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Allergy
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Allergy an abnormal reaction to a substance foreign to the body that is acquired, predictable and rapid. In the strict sense of its meaning, it is the first (type 1) of five forms of hypersensitivity described by Gell and Coombs in their 1963 classification.[1] However, by extension, the term "allergy" is often used for other abnormal reactions to substances. The term was coined by the Viennese pediatrician Clemens von Pirquet in 1906 after noting that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy", from the Greek words allos meaning "other" and ergon meaning "work".[3]

Type I hypersensitivity is characterized by excessive activation of mast cells and basophils by IgE, resulting in a systemic inflammatory response that can result in symptoms as benign as a runny nose, to life-threatening anaphylactic shock and death.

Knowing any allergies that a patient may have is important in a clinical setting. Full allergy history is taken down when obtaining a medical history of a patient. This ensures that no contradictory treatments are prescribed to the danger of the patient. In the United States physicians who hold certification by the American Board of Allergy and Immunology (ABAI) have successfully completed an accredited educational program and an evaluation process, including a secure, proctored examination to demonstrate the knowledge, skills, and experience to the provision of patient care in allergy and immunology[4]

In the United States, an allergist-immunologist is a physician specially trained to manage and treat asthma and the other allergic diseases. Becoming an allergist-immunologist requires completion of at least nine years of training. After completing medical school and graduating with a medical degree, a physician will then undergo three years of training in internal medicine (to become an internist) or pediatrics (to become a pediatrician). Once physicians have finished training in one of these specialties, they must pass the exam of either the American Board of Pediatrics (ABP) or the American Board of Internal Medicine (ABIM). Internists or pediatricians who wish to focus on the sub-specialty of allergy-immunology then complete at least an additional two years of study, called a fellowship, in an allergy-immunology training program. Allergist-immunologists who are listed as ABAI-certified have successfully passed the certifying examination of the American Board of Allergy and Immunology (ABAI), following their fellowship.[5]

History

Historically, all forms of hypersensitivity were classified as allergies, and all thought to be caused by an improper activation of the antibody class called Immunoglobulin E - Teruka and Kimishige Ishizaka were among the first to isolate and describe IgE in the 1960s.

Later, it became clear that several different disease mechanisms were implicated, with the common link between these varying hypersensitivities being a disordered activation of the immune system in one way or another. A new classification scheme was designed by P. Gell and R. Coombs[1] to reflect what were then rebaptized hypersensitivity reactions. The word "allergy" was then restricted to type I hypersensitivities, which are caused by the classical IgE mechanism.

Signs and symptoms

Allergy is a local or systemic inflammatory response to allergens. Local symptoms are:

Allergic rhinitis afflicts 20% of the U.S. population. [7] Also known as hayfever, symptoms can be in response to airborne pollen. Asthmatics are often allergic to dust mites. Apart from ambient allergens, allergic reactions can result from foods, insect stings and reactions to medications.

Systemic allergic response is also called anaphylaxis; multiple systems can be affected including the digestive system, the respiratory system, and the circulatory system. Depending of the rate of severity, it can cause cutaneous reactions, bronchoconstriction, edema, hypotension, coma and even death. This type of reaction can be triggered suddenly or the onset can be delayed. The severity of this type of allergic response often requires injections of epinephrine, sometimes through a device known as the Epi-Pen auto-injector. The nature of anaphylaxis is such that the reaction can seemingly be subsiding, but may recur throughout a prolonged period of time.

Diagnosis

Before a diagnosis of allergic disease can be confirmed, possible differential causation should be carefully considered and included or excluded.[8] Vasomotor rhinitis is one of many maladies that can mimic many of the symptoms of allergic rhinitis, underscoring the need for professional differential diagnosis.[9]

Once a diagnosis of asthma, rhinitis, anaphylaxis, or some other allergic disease has been made, there are several methods for finding out what the patient is allergic to.

Skin testing

For assessing the presence of specific IgE antibodies, allergy skin testing, when possible, is the preferred method in comparison with various blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive[10] . Different blood allergy testing methods are currently available; the radioallergosorbent test (RAST) test method, which uses radioactive isotopes for testing, has largely been replaced by more modern methods.[11]

The typical method of diagnosis and monitoring of Type I Hypersensitivity is skin testing, also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients.

Considerations with skin test

The skin prick test is the most preferred means of testing because of its simplicity, economic implications and its accuracy relative to the other tests available.

Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction.

Theoretical concerns include how to choose patients, interpret results, and maintain safety. If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has not avoided antihistamines for several days. Additionally, some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy[12] .

Some people may display a small, delayed reaction that can occur up to 6 hours after application of the allergen and last up to 72 hours. It is often easily treated with anti-inflammatory creams. Interpretation by well-trained allergists is often guided by relevant literature which can offer calculation of 95% and 99% predicted probabilities using logistic regression revealed predictive decision points [13] .

Another consideration with the application of previously un-encountered insect venom allergen is the theoretical possibility that this minute exposure can actually sensitize one to these allergen, causing the inception of a new sensitivity, but such a development is almost unheard of in clinical experience[citation needed]. For all these reasons skin testing should be offered by individuals with advanced training in the diagnosis and treatment of allergic disease.

Blood testing

This kind of testing is also known as a "total IgE level". This method measures the total amount of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. The levels of IgE specific to certain allergens can be measured through use of various blood allergy test methods. The radioallergosorbent test (RAST) method uses radioactive isotopes for the measuring process. Other newer methods use colorimetric or fluorometric technology. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study. -->[14]

A low total IgE level is not useful to rule out sensitization to common inhalant allergens.[15]. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.

Treatment

Template:Globalize/U.S. There have been enormous improvements in mainstream medical treatments developed by allergists. Recently, advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insects and in allergic skin disease include: the identification of food proteins to which IgE binding is associated with severe reactions, improvements in skin prick test predictions; evaluation of the atopy patch test; and advances in yellow jacket sting outcomes predictions and a rapidly disintegrating epinephrine tablet and development of low-allergen foods, and anti-IL-5 for eosinophilic diseases. [16]

Traditionally treatment and management of allergies revolved around simply avoiding the allergen in question or otherwise reducing exposure to said allegern. For instance, people with cat allergies were encouraged not to own cats and to avoid them as best as possible. While this had some effectiveness in reducing symptoms and avoiding life-threatening anaphylaxis for some, it was not always possible for those with pollen or similar air-borne allergies. For most allergies it is simply easier to reduce exposure rather than avoiding the allergens altogether. Strict avoidance still has a role in management though and is often used in managing food allergies.

Immunotherapy

Immunotherapy, once called hyposensitization or desensitization, is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG ("the blocking antibody") production, as opposed to the excessive IgE production seen in hypersensitivity type I cases. In a sense, the person builds up immunity to increasing amounts of the allergern in question.

Many national and international guidelines, including the Allergic Rhinitis and its Impact on Asthma guidelines, first published in 2001 and revised in 2007, confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed. [17].

Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy. [18].

A randomized trial demonstrated that injection immunotherapy reduces the risk of developing asthma.

Recent meta-analyses confirm its efficacy in allergic rhinitis in children and in asthma, and a recent review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy based on numerous well-designed scientific studies. [19]. The review cited multiple highly respected investigations and institutions to show that allergen immunotherapy is safe and effective for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect hypersensitivity. The conclusion states: "Allergen immunotherapy should be strongly considered for patients with poor symptom control or adverse reactions to medications".

A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell IgE, signalling such sources for destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells as this would stimulate the allergic inflammatory response. The first agent in this class is omalizumab. While these shots are very effective in curing most allergies, they should not be used in treating the majority of people with food allergies. Strict avoidance of the food in question appears to be a better form of treatment in these alleries.

Sublingual immunotherapy is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe. In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by otolarygologists who practice allergy treatment.

Unproven or ineffective treatments

An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[20] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[20]

Pharmacotherapy

Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. They include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Antileukotrienes, such as montelukast (Singulair) or zafirlukast (Accolate), have also been FDA approved for allergic diseases. Anticholinergics, decongestants, mast cell stabilizers, and other compounds (some of which might impair eosinophil chemotaxis) are also commonly used. These drugs help alleviate the symptoms of allergy but play little role in chronic alleviation of the disorder. They can play an imperative role in the acute recovery of someone suffering from anaphylaxis, which is why those allergic to bee stings, peanuts, nuts, and shellfish often carry a device for giving an emergency injection of epinephrine with them at all times.

Alternative therapies

In alternative medicine, a number of treatment modalities are considered effective by its practitioners in the treatment of allergies, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology, despite the lack of approval by the United States Food and Drug Administration. These modalities are frequently offered as treatment for those seeking additional help when mainstream medicine has failed to provide adequate relief from allergy symptoms[citation needed]. However, mainstream physicians[who?] maintain that these claims lack a scientific basis and warn that the efficacy of such treatments is only supported by anecdotal evidence.

Systematic literature searches conducted by the Mayo Clinic through 2006 in hundreds of articles studying mutliple conditions including asthma, and upper respiratory tract infection showed no effectiveness, and no difference compared with placebo and stated that based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments there is no convincing evidence [21]

Pathophysiology

The pathophysiology of allergic responses can be divided into two phases; firstly the acute response, which can then either subside or progress into a "late phase response" which can substantially prolong the symptoms of a response.

Acute response

A type I hypersensitivity reaction against an allergen via the normal humoral response against a foreign body results after plasma cells secrete IgE as opposed to other classes of immunoglobulins such as IgM (against novel antigens) or IgG (against immunized antigens). IgE binds to Fc epsilon R1 (high affinity) receptors on the surface of mast cells and basophils, both involved in the acute inflammatory response. The class switch in the plasma cell leading to IgE is tightly regulated by the immune system. CD45 plays a critical regulatory role in receptor signaling through its protein tyrosine phosphatase and Janus kinase (JAK) phosphatase activities. IL-4 is the primary interleukin which induces switch recombination. Class switch recombination to IgE can also be triggered by the TH2 cytokine IL-13. CD45 is able to function as JAK phosphatase in human B cells, and this activity is directly associated with negative regulation of the class switch recombination to IgE. IgE-bearing epidermal dendritic cells have also been found.

When IgE is first secreted it binds to the Fc receptors on a mast cell or basophil, and such an IgE-coated cell is said to be sensitized to the allergen in question. A later exposure by the same allergen causes reactivation of these IgE, which then signals for the degranulation of the sensitized mast cell or basophil. There is now strong evidence that mast cells and basophils require costimulatory signals for degranulation in vivo, derived from GPCRs such as chemokine receptors. These granules release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in the previously described symptoms of rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localised to particular body systems (for example, asthma to the respiratory system; eczema to the dermis).

Late-phase response

After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 4-6 hours after the original reaction and can last from 1-2 days. Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses.

Etiology

The exact cause of the IgE malfunctions that result in allergic reactions are not always apparent[citation needed], however, and several arguments[who?] from genetic-basis, environmental-basis and intermediate proponents exist with varying validity and acceptance.

Genetic basis

There is much evidence[citation needed] to support the genetic basis of allergy. Allergic parents are more likely to have allergic children, and their allergies are likely to be stronger than those from non-allergic parents. However some allergies are not consistent along genealogies with parents being allergic to peanuts, but having children allergic to ragweed, or siblings not sharing the same allergens. It seems that the likelihood of developing allergies is inherited (due to some irregularity in the way the immune system works) but the developing of an allergy to a specfic allergn is not.

Ethnicity has also been shown to play a role in some allergies. Interestingly, in regard to asthma, it has been suggested[who?] that different genetic loci are responsible for asthma in people of Caucasian, Hispanic, Asian, and African origins. It has also been suggested[who?] that there are both general atopy genes and tissue-specific allergy genes that target the allergic response to specific mucosal tissues. Potential disease associated alleles include both coding region variation and SNPs. Caucasians display the greatest incidence of asthma[citation needed].

Relationship with parasites

Some recent research has also begun to show that some kinds of common parasites, such as intestinal worms (e.g. hookworms), secrete immunosuppressant chemicals into the gut wall and hence the bloodstream which prevent the body from attacking the parasite. This gives rise to a new slant on the "hygiene hypothesis" — that co-evolution of man and parasites has in the past led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive. In particular, research suggests that allergies may coincide with the delayed establishment of infant gut flora. [22] Gutworms and similar parasites are present in untreated drinking water in undeveloped countries, and in developed countries until the routine chlorination and purification of drinking water supplies. This also coincides with the time period in which a significant rise in allergies has been observed.[citation needed] So far, there is only sporadic evidence to support this hypothesis — one scientist who suffered from seasonal allergic rhinitis (hayfever) infected himself with gutworms and was immediately 'cured' of his allergy with no other ill effects.[citation needed] Full clinical trials have yet to be performed however. It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[citation needed]

Increasing prevalence

One study estimated higher rates of positive responses to allergen skin test surveys from 1988 to 1994 then from 1976 to 1980. The researchers were unable to determine if this was the result of increased prevalence or survey differences.[23]

Increasing use of chemicals

Many believe[who?] that air quality is getting worse rather than better, particularly if one considers indoor air quality as well as outdoor.[citation needed] (Indoor air quality has become significantly worse since building codes changed in the 1970s to make buildings more air-tight to conserve energy. This affects buildings built since that time.)[citation needed] Adverse reactions to toxins vary considerably from one person to another, and can involve extremes in symptoms including the neurological and endocrine systems as well as the more commonly recognized allergy symptoms listed above.[citation needed][improper synthesis?]

In 2004, a joint Swedish-Danish research team found a association between allergic symptoms in children and exposure to household dust containing the phthalates DEHP and BBzP, commonly used in PVC production.[24] Allergies are also viewed by some medical practitioners[who?] as a negative consequence of the use and abuse of antibiotics and vaccinations.[citation needed] This mainstream Western approach to treatment and prevention of infectious disease has been used in the more affluent world for a longer period of time than in the rest of the world, hence the much greater commonality of allergies there.[citation needed][improper synthesis?] It is hypothesized[who?] that use of antibiotics and vaccination affect the immune system,[citation needed] and that allergies are a dysfunctional immune response.[citation needed]

The "hygiene hypothesis"

Main article: Hygiene hypothesis

The hygiene hypothesis maintains[25] that children in more affluent countries are leading an increasingly cleaner life in modern times (less exposure to dirt, extra use of disinfectants, etc), their immune systems have less exposure to parasites and other pathogens than children in other countries or in decades past. Their immune systems may, therefore, have many "loaded guns", cells which might have targeted, say, the intestinal worms that no longer cause trouble in affluent neighbourhoods. Having no reasonable target, these cells inadvertently become activated by environmental antigens that might only cause minor reactions in others. It is the symptoms of this exaggerated response that is seen as the allergic reaction.

Many common allergies such as asthma have seen huge increases [26] in the years since World War II, and many studies[citation needed] appear to show a correlation between this and the increasingly affluent and clean lifestyles in the West. This is supported by studies[citation needed] in less developed countries that do not enjoy western levels of cleanliness, and similarly do not show western levels of incidences of asthma and other allergies. During this same period, air quality, at one time considered the "obvious" cause of asthma, has shown a considerable improvement. This has led some researchers[who?] to conclude that it is our "too clean" upbringing that is to blame for the lack of immune system stimulation in early childhood.

Evidence for the hygiene hypothesis appears to be mounting more so than for the chemical hypothesis. Such data is still open to interpretation. Day care for children offers protective effects against asthma, as do early episodes of viral infection. Children raised on a farm also have a decreased atopy. This is also seen in children who live with pets. Previously it was thought that people were more likely to develop allergies to pets if they lived with them as babies and young children. However recent studies contradict this entirely; children raised with pets were less likely to develop allergies to them, even when one of their parents had pet allergies in some cases. Exposure to endotoxin and other components of bacteria may reduce atopic diseases. [27]

Environmental endotoxin showed a strong protection against hay fever and allergy. Endotoxin exposure reduces peripheral blood leukocytes release of inflammatory cytokines after lipopolysaccharide, including cytokines such as tumor necrosis factor alpha, interferon-gamma, interleukin-10, and interleukin-12 . [28] Toll-like receptors are thought to be involved. This is the basis for the new DNA vaccine being developed by Peter Creticos and others at the Johns Hopkins Division of Allergy.

One supporting fact[citation needed] is that many Chinese will develop hay fever after moving into the U.S. for three or more years. However, contradictory examples also exist[citation needed]. For instance many people in China also develop asthma (among other respiratory ailments) in direct response to pollution and poor air quality.

Common allergens

Main article: Allergen

See also

References

  1. ^ a b Gell PGH, Coombs RRA. Clinical Aspects of Immunology. London: Blackwell, 1963.
  2. ^ Clemens Peter Pirquet von Cesenatico at Who Named It?
  3. ^ "Glossary of Allergy Terms". Asthma and Allergy Foundation of America.
  4. ^ "ABAI: American Board of Allergy and Immunology". Retrieved 2007-08-05.
  5. ^ "AAAAI - What is an Allergist?". Retrieved 2007-08-05.
  6. ^ http://en.wikipedia.org/wiki/Sinusitis#Sinus_headache_vs_migraine
  7. ^ Bope, E (2005). Conn's Current Therapy. Philadelphia: Elsevier. p. 880. 0721638643. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ http://www.emedicine.com/med/topic3390.htm Allergic and Environmental Asthma Including discussion of DIFFERENTIALS at http://www.emedicine.com/med/topic3390.htm#section~Differentials
  9. ^ http://www.aafp.org/afp/20050915/1057.html Vasomotor Rhinitis September 15, 2005 AMERICAN FAMILY PHYSICIAN Patricia w. Wheeler, M.D., and Stephen F. Wheeler, M.D. University of Louisville School of Medicine, Louisville, Kentucky
  10. ^ Ten, R (1995). "Allergy Skin Testing". Mayo Clin Proc. 5 (70): 783–4. pmid 7630219.[1]
  11. ^ Ten, R (1995). "Allergy Skin Testing". Mayo Clin Proc. 5 (70): 783–4. pmid 7630219.[2]
  12. ^ Li JT (2005). "Accuracy of patient prediction of allergy skin test results". Ann Allergy Asthma Immunol. 85 (5): 382–4. PMID 11101180.
  13. ^ Verstege A (2005). "The predictive value of the skin prick test weal size for the outcome of oral food challenges". Clinical & Experimental Allerg. 35 (9): 1220.
  14. ^ Vidal C (2005). "Evaluation of the phadiatop test in the diagnosis of allergic sensitization in a general adult population". J Investig Allergol Clin Immunol. 15 (2): 124–30. PMID 16047713.
  15. ^ Kerkhof C (2003). "Role and interpretation of total serum IgE measurements in the diagnosis of allergic airway disease in adults". Allergy. 58 (9): 905.
  16. ^ Sicherer SH, Leung DY (2007). "Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects". J. Allergy Clin. Immunol. 119 (6): 1462–9. doi:10.1016/j.jaci.2007.02.013. PMID 17412401.
  17. ^ Passalacqua G (2007). "Allergic Rhinitis and its Impact on Asthma update: Allergen immunotherapy". J Allergy Clin Immunol. 119 (1): 881–91. 17418661.
  18. ^ Ross, R (Mar 2000), "Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-controlled studies.", Clin Ther., 22: 342–50{{citation}}: CS1 maint: date and year (link)
  19. ^ Rank, M (Sep), "Allergen immunotherapy.", Mayo Clinic Proceedings., 82: 1119–1123 {{citation}}: Check date values in: |date= and |year= / |date= mismatch (help)
  20. ^ a b Terr A (2004). "Unproven and controversial forms of immunotherapy". Clin Allergy Immunol. 18 (1): 703–10. PMID 15042943.
  21. ^ Altunc U (2007). "Homeopathy for childhood and adolescence ailments: systematic review of randomized clinical trials". Mayo Clinic Proceedings. 82 (1): 69–75. 17285788.
  22. ^ Emmanuelsson C (2007). "Allergens as eukaryotic proteins lacking bacterial homologues". Mol. Immunol. 44 (12): 3256–60. doi:10.1016/j.molimm.2007.01.019.
  23. ^ Arbes SJ (2005). "Prevalences of positive skin test responses to 10 common allergens in the U.S. population: results from the third National Health and Nutrition Examination Surve". J Allergy Clin Immunol. 116 (2): 377–83. 16083793.
  24. ^ Bornehag C, Sundell J, Weschler C, Sigsgaard T, Lundgren B, Hasselgren M, Hägerhed-Engman L (2004). "The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study". Environ Health Perspect. 112 (14): 1393–7. PMID 15471731.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Zeyrek CD, Zeyrek F, Sevinc E, Demir E (2006). "Prevalence of asthma and allergic diseases in Sanliurfa, Turkey, and the relation to environmental and socioeconomic factors: is the hygiene hypothesis enough?". Journal of investigational allergology & clinical immunology : official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología. 16 (5): 290–5. PMID 17039667.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ "Health Status of the United States: Human Health ( Draft Report on the Environment)". USEPA. Retrieved 2007-08-05.
  27. ^ von Mutius, E (2002), "Environmental factors influencing the development and progression of pediatric asthma", .J Allergy Clin Immunol., 109: S52532
  28. ^ Riedler, J (2002), "Environmental exposure to endotoxin and its relation to asthma in school-age children", .N Engl J Med, 347: 869–77
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