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__NOTOC__
{{Asthma}}
{{Asthma}}
{{CMG}}; [[Philip Marcus, M.D., M.P.H.]] [mailto:pmarcus192@aol.com]; {{AOEIC}} {{VK}}; {{LG}}


'''Editor(s)-in-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:mgibson@perfuse.org] Phone:617-632-7753; [[Philip Marcus, M.D., M.P.H.]] [mailto:pmarcus192@aol.com]
==Overview==
Asthma is a chronic inflammatory disease of the airways that is characterized by reversible airflow obstruction and airway inflammation, persistent airway hyperreactivity, and airway remodeling.<ref name="pmid11818486">Maddox L, Schwartz DA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11818486 The pathophysiology of asthma.] ''Annu Rev Med'' 53 ():477-98. [http://dx.doi.org/10.1146/annurev.med.53.082901.103921 DOI:10.1146/annurev.med.53.082901.103921] PMID: [http://pubmed.gov/11818486 11818486]</ref> The two major factors responsible for the pathogenesis of asthma include bronchial hyper-responsiveness and inflammatory reaction within the bronchial wall. The airways of asthmatics are [[hypersensitivity|hypersensitive]] to certain [[Asthma risk factors|triggers]] such as smoke, dust, or pollen. The term trigger is synonymous with [[Asthma pathophysiology#stimuli|stimuli]]. Exposure to these triggers causes repeated inflammation of the [[bronchiole|airways]] resulting in [[bronchospasm]]. Bronchospasm can lead to narrowing of airways and excess [[mucus]] production, making it [[Dyspnea|difficult to breathe]]. Airway inflammation is a [[Chronic (medical)|chronic]] [[inflammation]] driven by T<sub>H</sub>2 lymphocyte-predominant immune response. This immune response has been associated with [[atopy]] and [[IgE|IgE-synthesis]] through the production of [[Interleukin 4|IL-4]] and [[Eosinophilic|eosinophilic inflammation]] by means of [[Interleukin 5|IL-5]].<ref name="pmid11818486">Maddox L, Schwartz DA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11818486 The pathophysiology of asthma.] ''Annu Rev Med'' 53 ():477-98. [http://dx.doi.org/10.1146/annurev.med.53.082901.103921 DOI:10.1146/annurev.med.53.082901.103921] PMID: [http://pubmed.gov/11818486 11818486]</ref>
==Pathophyisology==
===Stimuli or Triggering Factors===
The [[allergens]] responsible for the pathogenesis of asthma enter the body either as inspired air or ingested food that subsequently stimulate the formation of [[IgE]] and result in an antigen-antibody reaction within the bronchial wall; which cause the release of active inflammatory mediators that provoke bronchial spasm and immediate asthmatic attack. Known stimuli or triggering factors include the following.


==Pathophysiology==
*[[Allergen|Allergenic air pollution]], such as: waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet [[epithelium|epithelial cells]]. These are typically inhaled and the body's introduction to the stimuli occurs through the respiratory system.
[[Image:Asthma before-after.png|thumb|left|470px|'''Inflamed airways and bronchoconstriction in asthma'''. Airways narrowed as a result of the inflammatory response cause wheezing.]]


===Bronchoconstriction===
*Indoor [[allergen|allergenic air pollution]] from [[volatile organic compound|volatile organic compounds (VCOs)]]. Potential VCOs 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 paints. This also includes perfumes and perfumed products.  
Asthma is the result of an [[immune response]] in the [[bronchial]] airways.<ref name=Maddox>Maddox L, Schwartz DA. The Pathophysiology of Asthma. ''Annu. Rev. Med.'' 2002, 53:477-98. PMID 11818486</ref>. During an asthma episode, inflamed [[bronchiole|airways]] react to the introduction of environmental triggers, such as smoke, dust, or pollen. The airways narrow and produce excess [[mucus]], making it difficult to breathe.


The airways of asthmatics are "[[hypersensitivity|hypersensitive]]" to certain triggers, also known as ''[[Asthma pathophysiology#stimuli|stimuli]]''. 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, this can lead to coughing and other breathing difficulties.
*[[Medication|Medications]] such as [[aspirin]],<ref name="pmid14976098">Jenkins C, Costello J, Hodge L (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14976098 Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice.] ''BMJ'' 328 (7437):434. [http://dx.doi.org/10.1136/bmj.328.7437.434 DOI:10.1136/bmj.328.7437.434] PMID: [http://pubmed.gov/14976098 14976098]</ref> [[beta blocker|β-adrenergic antagonists]], and [[penicillin]].


===Stimuli===
*An [[allergy]] to food such as: milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.  
* [[Allergen|Allergenic air pollution]], which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet [[epithelium|epithelial cells]]. These are typically inhaled and the body's introduction to the stimuli occurs through the respiratory system.
* Indoor [[allergen|allergenic air pollution]] from [[volatile organic compound|volatile organic compounds (VCOs)]]. This including perfumes and perfumed products.  Potential VCOs 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.
* [[Medication]]s, such as [[aspirin]],<ref name=Jenkins>Jenkins C, Costello J, Hodge L. [[Systematic review]] of prevalence of aspirin induced asthma and its implications for clinical practice. ''[[British Medical Journal|BMJ]]'' 2004;328:434. PMID 14976098</ref> [[beta blocker|β-adrenergic antagonist]]s (beta blockers), and [[penicillin]].
* Allergic to food such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.
* Use of fossil fuel related [[allergen|allergenic air pollution]], such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide. This is thought to be one of the major reasons for the high prevalence of asthma in urban areas.
* Various industrial compounds and other chemicals, notably sulfites; [[chlorine|chlorinated]] swimming pools generate [[chloramine]]s—monochloramine (NH<sub>2</sub>Cl), dichloramine (NHCl<sub>2</sub>) and trichloramine (NCl<sub>3</sub>)—in the air around them, which are known to induce asthma.<ref name=Nemery>Nemery B, Hoet PH, Nowak D. Indoor swimming pools, water chlorination and respiratory health. ''Eur Respir J''. 2002;19(5):790-3. PMID 12030714</ref>
* Early childhood [[infection|infections]], especially [[Respiratory infection|viral respiratory infections]]. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. 80% of asthma attacks in adults and 60% in children are caused by respiratory viruses.
* [[Exercise]], the effects of which differ somewhat from those of the other triggers.
* [[Allergen|Allergenic indoor air pollution]], in some countries, from newsprint & other literature such as, direct marketing/junk mail leaflets & glossy magazines.
* [[Hormone|Hormonal]] changes in adolescent girls and adult women associated with the [[menstrual cycle]] can lead to a worsening of asthma. The influence of hormones can be largely varied from person to person. 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.
* [[Stress (medicine)|Emotional stress]], the influence of this trigger is not well understood.
* '''Cold weather''' can adversely affect breathing in asthmatics.


===Bronchial inflammation===
*Use of fossil fuel, related to [[allergen|allergenic air pollution]], such as: ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide. This is believed to be one of major reasons for the high prevalence of asthma in urban areas.  
In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner [[bronchiole|airways]] are [[phagocytosis|ingested]] by antigen presenting cells, or APCs. APCs then present pieces of the allergen to other cells of [[immune system]]. In most people, these other immune cells ([[T helper cell|T<sub>H</sub>0 cells]]) usually ignore the allergen molecules. In asthmatics, however, these cells differentiate into T<sub>H</sub>2, for reasons that are not well understood. The resultant T<sub>H</sub>2 cells activate an important arm of the immune system, known as the [[humoral immunity|humoral immune system]]. The humoral immune system produces [[antibody|antibodies]] against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies recognize it and activate a humoral response. This results in inflammatory response where chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.


==Pathogenesis==
*Various industrial compounds and other chemicals. Most notably sulfites; [[chlorine|chlorinated]] swimming pools generate [[chloramine|chloramines]]— monochloramine (NH<sub>2</sub>Cl), dichloramine (NHCl<sub>2</sub>) and trichloramine (NCl<sub>3</sub>)— in the air around them, which are known to induce asthma.<ref name="pmid12030714">Nemery B, Hoet PH, Nowak D (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12030714 Indoor swimming pools, water chlorination and respiratory health.] ''Eur Respir J'' 19 (5):790-3. PMID: [http://pubmed.gov/12030714 12030714]</ref>
* The fundamental problem in asthma appears to be [[immunology|immunological]]. Young children in the early stages of asthma show signs of excessive inflammation in their airways.
* [[Epidemiology|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.<!--
*Early childhood [[infection|infections]], especially [[Respiratory infection|viral respiratory infections]]. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. 80% of asthma attacks in adults and 60% in children are caused by respiratory viruses.  
  --><ref>{{cite journal | author=Szentivanyi, Andor | title=The Beta Adrenergic Theory of the Atopic Abnormality in Asthma | jounal=J.Allergy | year=1968}}</ref>
Szentivanyi's Beta Adrenergic Theory is a citation classic<ref name=Tribute>Lockey, Richard, In lasting tribute: Andor Szentivanyi, MD. ''J. Allergy and Clinical Immunology'', January, 2006</ref> and has been cited more times than any other article in the history of the Journal of Allergy.


* In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.<!--
*[[Exercise]], see [[exercise induced asthma]]. The effects of exercise differ somewhat from those of the other triggers.
  --><ref>{{cite journal | author=Szentivanyi A., Ali K., Calderon EG., Brooks SM., Coffey RG., Lockey RF. | title=The ''in vitro'' effect of Imunnoglobulin E {IgE} on cyclic AMP concentrations in A549 human pulmonary epithelial cells with or without beta adrenergic stimulation | journal=J. Allergy Clin Immunol. | volume=91 | pages=379 | year=1993}} - Part of Abstracts from:<br/>
 
{{cite journal | author = | title = 50th Anniversary of the American Academy of Allergy and Immunology. 49th Annual Meeting. Chicago, Illinois, March 12–17, 1993. Abstracts. | journal = J Allergy Clin Immunol | volume = 91 | issue = 1 Pt 2 | pages = 141–379 | year = 1993 | id = PMID 8421135}}</ref>
*[[Allergen|Allergenic indoor air pollution]], in some countries, from newsprint & other literature such as: direct marketing/junk mail leaflets & glossy magazines.  
Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.<!--
 
  --><ref>{{cite book | editor=Kowalak JP, Hughes AS et al (eds) | title=Professional Guide To Diseases | edition=7th ed. | year=2001 | publisher=Springhouse}}</ref>
*[[Hormone|Hormone changes]] in adolescent girls and adult women, associated with the [[menstrual cycle]], can lead to a worsening of asthma. The influence of hormones can be largely varied from person to person. 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.  
 
*[[Stress (medicine)|Emotional stress]] is a recognized potential trigger/stimuli, however, the influence of such is not well understood.
 
* ''Cold weather'' can adversely affect breathing in asthmatics.
 
===Pathogenesis===
* Pathogenesis of asthma involves a number of cells such as, [[mast cells]], [[macrophages]], [[eosinophils]] and [[lymphocytes]], that cause the release of inflammatory mediators leading to the synthesis of [[IgE]] through [[IL-4]] production and [[eosinophilic|eosinophilic inflammation]] through [[IL-5]] production.
* [[Mast cells]] generate the release of inflammatory mediators such as [[histamine]], [[prostaglandin|prostaglandin D2]] and [[Leukotriene|leukotriene C4]] from the bronchial smooth muscles to cause an immediate asthmatic reaction and are found in increased concentration in the [[mucus]] secretions of asthmatics.
* [[Macrophages]], such as [[prostaglandins]], [[thromboxane]], [[Leukotriene|leukotriene C4]], are known as the ''antigen presenting cells'' that ingest the [[allergens]] and present to lymphocytes. Lmphocytes activate [[mast cells]] through the release [[IL-3]], [[IL-4]], [[IL-9]] and activate [[eosinophils]] through the release of [[IL-3]] and [[IL-5]].
* Secretion of [[IL-4]] helps in the switching of antibody production by B-cells to [[IgE]]-type.
* All these mediators subsequently lead to chronic bronchial inflammation, bronchial constriction and hypertrophy of the mucus-producing glands.
 
====Bronchial Inflammation====
* In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner [[bronchiole|airways]] are [[phagocytosis|ingested]] by antigen presenting cells, or APCs.
* APCs then present pieces of the allergen to other cells of [[immune system]].
* In most people, these other immune cells ([[T helper cell|T<sub>H</sub>0 cells]]) usually ignore the allergen molecules. In asthmatics, however, these cells differentiate into T<sub>H</sub>2, for reasons that are not well understood.<ref name="pmid11818486">Maddox L, Schwartz DA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11818486 The pathophysiology of asthma.] ''Annu Rev Med'' 53 ():477-98. [http://dx.doi.org/10.1146/annurev.med.53.082901.103921 DOI:10.1146/annurev.med.53.082901.103921] PMID: [http://pubmed.gov/11818486 11818486]</ref>
* The resultant T<sub>H</sub>2 cells activate an important arm of the immune system, known as the [[humoral immunity|humoral immune system]] that produces [[antibody|antibodies]] against the [[allergen|inhaled allergen]].
* Later, when an asthmatic inhales the same allergen, these antibodies recognize it and activate a humoral response.
 
====Bronchoconstriction====
* The resultant [[humoral immunity|humoral response]] following a [[Asthma pathophysiology#stimuli|specific stimuli]], causes the [[hypersensitivity|hypersensitive]] [[bronchial|bronchial airways]] to constrict and release more [[mucus]], and cause the activation of the cell-mediated arm of the immune system.<ref name="pmid11818486">Maddox L, Schwartz DA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11818486 The pathophysiology of asthma.] ''Annu Rev Med'' 53 ():477-98. [http://dx.doi.org/10.1146/annurev.med.53.082901.103921 DOI:10.1146/annurev.med.53.082901.103921] PMID: [http://pubmed.gov/11818486 11818486]</ref>
* This inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.
 
[[Image:Asthma before-after.png|thumb|left|470px|Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing.]]
<br clear="left"/>
 
===Theories of Pathogenesis===
*The fundamental problem in asthma appears to be [[immunology|immunological]]. Young children in the early stages of asthma show signs of excessive inflammation in their airways.


* The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),<ref name=Richard_F_Lockey>{{cite web | url = http://www.worldallergy.org/professional/allergic_diseases_center/anaphylaxis/anaphylaxissynopsis.shtml | title = Anaphylaxis: Synopsis | accessmonthday = September 23 | accessyear = 2006 | last = Lockey | first = Richard F. | work = Allergic Diseases Resource Center | publisher = World Allergy Organization }}</ref> Charles Reed (Chief of Allergy at Mayo Medical School),<ref name=Charles_Reed>{{cite journal | first = J. J. | last = Ouellette | coauthors = C. E. Reed | year = 1967 | month = March | title =  The effect of partial beta adrenergic blockade on the bronchial response of hay fever subjects to ragweed aerosol. | journal = Journal of Allergy | volume = 39 | issue = 3 | pages = 160-6 | id = {{PMID|5227155}}}}</ref> and Craig Venter (Human Genome Project).<ref name=Craig_Venter>{{cite journal | last = Fraser | first = Claire M. | coauthors = [[Craig Venter|J. Craig Venter]] | date = May 14, 1980 | title = The synthesis of beta-adrenergic receptors in cultured human lung cells: induction by glucocorticoids. | journal = Biochemical and Biophysical Research Communications | volume = 94 | issue = 1 | pages = 390–397 | doi = 10.1016/S0006-291X(80)80233-6 | id = {{PMID|6248064}} | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WBK-4G0VNMJ-S8&_coverDate=05%2F14%2F1980&_alid=454587819&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6713&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f3bc10fca4f32364a318857c0262f252 | format = PDF}}</ref>
*[[Asthma epidemiology and demographics|Epidemiological findings]] give a clue to the pathogenesis of asthma. The incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.


* Many studies have linked asthma, [[bronchitis]], and acute respiratory illnesses to [[Air pollution|air quality]] experienced by children.<ref name=asthma_air_quality>{{cite web | url = http://ewg.org/sites/asthmaindex/about/kidshealth.php | title = Asthma and Air Quality}}</ref> One of the largest of said studies is the California Children's Health Study.<ref name=childrens_health_study>{{cite web | url = http://www.arb.ca.gov/research/chs/chs.htm | title = California Children's Health Study}}</ref>.
*In 1968, ''Andor Szentivanyi'' first described ''The Beta Adrenergic Theory of Asthma''; in which [[Beta-blockers|blockage of the beta-2 receptors]] of pulmonary smooth muscle cells, decreased the adrenergic bronchodilator activity and associated hypersensitivity to mediators and contributed to the pathogenesis of asthma.<ref name="pmid17910324">Townley RG (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17910324 Interleukin 13 and the beta-adrenergic blockade theory of asthma revisited 40 years later.] ''Ann Allergy Asthma Immunol'' 99 (3):215-24. [http://dx.doi.org/10.1016/S1081-1206(10)60656-4 DOI:10.1016/S1081-1206(10)60656-4] PMID: [http://pubmed.gov/17910324 17910324]</ref>
* This study showed that children in the high ozone communities who played three or more sports developed asthma at a rate three times higher than those in the low ozone communities. Because participation in some sports can result in a child drawing up to 17 times the “normal” amount of air into the lungs, young athletes are more likely to develop asthma.
* Additionally, the concentrations of ozone have risen steadily in Europe since 1870. [http://www.eoearth.org/image/Histconc.gif]


* Another theory of [[pathogenesis]] is that asthma is a disease of hygiene. In nature, babies are exposed to [[bacteria]] and other [[antigen]]s soon after birth, "switching on" the T<sub>H</sub>1 [[lymphocyte]] cells of the [[immune system]] that deal with bacterial infection. If this stimulus is insufficient, as it may be in modern, clean environments, then T<sub>H</sub>2 cells predominate, and asthma and other allergic diseases may develop. This "[[hygiene hypothesis]]" may explain the increase in asthma in affluent populations. The T<sub>H</sub>2 lymphocytes and [[eosinophil]] cells that protect us against [[parasite]]s and other infectious agents are the same cells responsible for the allergic reaction. [[Charcot-Leyden crystals]] are formed when crystalline material in eosinophils coalesce. These crystals are significant in sputum samples of people with asthma. In the developed world, the [[parasite]]s that eosinophils are programmed to combat are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.
*In 1995, Szentivanyi and colleagues demonstrated that [[IgE]] blocks [[Beta-2 adrenergic receptor|beta-2 receptors]].<ref name="pmid8421135"> (1993) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8421135 50th Anniversary of the American Academy of Allergy and Immunology. 49th Annual Meeting. Chicago, Illinois, March 12-17, 1993. Abstracts.] ''J Allergy Clin Immunol'' 91 (1 Pt 2):141-379. PMID: [http://pubmed.gov/8421135 8421135]</ref> Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.<!--


It has been postulated that some forms of asthma may be related to infection, in particular by ''[[Chlamydophila pneumoniae|Chlamydia pneumoniae]]''.<!--
   --><ref>{{cite book | editor=Kowalak JP, Hughes AS et al (eds) | title=Professional Guide To Diseases | edition=7th ed. | year=2001 | publisher=Springhouse}}</ref>
  --><ref name="Thorax2006-Terttu">{{cite journal | author=Terttu HH, Leinonen M, Nokso-Koivisto J, Korhonen T, Raty R, He Q, Hovi T, Mertsola J, Bloigu A, Rytila P, Saikku P | title=Non-random distribution of pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma | journal=Thorax | year=2006 | pages= | volume= | id=PMID 16517571}}</ref>
This issue remains controversial, as the relationship is not borne out by [[meta-analysis]] of the research.<!--
  --><ref name="Cochrane2005-Richeldi">{{cite journal | author=Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG | title=Macrolides for chronic asthma | journal=Cochrane Database Syst Rev | year=2005 | pages=CD002997 | volume= | issue=4 | id=PMID 16235309}}</ref>
The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma.<!--
   --><ref name="JAllergyClinImmunol2005-Pasternack">{{cite journal | author=Pasternack R, Huhtala H, Karjalainen J | title=Chlamydophila (Chlamydia) pneumoniae serology and asthma in adults: a longitudinal analysis | journal=J Allergy Clin Immunol | year=2005 | pages=1123–8 | volume=116 | issue=5 | id=PMID 16275386}}</ref>
One possible explanation is that some asthmatics may have altered immune response that facilitates  long-term chlamydia pneumonia infection.<!--
  --><ref name="PediatrAllergyImmunol2005-Ronchetti">{{cite journal | author=Ronchetti R, Biscione GL, Ronchetti F, Ronchetti MP, Martella S, Falasca C, Casini C, Barreto M, Villa MP | title=Why Chlamydia pneumoniae is associated with asthma and other chronic conditions? Suggestions from a survey in unselected 9 years old schoolchildren | journal=Pediatr Allergy Immunol | year=2005 | pages=145-50 | volume=16 | issue=2 | id=PMID 15787872}}</ref>
The response to targeting with [[macrolide]] antibiotics has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their antimicrobic action.<!--
  --><ref name="Cochrane2005-Richeldi" />


One group of researchers suggested that, in part, asthma has a neurogenic paroxysmal component,<!--
*Many studies have linked asthma, [[bronchitis]], and acute respiratory illnesses to [[Air pollution|air quality]] experienced by children.<ref name=asthma_air_quality>{{cite web | url = http://ewg.org/sites/asthmaindex/about/kidshealth.php | title = Asthma and Air Quality}}</ref> This study showed that children in the high ozone communities who played three or more sports developed asthma at a rate three times higher than those in the low ozone communities. Because participation in some sports can result in a child drawing up to 17 times the normal amount of air into the lungs, young athletes are more likely to develop asthma.
  --><ref>{{cite web |author=Lomia M |title=Bronchial asthma as neurogenic paroxysmal and inflammatory disease -- Scientific background of effective use of anticonvulsants for pharmacotherapy of bronchial asthma |url=http://www.asthma.ge/Doctors.htm |date=March 20, 2006}}</ref>
and that several anti-eleptic drugs have an effect. However only one paper<!--
  --><ref name="pmid16597501">{{cite journal |author=Lomia M, Tchelidze T, Pruidze M |title=Bronchial asthma as neurogenic paroxysmal inflammatory disease: a randomized trial with carbamazepine |journal=Respiratory medicine |volume=100 |issue=11 |pages=1988-96 |year=2006 |pmid=16597501 |doi=10.1016/j.rmed.2006.02.018}}</ref>
has been published as listed by [[PubMed]] and its conclusions criticized.<!--
  --><ref name="pmid17223330">{{cite journal |author=Singh N |title=Carbamazepine in asthma: first do no harm! |journal=Respiratory medicine |volume=101 |issue=3 |pages=676; author reply 677-8 |year=2007 |pmid=17223330 |doi=10.1016/j.rmed.2006.11.025}}<br>'''Related warnings:'''
* {{cite journal |author=Lee T, Cochrane GM, Amlot P |title=Pulmonary eosinophilia and asthma associated with carbamazepine |journal=British medical journal (Clinical research ed.) |volume=282 |issue=6262 |pages=440 |year=1981 |pmid=6780065 |doi= |url=http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1504286&pageindex=1 |format=Scanned image}}
* {{cite journal |author=Lewis IJ, Rosenbloom L |title=Glandular fever-like syndrome, pulmonary eosinophilia and asthma associated with carbamazepine |journal=Postgraduate medical journal |volume=58 |issue=676 |pages=100-1 |year=1982 |pmid=7100019 |doi=}}</ref>


A study conducted by the National Jewish Medical and Research Center concluded that factors such as being overweight and or obese were associated with a dose-dependent increase in the odds of incident asthma in men and women. This demonstrates that asthma incidence could be reduced by interventions targeting overweight and obese populations. <ref>journal=American Journal of Respiratory and Critical Care Medicine | volume=175 |pages=661-666 | year=2007 |</ref>
*Another theory of [[pathogenesis]] is that asthma is a disease of hygiene. In nature, children are exposed to [[bacteria]] and other [[antigen]]s soon after birth, switching on the T<sub>H</sub>1 [[lymphocyte]] cells of the [[immune system]] that deal with bacterial infection. If this stimulus is insufficient, as it may be in modern, clean environments, then T<sub>H</sub>2 cells predominate, and asthma and other allergic diseases may develop. This [[hygiene hypothesis]] may explain the increase in asthma in affluent populations.
:*The T<sub>H</sub>2 lymphocytes and [[eosinophil|eosinophil cells]] that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. [[Charcot-Leyden crystals]] are formed when crystalline material in eosinophils coalesce. These crystals are significant in sputum samples of people with asthma. In the developed world, the parasites that eosinophils are programmed to combat are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.
 
*It has been postulated that some forms of asthma may be related to infection, particularly to [[Chlamydophila pneumoniae|Chlamydia pneumoniae]].<ref name="pmid16517571">Harju TH, Leinonen M, Nokso-Koivisto J, Korhonen T, Räty R, He Q et al. (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16517571 Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma.] ''Thorax'' 61 (7):579-84. [http://dx.doi.org/10.1136/thx.2005.056291 DOI:10.1136/thx.2005.056291] PMID: [http://pubmed.gov/16517571 16517571]</ref> This issue remains controversial, as the relationship is not borne out by [[meta-analysis]] of the research.<ref name="pmid16235309">Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16235309 Macrolides for chronic asthma.] ''Cochrane Database Syst Rev''  (4):CD002997. [http://dx.doi.org/10.1002/14651858.CD002997.pub3 DOI:10.1002/14651858.CD002997.pub3] PMID: [http://pubmed.gov/16235309 16235309]</ref> The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma.<ref name="pmid16275386">Pasternack R, Huhtala H, Karjalainen J (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16275386 Chlamydophila (Chlamydia) pneumoniae serology and asthma in adults: a longitudinal analysis.] ''J Allergy Clin Immunol'' 116 (5):1123-8. [http://dx.doi.org/10.1016/j.jaci.2005.08.030 DOI:10.1016/j.jaci.2005.08.030] PMID: [http://pubmed.gov/16275386 16275386]</ref> One possible explanation is that some asthmatics may have altered immune response that facilitates  long-term chlamydia pneumonia infection.<ref name="pmid15787872">Ronchetti R, Biscione GL, Ronchetti F, Ronchetti MP, Martella S, Falasca C et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15787872 Why Chlamydia pneumoniae is associated with asthma and other chronic conditions? Suggestions from a survey in unselected 9 yr old schoolchildren.] ''Pediatr Allergy Immunol'' 16 (2):145-50. [http://dx.doi.org/10.1111/j.1399-3038.2005.00244.x DOI:10.1111/j.1399-3038.2005.00244.x] PMID: [http://pubmed.gov/15787872 15787872]</ref> The response to targeting with [[macrolide|macrolide antibiotics]] has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their anti- microbic action.<ref name="pmid16034882">Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16034882 Macrolides for chronic asthma.] ''Cochrane Database Syst Rev''  (3):CD002997. [http://dx.doi.org/10.1002/14651858.CD002997.pub2 DOI:10.1002/14651858.CD002997.pub2] PMID: [http://pubmed.gov/16034882 16034882]</ref>
 
*A study conducted by the National Jewish Medical and Research Center concluded that factors such as being overweight and or [[obese]] were associated with a dose-dependent increase in the odds of incident asthma in men and women. This demonstrates that asthma incidence could be reduced by interventions targeting overweight and obese populations.<ref name="pmid17234901">Beuther DA, Sutherland ER (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17234901 Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies.] ''Am J Respir Crit Care Med'' 175 (7):661-6. [http://dx.doi.org/10.1164/rccm.200611-1717OC DOI:10.1164/rccm.200611-1717OC] PMID: [http://pubmed.gov/17234901 17234901]</ref>


==References==
==References==
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[[Category:Disease]]
[[Category:Pulmonology]]
[[Category:Pulmonology]]
[[Category:Immunology]]
[[Category:Emergency medicine]]
[[Category:Emergency medicine]]
[[Category:Intensive care medicine]]
[[Category:Mature chapter]]
 
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Philip Marcus, M.D., M.P.H. [2]; Associate Editor(s)-In-Chief: Varun Kumar, M.B.B.S. [3]; Lakshmi Gopalakrishnan, M.B.B.S. [4]

Overview

Asthma is a chronic inflammatory disease of the airways that is characterized by reversible airflow obstruction and airway inflammation, persistent airway hyperreactivity, and airway remodeling.[1] The two major factors responsible for the pathogenesis of asthma include bronchial hyper-responsiveness and inflammatory reaction within the bronchial wall. The airways of asthmatics are hypersensitive to certain triggers such as smoke, dust, or pollen. The term trigger is synonymous with stimuli. Exposure to these triggers causes repeated inflammation of the airways resulting in bronchospasm. Bronchospasm can lead to narrowing of airways and excess mucus production, making it difficult to breathe. Airway inflammation is a chronic inflammation driven by TH2 lymphocyte-predominant immune response. This immune response has been associated with atopy and IgE-synthesis through the production of IL-4 and eosinophilic inflammation by means of IL-5.[1]

Pathophyisology

Stimuli or Triggering Factors

The allergens responsible for the pathogenesis of asthma enter the body either as inspired air or ingested food that subsequently stimulate the formation of IgE and result in an antigen-antibody reaction within the bronchial wall; which cause the release of active inflammatory mediators that provoke bronchial spasm and immediate asthmatic attack. Known stimuli or triggering factors include the following.

  • Allergenic air pollution, such as: waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells. These are typically inhaled and the body's introduction to the stimuli occurs through the respiratory system.
  • Indoor allergenic air pollution from volatile organic compounds (VCOs). Potential VCOs 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 paints. This also includes perfumes and perfumed products.
  • An allergy to food such as: milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.
  • Use of fossil fuel, related to allergenic air pollution, such as: ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide. This is believed to be one of major reasons for the high prevalence of asthma in urban areas.
  • Various industrial compounds and other chemicals. Most 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.[3]
  • Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. 80% of asthma attacks in adults and 60% in children are caused by respiratory viruses.
  • Hormone changes in adolescent girls and adult women, associated with the menstrual cycle, can lead to a worsening of asthma. The influence of hormones can be largely varied from person to person. 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.
  • Emotional stress is a recognized potential trigger/stimuli, however, the influence of such is not well understood.
  • Cold weather can adversely affect breathing in asthmatics.

Pathogenesis

Bronchial Inflammation

  • In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by antigen presenting cells, or APCs.
  • APCs then present pieces of the allergen to other cells of immune system.
  • In most people, these other immune cells (TH0 cells) usually ignore the allergen molecules. In asthmatics, however, these cells differentiate into TH2, for reasons that are not well understood.[1]
  • The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system that produces antibodies against the inhaled allergen.
  • Later, when an asthmatic inhales the same allergen, these antibodies recognize it and activate a humoral response.

Bronchoconstriction

  • The resultant humoral response following a specific stimuli, causes the hypersensitive bronchial airways to constrict and release more mucus, and cause the activation of the cell-mediated arm of the immune system.[1]
  • This inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.
Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing.


Theories of 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 a clue to the pathogenesis of asthma. 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, decreased the adrenergic bronchodilator activity and associated hypersensitivity to mediators and contributed to the pathogenesis of asthma.[4]
  • In 1995, Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.[5] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.[6]
  • Many studies have linked asthma, bronchitis, and acute respiratory illnesses to air quality experienced by children.[7] This study showed that children in the high ozone communities who played three or more sports developed asthma at a rate three times higher than those in the low ozone communities. Because participation in some sports can result in a child drawing up to 17 times the normal amount of air into the lungs, young athletes are more likely to develop asthma.
  • Another theory of pathogenesis is that asthma is a disease of hygiene. In nature, children are exposed to bacteria and other antigens soon after birth, switching on the TH1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient, as it may be in modern, clean environments, then TH2 cells predominate, and asthma and other allergic diseases may develop. This hygiene hypothesis may explain the increase in asthma in affluent populations.
  • The TH2 lymphocytes and eosinophil cells that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. Charcot-Leyden crystals are formed when crystalline material in eosinophils coalesce. These crystals are significant in sputum samples of people with asthma. In the developed world, the parasites that eosinophils are programmed to combat are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.
  • It has been postulated that some forms of asthma may be related to infection, particularly to Chlamydia pneumoniae.[8] This issue remains controversial, as the relationship is not borne out by meta-analysis of the research.[9] The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma.[10] One possible explanation is that some asthmatics may have altered immune response that facilitates long-term chlamydia pneumonia infection.[11] The response to targeting with macrolide antibiotics has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their anti- microbic action.[12]
  • A study conducted by the National Jewish Medical and Research Center concluded that factors such as being overweight and or obese were associated with a dose-dependent increase in the odds of incident asthma in men and women. This demonstrates that asthma incidence could be reduced by interventions targeting overweight and obese populations.[13]

References

  1. ↑ 1.0 1.1 1.2 1.3 Maddox L, Schwartz DA (2002) The pathophysiology of asthma. Annu Rev Med 53 ():477-98. DOI:10.1146/annurev.med.53.082901.103921 PMID: 11818486
  2. ↑ Jenkins C, Costello J, Hodge L (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 328 (7437):434. DOI:10.1136/bmj.328.7437.434 PMID: 14976098
  3. ↑ Nemery B, Hoet PH, Nowak D (2002) Indoor swimming pools, water chlorination and respiratory health. Eur Respir J 19 (5):790-3. PMID: 12030714
  4. ↑ Townley RG (2007) Interleukin 13 and the beta-adrenergic blockade theory of asthma revisited 40 years later. Ann Allergy Asthma Immunol 99 (3):215-24. DOI:10.1016/S1081-1206(10)60656-4 PMID: 17910324
  5. ↑ (1993) 50th Anniversary of the American Academy of Allergy and Immunology. 49th Annual Meeting. Chicago, Illinois, March 12-17, 1993. Abstracts. J Allergy Clin Immunol 91 (1 Pt 2):141-379. PMID: 8421135
  6. ↑ Kowalak JP, Hughes AS et al (eds), ed. (2001). Professional Guide To Diseases (7th ed. ed.). Springhouse.
  7. ↑ "Asthma and Air Quality".
  8. ↑ Harju TH, Leinonen M, Nokso-Koivisto J, Korhonen T, Räty R, He Q et al. (2006) Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma. Thorax 61 (7):579-84. DOI:10.1136/thx.2005.056291 PMID: 16517571
  9. ↑ Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG (2005) Macrolides for chronic asthma. Cochrane Database Syst Rev (4):CD002997. DOI:10.1002/14651858.CD002997.pub3 PMID: 16235309
  10. ↑ Pasternack R, Huhtala H, Karjalainen J (2005) Chlamydophila (Chlamydia) pneumoniae serology and asthma in adults: a longitudinal analysis. J Allergy Clin Immunol 116 (5):1123-8. DOI:10.1016/j.jaci.2005.08.030 PMID: 16275386
  11. ↑ Ronchetti R, Biscione GL, Ronchetti F, Ronchetti MP, Martella S, Falasca C et al. (2005) Why Chlamydia pneumoniae is associated with asthma and other chronic conditions? Suggestions from a survey in unselected 9 yr old schoolchildren. Pediatr Allergy Immunol 16 (2):145-50. DOI:10.1111/j.1399-3038.2005.00244.x PMID: 15787872
  12. ↑ Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG (2005) Macrolides for chronic asthma. Cochrane Database Syst Rev (3):CD002997. DOI:10.1002/14651858.CD002997.pub2 PMID: 16034882
  13. ↑ Beuther DA, Sutherland ER (2007) Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 175 (7):661-6. DOI:10.1164/rccm.200611-1717OC PMID: 17234901

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