Allergy

This is a background article. See Psychological factors in allergic reactions

The word "allergy" was coined by the Viennese pediatrician Clemens von Pirquet in 1906. Pirquet noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods. He called this phenomenon "allergy", from the Greek words allos meaning "other" and ergon meaning "work".

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 (IgE). 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 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.

Type I hypersensitivity is characterised 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 be prescribed to the danger of the patient.

Allergy is a very common disorder and more than 50 million Americans suffer from allergic diseases. Allergies are the sixth leading cause of chronic disease in the United States, costing the health care system $18 billion annually. In fact, 60% of people with allergies are said to develop asthma as well.

Signs and symptoms
Allergy is a local or systemic inflammatory response to allergens. Local symptoms are:
 * Nose: swelling of the nasal mucosa (allergic rhinitis)
 * Eyes: redness and itching of the conjunctiva (allergic conjunctivitis)
 * Airways: bronchoconstriction, wheezing and dyspnoea, sometimes outright attacks of asthma, in severe cases the airway constricts due to swelling known as anaphylaxis.
 * Ears: feeling of fullness, possibly pain, and impaired hearing due to the lack of eustachian tube drainage.
 * Skin: various rashes, such as eczema, hives (urticaria) and contact dermatitis.
 * Head: while not as common, headaches are seen in some with environmental or chemical allergies.

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, 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.

Hay fever is one example of an exceedingly common minor allergy — large percentages of the population suffer from hayfever symptoms in response to airborne pollen. Asthmatics are often allergic to dust mites. Apart from ambient allergens, allergic reactions can be result from foods, insect stings and reactions to medications.

Diagnosis
There are several methods for the diagnosis and assessment of allergies.

Skin testing
The typical and most simple method of diagnosis and monitoring of Type I Hypersensitivity is by skin testing, also known as "scratch testing" and "prick testing" due to the series of pricks and/or scratches 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). The allergens are either injected intradermally or into small scratchings made into the patient's skin, often with a lancet. 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 full-blown hives in extremely sensitive patients.

After performing the skin test and receiving results, the doctor may apply a steroid cream, also known as corticosteriods, to the test area to reduce discomfort (such as itching and inflammation).

Problems 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 test available. Some people may display a delayed-type hypersensitivity (DTH) reaction which can occur up 6 hours after application of the allergen and last up to 72 hours. These reactions are from IgG antibodies and are called Arthus reactions. They usually are easily treated with anti-inflammatory creams and should not cause reason for alarm.

These types of reactions are fairly common and easily interpreted by a board certified allergist who is well versed in immunology.

Additionally, there are as many false negatives as there are false positives for the skin prick testing. The result is that people may be allergic to items that they did not show to be allergic to, and others may not be allergic to the item that had a positive reaction.

Testing for food allergies for peanuts, tree nuts and shellfish can be a delicate process. If a serious reaction has already been experienced most allergists will prefer a blood test to the skin prick to avoid the possibility of another allergic reaction.

One concern with the application of previously un-encountered insect venom allergen is the theoretical possibility that this exposure can actually sensitize one to these allergen, causing the inception of a new allergy in susceptible individuals.

Skins tests also are not always able to pinpoint a patient's specific allergies if the patient has significant skin conditions affecting the area of skin to be tested or a person has not avoided antihistamines of all types for the required period of time necessary for them to leave the body prior to testing.

Skin prick test for food allergens are very accurate if negative, if positive they must be correlated with elimination-challenge diets and clinical histories.

Blood testing
This kind of testing is also known as a "total IgE count". In order to qualify type I hypersensitivity, this method measures the amount of serum IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Even the levels the amount of IgE specific to certain allergens can be measured through use of the radioallergosorbent test (RAST).

Treatment
There are limited mainstream medical treatments for allergies. Probably the most important factor in rehabilitation is the removal of sources of allergens from the home environment, and avoiding environments in which contact with allergens is likely.

Immunotherapy
Hyposensitization is a form of immunotherapy where the patient is gradually vaccinated against 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. Delivery can occur via allergy injection, or sublingual immunotherapy - allergy drops taken under the tongue. Though not commonly offered in the U.S., sublingual immunotherapy is gaining attention internationally and is very common in Europe.

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.

An experimental treatment, enzyme potentiated desensitization (EPD), has been tried with some success but has yet to achieve widespread use. EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes respond by favouring desensitization, or down-regulation, rather than sensitization. EPD is also under development for the treatment of autoimmune diseases.

Chemotherapy
Several antagonistic drugs are used to block the action of allergic mediators, preventing activation of cells and degranulation processes. They include antihistamines, cortisone, epinephrine (adrenaline), theophylline and Cromolyn sodium. 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 an adrenaline needle 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. These modalities are frequently offered as treatment for those seeking additional help when mainstream medicine has failed to provide adequate relief from allergy symptoms. However, mainstream physicians maintain that these claims lack a scientific basis and warn that the efficacy of such treatments is only supported by anecdotal evidence.

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
The difference between a type I hypersensitivity reaction against an allergen to the normal humoral response against a foreign body is that plasma cells secrete IgE as opposed to either IgM (against novel antigens) or IgG (against immunized antigens). IgE binds to Fc receptors on the surface of mast cells and basophils, both involved in the acute inflammatory response.

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 (calliscal 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.

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

Genetic basis
There is much evidence 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.

Ethnicity has also been shown to play a role in some allergies. Interestingly, in regard to asthma, it has been suggested that different genetic loci are responsible for asthma in people of Caucasian, Hispanic, Asian, and African origins. It has also been suggested 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. Caucasian people seem to have the most asthma.

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. 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. 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. 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.

Increasing prevalence
There has been a notable increase in the commonness of allergies in the past decades, and there are multiple hypotheses explaining this phenomenon. This is in part because we know what they are, in contrast to earlier humans who would think that the symptoms pointed towards a non-important illness.

Increasing use of chemicals
One theory is the exponential use and abuse of chemicals in affluent nations since the second world war. Vast numbers of chemicals are introduced into our indoor and outdoor environments with little or no testing regarding their toxicity to living beings. Many believe that air quality is getting worse rather than better, particularly if one considers indoor air quality as well as outdoor. (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.) 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.

In 2004, a joint Swedish-Danish research team found a very strong link between allergies in children and the phthalates DEHP and BBzP, commonly used in PVC. Allergies are also viewed by some medical practitioners as a negative consequence of the use and abuse of antibiotics and vaccinations. 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. It is hypothesized that use of antibiotics and vaccination affect the immune system, and that allergies are a dysfunctional immune response.

The "hygiene hypothesis"
Another theory that has been gaining strength is the "hygiene hypothesis". This theory maintains that since children in more affluent countries are leading a cleaner and cleaner life (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 in the years since the second world war, and many studies appear to show a correlation between this and the increasingly affluent and clean lifestyles in the West. This is supported by studies 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 to conclude that it is our "too clean" upbringing that is to blame for the lack of immune system stimulation in early childhood.

So far the evidence to support this theory is limited. One supporting fact is that many Chinese will develop hay fever after moving into the USA for three or more years. However, contradictory examples also exist.

Common allergens




In addition to foreign proteins found in foreign serum (from blood transfusions) and vaccines, common allergens include:
 * Plant pollens (Hay fever):
 * Rye grass
 * Ragweed
 * Timothy grass
 * Birch trees
 * Mold spores
 * Drugs:
 * Penicillins
 * Sulfonamides
 * Salicylates (also found naturally in numerous fruits)
 * Local anaesthetics
 * Foods (food allergy):
 * Nuts (2 separate cases)
 * Peanuts
 * Nuts
 * Sesame
 * Seafood
 * Egg (typically albumen, the white)
 * Peas, beans, peanuts, soybeans and other legumes
 * Soy
 * Milk
 * Wheat
 * Maize (corn)
 * Insect stings:
 * Bee sting venom
 * Wasp sting venom
 * Animal products (animal allergy):
 * Animal hair and dander
 * Cockroach calyx
 * Dust mite excretion
 * Other
 * Latex