in body-mass index.[55]

Several factorsassociated with obesity may play a role in the pathogenesis of asthma, including decreased respiratoryfunction due to a buildup of adipose tissue (fat) and the fact that adipose tissue leads to a pro-inflammatorystate, which has been associated with non-eosinophilic asthma.

[56]

Asthma has been associated with ChurgStrauss syndrome, and individuals with immunologically mediatedurticaria may also experience systemic symptoms with generalized urticaria, rhino-conjunctivitis,


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orolaryngeal and gastrointestinal symptoms, asthma, and, at worst, anaphylaxis.[57]

Additionally, adult-onsetasthma has been associated with periocularxanthogranulomas.

[58]

Environmental

Many environmental risk factors have been associated with asthma development and morbidity in children.Recent studies show a relationship between exposure to air pollutants (e.g. from traffic) and childhoodasthma.[59] This research finds that both the occurrence of the disease and exacerbation of childhoodasthma are affected by outdoor air pollutants. High levels ofendotoxin exposure may contribute to asthmarisk.

[60]

Viral respiratory infections are not only one of the leading triggers of an exacerbation but may increase one'srisk of developing asthma especially in young children.

[15][38]

Respiratory infections such as rhinovirus, Chlamydia pneumoniae and Bordetella pertussis are correlatedwith asthma exacerbations.

[61]

Psychological stress has long been suspected of being an asthma trigger, but only in recent decades hasconvincing scientific evidence substantiated this hypothesis. Rather than stress directly causing the asthmasymptoms, it is thought that stress modulates the immune system to increase the magnitude of the airway

inflammatory response to allergens and irritants.

[62][63]

Beta blockermedications such as metoprolol may trigger asthma in those who are susceptible.[64]

Tobacco

Maternal tobacco smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms, wheezing, and respiratory infections during childhood.

[65]Low air quality, from traffic pollution

or high ozone levels,[66]

has been repeatedly associated with increased asthma morbidity and has asuggested association with asthma development that needs further research.

[62][67]

Hygiene hypothesis

Antibiotic use early in life has been linked to development of asthma

[68]

in several examples; it is thought thatantibiotics make children who are predisposed to atopic immune responses susceptible to development ofasthma because they modify gut flora, and thus the immune system (as described by the hygienehypothesis).

[69]The hygiene hypothesis (see below) is a hypothesis about the cause of asthma and other

allergic disease, and is supported by epidemiologic data for asthma.[70]

All of these things may negativelyaffect exposure to beneficial bacteria and other immune system modulators that are important duringdevelopment, and thus may cause an increased risk for asthma and allergy.

Caesarean sections have been associated with asthma, possibly because of modifications to the immunesystem (as described by the hygiene hypothesis).

[71]

Volatile organic compounds

Observational studies have found that indoor exposure to volatile organic compounds (VOCs) may be one of

the triggers of asthma, however experimental studies have not confirmed these observations.[72]

Even VOCexposure at low levels has been associated with an increase in the risk of pediatric asthma. Because thereare so many VOCs in the air, measuring total VOC concentrations in the indoor environment may notrepresent the exposure of individual compounds.

[73][74]Exposure to VOCs is associated with an increase in

the IL-4 producing Th2 cells and a reduction in IFN- producing Th1 cells. Thus the mechanism of action ofVOC exposure may be allergic sensitization mediated by a Th2 cell phenotype.

[75]Different individual

variations in discomfort, from no response to excessive response, were seen in one of the studies. Thesevariations may be due to the development of tolerance during exposure.

[76]Another study has concluded

that formaldehyde may cause asthma-like symptoms. Low VOC emitting materials should be used whiledoing repairs or renovations which decreases the symptoms related to asthma caused by VOCsand formaldehyde.

[77]In another study "the indoor concentration of aliphatic compounds (C8-C11), butanols,


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and 2,2,4-trimethyl 1,3-pentanediol diisobutyrate (TXIB) was significantly elevated in newly painteddwellings. The total indoor VOC was about 100 micrograms/m3 higher in dwellings painted in the last year".The author concluded that some VOCs may cause inflammatory reactions in the airways and may be thereason for asthmatic symptoms.

[78][79]

Phthalates

There is a significant association between asthma-like symptoms (wheezing) among preschool children andthe concentration of DEHP (phthalates) in indoor environment.

[80]DEHP (di-ethylhexyl phthalate) is a

plasticizer that is commonly used in building material. The hydrolysis product of DEHP (di-ethylhexylphthalate) is MEHP (Mono-ethylhexyl phthalate) which mimics the prostaglandins and thromboxanes in theairway leading to symptoms related to asthma.

[81]Another mechanism that has been studied regarding

phthalates causation of asthma is that high phthalates level can "modulate the murine immune response to acoallergen". Asthma can develop in the adults who come in contact with heated PVC fumes.

[82]Two main

type of phthalates, namely n-butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP), havebeen associated between the concentration of polyvinyl chloride (PVC) used as flooring and the dustconcentrations. Water leakage were associated more with BBzP, and buildings construction wereassociated with high concentrations of DEHP.

[83]Asthma has been shown to have a relationship with plaster

wall materials and wall-to wall carpeting. The onset of asthma was also related to the floorleveling plasterat home. Therefore, it is important to understand the health aspect of these materials in the indoorsurfaces.

[84]

Nitrogen Dioxide

Gas cooking stoves have emissions ofCarbon monoxide, CO2, NO2, NO, aldehydes, RSP, and otherVOCs. The exposure concentration of NO2 is 1835 ppbv, These numbers are significantly high and canhad adverse effects on asthma. The inhalation of NO2 has an increased risk of respiratory symptoms andcan change the lung function in children. According to the United States Environmental Protection

Agency[85]

it is significantly important to use the exhaust fan when cooking with gas stoves to eliminate asmany compounds from the air as possible.

The effects of NO2 on the respiratory system can be detrimental to one's health in a range of ways. Inpatients who are already asthmatic, lung function can decrease but non-asthmatic patients see no effectswith concentrations under 1000 ppb.

[86]This article states that there is a dose-response relationship

between NO2 and lung function; significant decrease in lung function at higher NO2 levels. The effects

of NO2 from gas stoves, according to this study, are inconsistent and this is because the actual amountof NO2 was not measured. However, in the indoor environment, with the use of gas stoves for cooking,children had a 20% increase of asthmatic symptoms.

Genetic

Over 100 genes have been associated with asthma in at least one genetic association study.[87]

However,such studies must be repeated to ensure the findings are not due to chance. Through the end of 2005, 25genes had been associated with asthma in six or more separate populations:

[87]

GSTM1 IL10 CTLA-4 SPINK5 LTC4S

LTA GRPA NOD1 CC16 GSTP1

STAT6 NOS1 CCL5 TBXA2R TGFB1

IL4 IL13 CD14 ADRB2 (-2 adrenergic

receptor) HLA-DRB1

HLA-DQB1

TNF FCER1B IL4R ADAM33

Many of these genes are related to the immune system or to modulating inflammation. However, evenamong this list of highly replicated genes associated with asthma, the results have not been consistentamong all of the populations that have been tested.

[87]This indicates that these genes are not associated

with asthma under every condition, and that researchers need to do further investigation to figure out thecomplex interactions that cause asthma. One theory is that asthma is a collection of several diseases, and


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that genes might have a role in only subsets of asthma.[citation needed]

For example, one group of geneticdifferences (single nucleotide polymorphisms in 17q21) was associated with asthma that develops inchildhood.

[88]

Geneenvironment interactions

CD14-endotoxin interaction based on CD14 SNP C-159T[89]

Endotoxin levels CC genotype TT genotype

High exposure Low risk High risk

Low exposure High risk Low risk

Research suggests that some genetic variants may only cause asthma when they are combined withspecific environmental exposures, and otherwise may not be risk factors for asthma.

[5]

The genetic trait, CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (abacterial product) are a well-replicated example of a gene-environment interaction that is associated withasthma. Endotoxin exposure varies from person to person and can come from several environmentalsources, including environmental tobacco smoke, dogs, and farms. Researchers have found that risk forasthma changes based on a person's genotype at CD14 C-159T and level of endotoxin exposure.

[89]

Exacerbation

Some individuals will have stable asthma for weeks or months and then suddenly develop an episode ofacute asthma. Different asthmatic individuals react differently to various factors.

[90]However, most

individuals can develop severe exacerbation of asthma from several triggering agents.[90][91]

Home factors that can lead to exacerbation include dust, house mites, animal dander(especially cat anddog hair), cockroach allergens and molds at any given home.

[90]Perfumes are a common cause of acute

attacks in females and children. Both virus and bacterial infections of the upper respiratory tract infection canworsen asthma.

[90]

Hygiene hypothesis

Main article: Hygiene hypothesis

One theory for the cause of the increase in asthma prevalence worldwide is the "hygiene hypothesis"[15]

that the rise in the prevalence of allergies and asthma is a direct and unintended result of reduced exposureto a wide variety of different bacteria and virus types in modern societies, or modern hygienic practicespreventing childhood infections.

[92]Children living in less hygienic environments (East Germany vs. West

Germany,[93]

families with many children,[94][95][96]

day care environments[97]

) tend to have lower incidences ofasthma and allergic diseases. This seems to run counter to the logic that viruses are often causative agentsin exacerbation of asthma.

[98][99][100]Additionally, other studies have shown that viral infections of the lower

airway may in some cases induce asthma, as a history ofbronchiolitis orcroup in early childhood is apredictor of asthma risk in later life.

[101]Studies which show that upper respiratory tract infections are


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protective against asthma risk also tend to show that lower respiratory tract infections conversely tend toincrease the risk of asthma.

[102]

Socioeconomic factors

The incidence of asthma is highest among low-income populations worldwide. Asthma deaths are mostcommon in low and middle income countries,

[103]and in the Western world, it is found in those low-income

neighborhoods whose populations consist of large percentages of ethnic minorities.[104] Additionally, asthmahas been strongly associated with the presence ofcockroaches in living quarters; these insects are morelikely to be found in those same neighborhoods.

[105]

Most likely due to income and geography, the incidence of and treatment quality for asthma varies amongdifferent racial groups.

[106]The prevalence of "severe persistent" asthma is also greater in low-income

communities than those with better access to treatment.[106][107]

Diagnosis

Severity of acute asthma exacerbations[19]

Near-fatal asthma High PaCO2 and/or requiring mechanical ventilation

Life threatening asthma

Any one of the following in a person with severe asthma:-

Clinical signs Measurements

Altered level of consciousness Peak flow < 33%

Exhaustion Oxygen saturation < 92%

Arrhythmia PaO2 < 8 kPa

Low blood pressure "Normal" PaCO2

Cyanosis

Silent chest

Poor respiratory effort

Acute severe asthma

Any one of:-

Peak flow 3350%

Respiratory rate 25 breaths per minute

Heart rate 110 beats per minute

Unable to complete sentences in one breath

Moderate asthma exacerbation

Worsening symptoms

Peak flow 8050% best or predicted

No features of acute severe asthma


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Obstruction of the lumen of the bronchiole by mucoid exudate, goblet cell metaplasia, epithelial basementmembrane thickening and severe inflammation of bronchiole in a patient with asthma.

There is currently not a precise physiologic, immunologic, or histologic test for diagnosing asthma. Thediagnosis is usually made based on the pattern of symptoms (airways obstruction and hyperresponsiveness)and/or response to therapy (partial or complete reversibility) over time.

[10]

The British Thoracic Society determines a diagnosis of asthma using a response to therapy approach. If thepatient responds to treatment, then this is considered to be a confirmation of the diagnosis of asthma. Theresponse measured is the reversibility of airway obstruction after treatment. Airflow in the airways ismeasured with a peak flow meterorspirometer, and the following diagnostic criteria are used by the BritishThoracic Society:[108]

20% difference on at least three days in a week for at least two weeks; 20% improvement of peak flow following treatment, for example:

10 minutes of inhaled -agonist (e.g.,salbutamol); six weeks of inhaled corticosteroid (e.g.,beclometasone); 14 days of 30 mg prednisolone.

20% decrease in peak flow following exposure to a trigger (e.g., exercise).

In contrast, the US National Asthma Education and Prevention Program (NAEPP) uses a symptom patternsapproach.

[109]Their guidelines for the diagnosis and management of asthma state that a diagnosis of asthma

begins by assessing if any of the following list of indicators is present.[109][13]

While the indicators are notsufficient to support a diagnosis of asthma, the presence of multiple key indicators increases the probability

of a diagnosis of asthma.

[109]

Spirometry is needed to establish a diagnosis of asthma.

[109]

Wheezinghigh-pitched whistling sounds when breathing outespecially in children. (Lack ofwheezing and a normal chest examination do not exclude asthma.)

history of any of the following: Cough, worse particularly at night Recurrent wheeze Recurrent difficulty in breathing Recurrent chest tightness

Symptoms occur or worsen in the presence of: Exercise Viral infection Animals with fur or hair House-dust mites (in mattresses, pillows, upholstered furniture, carpets) Mold Smoke (tobacco, wood) Pollen Changes in weather Strong emotional expression (laughing or crying hard) Airborne chemicals or dusts Menstrual cycles

Symptoms occur or worsen at night, awakening the patient


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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 arestabilized, whenever control of symptoms deteriorates, and every 1 or 2 years on a regular basis.

[110]The

NAEPP guidelines do not recommend testing peak expiratory flow as a regular screening method because itis more variable than spirometry. However, testing peak flow at rest (or baseline) and after exercise can behelpful, especially in young patients who may experience only exercise-induced asthma. It may also beuseful for daily self-monitoring and for checking the effects of new medications.

[110]Peak flow readings can

be charted together with a record of symptoms or use peak flow charting software. This allows patients totrack their peak flow readings and pass information back to their doctor or respiratory therapist.[111]

Differential diagnosis

Differential diagnoses include:[109]

Infants and Children Upper airway diseases

Allergic rhinitisand allergic sinusitis Obstructions involving large airways

Foreign body in trachea or bronchus Vocal cord dysfunction Vascular rings orlaryngeal webs Laryngotracheomalacia, tracheal stenosis, orbronchostenosis Enlarged lymph nodes or tumor

Obstructions involving small airways Viral bronchiolitis orobliterative bronchiolitis Cystic fibrosis Bronchopulmonary dysplasia Heart disease

Other causes Recurrent cough not due to asthma Aspiration from swallowing mechanism dysfunction or gastroesophageal reflux Medication induced

Adults COPD (e.g., chronic bronchitis or emphysema) Congestive heart failure Pulmonary embolism Mechanical obstruction of the airways (benign and malignant tumors) Pulmonary infiltration with eosinophilia Cough secondary to drugs (e.g., angiotensin-converting enzyme (ACE) inhibitors) Vocal cord dysfunction

Before diagnosing asthma, alternative possibilities should be considered such as the use of knownbronchoconstrictors (substances that cause narrowing of the airways, e.g. certain anti-inflammatory agentsorbeta-blockers). Among elderly people, the presenting symptom may be fatigue, cough, or difficultybreathing, all of which may be erroneously attributed to Chronic obstructive pulmonarydisease(COPD), congestive heart failure, or simple aging.

[112]

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronicasthma. After the age of 65 most people with obstructive airway disease will have asthma and COPD. In thissetting, COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness,and increased smooth muscle in the bronchi. However, this level of investigation is not performed due toCOPD and asthma sharing similar principles of management: corticosteroids, long acting beta agonists, andsmoking cessation.

[113]It closely resembles asthma in symptoms, is correlated with more exposure to

cigarette smoke, an older age, less symptom reversibility after bronchodilator administration (as measuredby spirometry), and decreased likelihood of family history ofatopy.

[114][115]


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Others

The term "atopy" was coined to describe this triad of atopic eczema, allergic rhinitis and asthma.[57]

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 aspirationpneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a modified barium swallow test. Ifthe aspiration is indirect (from acid reflux), then treatment is directed at this is indicated. [citation needed]

Prevention

The evidence for the effectiveness of measures to prevent the development of asthma is weak.[116]

Oneswhich show some promise include limiting smoke exposure both in utero and after delivery, breastfeeding,increased exposure to respiratory infection per the hygiene hypothesis (such as in those who attend daycareor are from large families).

[116]

Management

A specific, customized plan for proactively monitoring and managing symptoms should be created.Someone who has asthma should understand the importance of reducing exposure to allergens, testing to

assess the severity of symptoms, and the usage of medications. The treatment plan should be written downand adjusted according to changes in symptoms.

[117]

The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, oraspirin, andeliminating exposure to them. If trigger avoidance is insufficient, medical treatment is recommended.Medical treatments used depend on the severity of illness and the frequency of symptoms. Specificmedications for asthma are broadly classified into fast-acting and long-acting categories.

[118][119]

Bronchodilators are recommended for short-term relief of symptoms. In those with occasional attacks, noother medication is needed. If mild persistent disease is present (more than two attacks a week), low-doseinhaled glucocorticoids or alternatively, an oral leukotriene antagonist or a mast cell stabilizerisrecommended. For those who suffer daily attacks, a higher dose of inhaled glucocorticoid is used. In asevere asthma exacerbation, oral glucocorticoids are added to these treatments.

[109]

Lifestyle modification

Avoidance of triggers is a key component of improving control and preventing attacks. The most commontriggers include allergens, smoke (tobacco and other), air pollution, non selective beta-blockers, and sulfite-containing foods.

[109][120][121][122]

Cigarette smoking and second hand smoke (passive smoke) in regard to people with asthma causesproblems in effectiveness of management medications such as steroid/corticosteroid therapies.

[123]

Medications

Medications used to treat asthma are divided into two general classes: quick-relief medications used to treatacute symptoms; and long-term control medications used to prevent further exacerbation.

[118]

Fast acting

Salbutamol metered dose inhaler commonly used to treat asthma attacks.

Short acting beta2-adrenoceptor agonists (SABA), such as salbutamol (albuterolUSAN) are thefirst line treatment for asthma symptoms.

[6]

Anticholinergic medications, such as ipratropium bromide, provide additional benefit when used incombination with SABA in those with moderate or severe symptoms.

[6]Anticholinergic bronchodilators

can also be used if a person cannot tolerate a SABA.[15]


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Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy toSABAs.

[124]They are however not recommended due to concerns regarding excessive cardiac

stimulation.[125]

Long term control

Fluticasone propionate metered dose inhaler commonly used for long term control.

Glucocorticoids are the most effective treatment available for long term control. [118] Inhaled formsare usually used except in the case of severe persistent disease, in which oral steroids may beneeded.

[118]Inhaled formulations may be used once or twice daily, depending on the severity of

symptoms.[126]

Long acting beta-adrenoceptor agonists (LABA) have at least a 12-hour effect. They are howevernot to be used without a steroid due to an increased risk of severe symptoms.

[127][128][129]In December

2008, members of the FDA's drug-safety office recommended withdrawing approval for thesemedications in children. Discussion is ongoing about their use in adults.

[130]

Leukotriene antagonists (such as zafirlukast) are an alternative to inhaled glucocorticoids, but arenot preferred. They may also be used in addition to inhaled glucocorticoids but in this role are secondline to LABA.

[118]

Mast cell stabilizers (such as cromolyn sodium) are another non-preferred alternative toglucocorticoids.[118]

Delivery methods

Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthmaspaceror as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, makingit easier to receive a full dose of the drug. A nebulizermay also be used. Nebulizers and spacers are equallyeffective in those with mild to moderate symptoms however insufficient evidence is available to determinewhether or not a difference exists in those severe symptomatology.

[131]

Safety and adverse effects

Long-term use of glucocorticoids carries a significant potential for adverse effects. The incidence

ofcataracts is increased in people undergoing treatment for asthma with corticosteroids, due to alteredregulation of lens epithelial cells.

[132]The incidence ofosteoporosis is also increased, due to changes

in bone remodeling.[133][134]

Other

When asthma is unresponsive to usual medications, other options are available for both emergencymanagement and prevention of flairs. For emergency management other options include:

Oxygen is used to alleviate hypoxia ifsaturations fall below 92%.[135] Magnesium sulfate intravenous treatment has been shown to provide a bronchodilating effect when

used in addition to other treatment in severe acute asthma attacks.[136][137]

Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases. [137] Intravenous salbutamol is not supported by available evidence and is thus used only in extreme

cases.[135]

Methylxanthines (such as theophylline) were once widely used, but do not add significantly to theeffects of inhaled beta-agonists.

[135]

The dissociative anesthetic ketamine is theoretically useful ifintubation and mechanicalventilation is needed in people who are approaching respiratory arrest; however, there is no evidencefrom clinical trials to support this.

[138]

For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs bronchialthermoplasty can lead to clinical improvements.

[139]It involves the delivery of controlled thermal energy to


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the airway wall during a series ofbronchoscopies and result in a prolonged reduction in airway smoothmusclemass.

[139]

Complementary medicine

Many people with asthma, 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.

[140][141]There

is little data to support the effectiveness of most of these therapies. Evidence is insufficient to support theusage of Vitamin C.

[142]Acupuncture is not recommended for the treatment as there is insufficient evidence

to support its use.[143][144]

Air ionisers show no evidence that they improve asthma symptoms or benefit lungfunction; this applied equally to positive and negative ion generators.

[145]

Dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers andothers methods had no effect on asthma symptoms.

[146]However, a review of 30 studies found that "bedding

encasement might be an effective asthma treatment under some conditions" (when the patient is highlyallergic to dust mite and the intervention reduces the dust mite exposure level from high levels to lowlevels).

[147]Washing laundry/rugs in hot water was also found to improve control of allergens.

[15]

A study of "manual therapies" for asthma,including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvres, found there isinsufficient evidence to support their use in treating.

[148]The Buteyko breathing technique for controlling

hyperventilation may result in a reduction in medications use however does not have any effect on lungfunction.

[119]Thus an expert panel felt that evidence was insufficient to support its use.

[143]

Prognosis

The prognosis for asthma is good, especially for children with mild disease.[13]

Of asthma diagnosed duringchildhood, 54% of cases will no longer carry the diagnosis after a decade.

[citation needed]The extent of

permanent lung damage in people with asthma is unclear. Airway remodeling is observed, but it is unknownwhether these represent harmful or beneficial changes.

[149]Although conclusions from studies are mixed,

most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung functionas measured by several parameters.

[150]For those who continue to suffer from mild symptoms,

corticosteroids can help most to live their lives with few disabilities. It is more likely to consider immediatemedication of inhaled corticosteroids as soon as asthma attacks occur. According to studies conducted,patients with relatively mild asthma who have received inhaled corticosteroids within 12 months of their first

asthma symptoms achieved good functional control of asthma after 10 years of individualized therapy ascompared to patients who received this medication after 2 years (or more) from their first attacks.

[citation

needed]Though they (delayed) also had good functional control of asthma, they were observed to exhibit

slightly less optimal disease control and more signs of airway inflammation.[citation needed]

Asthma mortality has decreased over the last few decades due to better recognition and improvement incare.

[151]

Epidemiology

Disability-adjusted life yearfor asthma per 100,000 inhabitants in 2004.[152]

no data


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600

The prevalence of childhood asthma in the United States has increased since 1980, especially in younger

children.

As of 2009, 300 million people worldwide were affected by asthma leading to approximately 250,000 deathsper year.

[12][127][153][154]

It is estimated that asthma has a 7-10% prevalence worldwide.[155]

As of 1998, there was a great disparity intheprevalence of asthma across the world, with a trend toward more developed and westernized countrieshaving higher rates of asthma

[156], with as high as a 20 to 60-fold difference. Westernization however does

not explain the entire difference in asthma prevalence between countries, and the disparities may also beaffected by differences in genetic, social and environmental risk factors.

[62]Mortality however is most

common in low to middle income countries,[157]

while symptoms were most prevalent (as much as 20%) inthe United Kingdom, Australia, New Zealand, and Republic of Ireland; they were lowest (as low as 23%) inEastern Europe, Indonesia, Greece, Uzbekistan, India, and Ethiopia.

[156]

While asthma is more common in affluent countries, it is by no means a restricted problem; the WHOestimate that there are between 15 and 20 million people with asthma in India.

[citation needed]In the U.S., urban

residents, Hispanics, and African Americans are affected more than the population as a whole.[citation

needed]Striking increases in asthma prevalence have been observed in populations migrating from a rural

environment to an urban one,[158]

or from a third-world country to Westernized one.[159]

Asthma affects approximately 7% of the population of the United States[127]

and 5% of people in the UnitedKingdom.

[160]Asthma causes 4,210 deaths per year in the United States.

[155][161]In 2005 in the United States

asthma affected more than 22 million people including 6 million children.[151]

It accounted for nearly 1/2million hospitalizations that same year.

[151]More boys have asthma than girls, but more women have it than

men.[162]

Of all children, African Americansand Latinos who live in cities are more at risk for developingasthma.

[citation needed]African American children in the U.S. are four times more likely to die of asthma and

three times more likely to be hospitalized, compared to their white counterparts.[citation needed]

In some Latinoneighborhoods, as many as one in three children has been found to have asthma.

[163]

In England, an estimated 261,400 people were newly diagnosed with asthma in 2005; 5.7 million people hadan asthma diagnosis and were prescribed 32.6 million asthma-related prescriptions.

[164]

The frequency of atopic dermatitis, asthma, urticaria and allergic contact dermatitis has been found to belower in psoriaticpatients.

[57]


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Increasing frequency

Rates of asthma have increased significantly between the 1960s and 2008.[165][166]

Some 9% of US childrenhad asthma in 2001, compared with just 3.6% in 1980. The World Health Organization (WHO) reports thatsome 10% of the Swiss population suffers from asthma today,

[167]compared with just 2% some 2530 years

ago. In the United States specifically data from several national surveys in the United States reveal the age-adjusted prevalence of asthma increased from 7.3 to 8.2 percent during the years 2001 through 2009

.[168] Previous analysis of data from 2001 to 2007 had suggested the prevalence of asthma was stable. [168]

Variability

Asthma prevalence in the US is higher than in most other countries in the world, but varies drasticallybetween diverse US populations.

[62]In the US, asthma prevalence is highest in Puerto Ricans, African

Americans, Filipinos, Irish Americans, and Native Hawaiians, and lowest in Mexicans andKoreans.

[169][170][171]Mortality rates follow similar trends, and response to salbutamol is lower in Puerto Ricans

than in African Americans or Mexicans.[172][173]

As with worldwide asthma disparities, differences in asthmaprevalence, mortality, and drug response in the US may be explained by differences in genetic, social andenvironmental risk factors.

Asthma prevalence also differs between populations of the same ethnicity who are born and live in differentplaces.

[174]US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican

populations that are living in the US.[175]

There is no correlation between asthma and gender in children. More adult women are diagnosed withasthma than adult men, but this does not necessarily mean that more adult women have asthma.

[176]

History

Asthma was first recognized and named by Hippocrates circa 450 BC. During the 1930s50s, asthma wasconsidered as being one of the 'holy seven'psychosomatic illnesses. Its aetiology was considered to bepsychological, with treatment often based on psychoanalysis and other 'talking cures'.

[177]As these

psychoanalysts interpreted the asthmatic wheeze as the suppressed cry of the child for its mother, so theyconsidered that the treatment of depression was especially important for individuals with asthma.

[177]among

the first papers in modern medicine, is one that was published in 1873 and this paper tried to explain

thepathophysiology of the disease.

[178]

And one of the first papers discussing treatment of asthma wasreleased in 1872, the author concluded in his paper that asthma can be cured by rubbing the chestwith chloroform liniment.

[179]Among the first times researchers referred to medical treatment was in 1880,

when Dr. J. B. Berkart used IV therapy to administer doses of a drug called pilocarpin.[180]

In 1886, F.H.Bosworth FH suspected a connection between asthma and hay fever.

[181]Epinephrine was first referred to in

the treatment of asthma in 1905,[182]

and for acute asthma in 1910.[183]

Asthma is common in adults over age 65 [1,2]. It substantially reduces both psychological and physical

quality of life among the elderly [2-5]. Some experts distinguish two categories of asthma in older adults. The

first category comprises older patients whose typical symptoms of asthma developed in childhood or early

adulthood and persisted through later life. Normal lung function is usually interspersed with intermittent

periods of airflow obstruction. The second category comprises patients who first develop new symptoms of

asthma as older adults. In these patients, the diagnosis may be challenging due to the higher incidence of

COPD and the longer list of differential diagnoses.

We find these two categories helpful for the discussion of the disease, but acknowledge their limitations. The

clinical course may be more complex: for example, childhood asthma usually remits in adolescence, but

often reappears later in adulthood. Evidence is lacking for the definition of these categories and for

treatment strategies based upon these categories.


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Differentiation of asthma from chronic obstructive pulmonary disease (COPD) is important because the

approach to treatment of asthma is different from that of COPD [6]. The frequent overlap of these two

disorders in clinical practice also makes the distinction challenging in some cases.

The prevalence of asthma in adults age 65 and older is about 4 to 8 percent [1,2,7]. Older adults report the

onset of their asthma relatively equally over all decades of life [8], but adult onset asthma is more likely to

become life-long when compared to asthma beginning in childhood.

Although hospitalization rates for elders with asthma generally declined during the last two decades, a

prospective cohort study in 15 managed care organizations in the United States reported that older patients

with asthma were twice as likely as young adults with asthma to be hospitalized during one year of follow-up

(14 versus 7 percent) [9]. In contrast, The Epidemiology and Natural History of Asthma: Outcomes and

Treatment Regimens (TENOR) study reported that the hospitalization rate was actually lower among the

cohort age 65 and older than the younger cohort

Pa Tho Physiology of Asthma

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