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Allergic Reactions

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Author:    Jeff Thompson (Senior Developer)

Purpose/Goals

The purpose of this course is to prepare healthcare workers to prevent, identify and react to allergic reactions in their patients.

Objectives

Upon completion of the course, the learner will be able to:

  1. Define what an allergy is and some theories as to how allergies are acquired (environmentally, genetically, etc.)   
  2. Describe the four types of hypersensitivity reactions.   
  3. Describe the pathophysiology of an allergic reaction.   
  4. Describe some signs and symptoms of various allergic reactions in relation to their causes.   
  5. Describe how a diagnosis of an allergic reaction is made, and some treatments and prevention techniques for allergic reactions.

Introduction

An allergy is "an acquired, abnormal immune response to a substance (allergen) that does not normally cause a reaction" (Thomas, 1997, pp. 66-67). Thus, they are not related to exposure to infection or due to injury (Merck, 2005). In simpler terms, it is the body’s way of responding to some kind of foreign substance. In normal cases where the body reacts to a foreign body, the body’s immune system is activated which normally protects the body from harmful substances. When the body reacts to a substance that is in no way innately harmful (an allergen), this is called an allergic or hypersensitivity reaction (Haith, 2005).

Allergens can be almost anything such as pollen, dust, plants, medications, foods, or insect venom. Viruses or even bacteria can be allergens as they can trigger a reaction unrelated to their normal viral or bacterial influence in the body (Haith, 2005). An allergen is defined as something that can induce IgE-mediated and T-helper 2 cell immune response. They are mostly low molecular weight proteins which are often able to be made particulates in the air (Merck, 2007).

The terms allergy, atopy, and hypersensitivity are often interchanged and confused. Allergies are categorized into four different hypersensitivity reactions by Gell and Coombs and atopy refers simply to the first type (type I hypersensitivity reactions) only (Merck, 2005). There are many diseases and reactions that fall under the general classification of allergy. These will be described below as well as their subsequent etiologies, pathophysiology, treatment, and prevention.

Etiology of Allergies

It is thought that genetic, environmental, and site-specific factors contribute to the development of allergies. Because allergies seem to be inherited (as evidenced by strong family histories, association between atopic disease and specific genetic factors), genetics is partially implicated in the development of the disease.

Allergic reactions are mediated through the T-helper 2 responses which activate eosinophils and IgE production. This response is a generalized response and causes the generalized inflammatory reaction common with exposure to allergens. The T-helper 1 responses are more specific, and the body develops antibodies to these allergens when the T-helper 1 system is activated. Upon exposure a second time to the allergen, the body targets the allergen itself specifically, and does not cause the generalized swelling that the T-helper 2 response does. In fact, T-helper 1 responses actually suppress the T-helper 2 response. Early childhood exposure to bacterial/viral infection can shift the T-helper 2 cell responses to the more specific T-helper 1 responses. The "hygiene hypothesis" suggests that in more developed countries where there are fewer children per family, cleaner indoor environments, and early vaccination and antibiotic usage, children may be deprived of the ability to develop this natural "shifting" towards the T-helper 1 cell response.

The site-specific response refers to molecules in the lungs and gastrointestinal tract that direct T-helper 2 cells to certain tissues which can react to allergens in those specific areas. It is also thought that chronic exposure to an allergen sensitizes the patient (Merck, 2007).

Types of Allergic Reactions

As mentioned above, there are four different categories into which allergic reactions lie. They are as follows:

1. Type I (immediate hypersensitivity) reactions. These reactions are local or systemic anaphylactic inflammatory responses which are IgE-mediated and underlie all atopic diseases (Thomas, 1997). Antigen binds to IgE (bound to tissue mast cells and blood basophils), trigger the release of mediators (histamine, chemotactic factors, etc.), and synthesize other mediators (prostaglandins, leukotrienes, platelet-activating factor, interleukins). These mediators cause the common symptoms of an atopic reaction by causing vasodilation, capillary permeability, mucus production, smooth muscle spasm, eosinophil and T-infiltration into tissue as well as other inflammatory cells. Atopic disease most commonly affects the nose, eyes, skin, and lungs. Disorders that fall into this category can include atopic dermatitis, contact dermatitis, urticaria, angioedema, latex allergy, asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and allergic reactions to venomous stings (bees, ants, etc.) (Merck, 2005; Merck 2007). The anaphylactic reactions occur when the allergen reaches the bloodstream and causes a massive release of chemical mediators (Thomas, 1997).
   
2. Type II (cytotoxic) reactions. Type II reactions involve more specific immune response in which antigen-antibody complexes activate cytotoxic T cells or macrophages and complement which cause cell and tissue damage. In this case, the body is sensitized to an allergen and the body produces an antibody to the specific antigen. Then the antibody binds to cellular or tissue antigens or to a hapten (which is a small molecule which can cause an immune response only when attached to a larger protein-like carrier. The carrier does not elicit a response by itself, only when the hapten is coupled to it) coupled to a cell or tissue. This leads to the tissue damage described above (Merck, 2005). Generally larger molecules tend to elicit an immune response in the body. Reaction to these hapten-carrier products are the same as for antigens in that the body that generate antibodies to the material. Upon recognition of the complex a second time, an immune response occurs (Wikipedia, 2008). These reactions are mediated by IgG and IgM and are the ones that cause transfusion reactions and many of the drug reactions. Due to the release of complement, blood cells are destroyed (Thomas, 1997). Disorders that involve type II reactions include transfusion reaction, graft rejection (in organ transplantation), Coombs’-positive hemolytic anemia, Hashimoto thyroiditis, etc. (Merck, 2005; Thomas 1997).
   
3. Type III (immune complex) reactions. In these reactions, IgG or IgM antibodies attach to antigen, causing circulating antigen-antibody complexes. These complexes become deposited in vessels or tissue (including glomeruli) and adhere to the walls and cause an acute inflammation reaction. They can activate the complement system, bind to and activate immune cells, resulting in the release of inflammatory mediators. How much antigen is present in relation to how much antibody is present factors into how severe the reaction is (i.e. a more balanced proportion allows for more systemic reactions as larger complexes are formed). Some type III reactions include serum sickness, systemic lupus erythematosus, rheumatoid arthritis, cryoglobulinemia, hypersensitivity pneumonitis, among others (Merck, 2005; Thomas 1997).
   
4. Type IV (cell mediated or delayed hypersensitivity) reactions. These reactions are mediated by T-cells (instead of antibodies) and there are four subtypes depending on the types of T-cells that are involved.
 

a. T-helper 1 cells.
   
b. T-helper 2 cells.
   
c. Cytotoxic T-cells.
   
d. Interleukin-8-secreting T-cells.

These cells are sensitized after an initial contact with an antigen. When the antigens present in the body a second time, they are activated and damage tissue directly through the release of cytokines or toxins. The cytokines activate eosinophils, monocytes, macrophages, neutrophils, and killer cells. Type IV reactions include contact dermatitis, hypersensitivity pneumonitis, allograft rejection, and drug hypersensitivity reactions (Merck, 2005). In contact dermatitis, allergens combine proteins in the skin and alter their normal self-antigens so that foreign antigens are created. Skin testing for allergic reactions is performed on the basis of type IV delayed hypersensitivity reactions in which the allergen is introduced into the skin (see below) (Thomas, 1997).

Pathophysiology of an Allergic Reaction

White blood cells produce antibodies to antigens when they are exposed to them. This process is called “sensitization.” These antibodies detect and destroy these antigens when the body is exposed to them a second time. The antibody associated with allergic reactions is called IgE (Haith, 2005).

There are two phases of an allergic reaction, an acute response and a late phase response. The acute phase occurs immediately after exposure to an antigen and will subside or progress into a late phase reaction which prolongs the symptoms of the response and can cause tissue damage (Wikipedia, 2008). After the acute response subsides, a late phase response may occur as leukocytes (neutrophils, lymphocytes, eosinophils, and macrophages) migrate back to the initial site, causing a reaction two to 24 hours after the initial one (Wikipedia, 2008).

Histamine is the major culprit in the mediation of an allergic reaction. An allergen will bind to IgE (an antibody) which causes histamine release from mast cells. Mast cells are widely distributed throughout the body, but are in highest concentration in the skin, lungs, and in the gastrointestinal tract (Merck, 2007).

Histamine causes: 1) erythema (due to vasodilation), 2) increased capillary permeability (edema which results in swelling/wheals), 3) vasodilation (via neuronal reflex mechanisms causing flare), and 4) will stimulate sensory nerves (which causes itching). Smooth muscle contraction in the airways causes bronchoconstriction and increased gastrointestinal motility as well as secretions into the lungs and via salivary glands in the mouth. If a systemic reaction occurs, peripheral pooling is a result secondary to arterial dilation. This can lead to hypotension and shock (Merck, 2007).

In the early stages of an allergic reaction (specifically type I hypersensitivity) to an allergen that is encountered for the first time, a response occurs in the T-helper 2 cells (a type of T-cell that produces cytokines and interleukin 4). These cells also stimulate B cells to produce IgE in response to interaction with interleukin 4. IgE then binds to the FcεRI receptor on mast cells and basophils which further exacerbate the immune response. Once these cells are coated with IgE, they are then sensitized to the allergen (Wikipedia, 2008). When future exposure to the allergen occurs, the allergen then binds to the IgE molecules on the mast cell or basophil. When more than one IgE- FcεRI receptor complex interacts with an allergen molecule, it activates the sensitized cell. Once they are activated, the cells degranulate and release histamine and other mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules, causing vasodilation, mucus production, nerve stimulation, and smooth muscle contraction (Wikipedia, 2008).

See: Degranulation Process in an Allergic Reaction

Degranulation Process in an Allergic Reaction

 

Each type of IgE is specific for only one type of allergen. This explains why some people are allergic to one allergen (example: dog dander-as they only have the IgE antibodies specific to that allergen), and others are allergic to other things (as they may have other types of IgE antibodies circulating in their bloodstream) (AAAAI, 2007).

Signs and Symptoms of an Allergic Reaction

Signs and symptoms of an allergic reaction can vary depending on the body type involved and type of reaction (Haith, 2005). Common symptoms of an allergic reaction include runny nose (rhinorrhea), stuffy nose, sneezing, itching, headache, watery eyes, wheezing, and dyspnea. Signs of an allergic reaction may include blistering, weeping of the skin, rash, hives, welts, swelling of the face (or eyes, lips, tongue, or throat), edema of the airways, sinus pain, wheezing, red eyes (conjunctival hyperemia), swelling of the face, and skin lichenification. If a patient has stridor, inability to breathe, wheezing, hypotension, becomes unconscious, or confused, they may be exhibiting signs of anaphylactic shock which is caused by extensive vasodilation. A person in shock may be pale or red, sweaty or dry, confused, anxious or unconscious (Merck, 2007; Haith, 2005). The symptoms can vary being system-wide or localized to a particular site depending on the individual, allergen, and mode of introduction (Wikipedia, 2008).

Type of Allergic C

 Body System Involved

Symptoms of Reaction

Allergic rhinitis (hay fever)

Allergens touch the mucous membranes of the nose

Congestion, itching, runny nose, itchy, watery eyes, sinusitis, and otitis media.

Allergic conjunctivitis

Allergens touch the lining of the eyes.

Red eyes, itchy eyes, swollen eyes.

Atopic dermatitis (eczema)

Allergen exposure to the skin.

Itching, reddening, flaking/peeling skin.

Urticaria (hives)

Allergen exposure to the skin.

Itchy, red bumps.

Asthma

Allergen exposure to the lining of the lungs.

Coughing, chest tightness, shortness of breath, wheezing.

Anaphylaxis

Allergen exposure to certain stimuli which makes its way into the bloodstream and causes a rapid, severe reaction.

Swelling, flushing, tingling, rash, lightheadedness, shortness of breath, severe sneezing, anxiety, abdominal cramping, vomiting, diarrhea, loss of consciousness, and shock.

(AAAAI, 2007)

 

Diagnosis

The most reliable diagnosis of an allergy is obtained through the patient’s history (Haith, 2005; Merck, 2007). Triggering factors, frequency of allergic reaction, duration, situations around attacks (where attacks occur and what activities are being done), family history of similar allergic reactions, etc. are all important to obtain when diagnosing an allergy. For patients who have asthma, whether they began having asthma attacks after the age of 30 or not helps to determine whether or not their asthma is secondary to allergy, as childhood asthma is usually secondary to allergy, and adult-onset asthma usually is not (Merck, 2007).

There are some tests that are rather nonspecific that might suggest allergy and can include CBC (to detect the presence of eosinophilia), sputum cultures (to examine for leukocytes, eosinophils), or serum IgE level (elevated in atopic disorders). Although these levels are increased in allergic disorders, they are nonspecific and do not rule out other causes for elevation (Merck, 2007; Wikipedia, 2008).

A more specific allergy test for allergic responses is skin testing. Skin testing is done by introducing a very small amount of a specific antigen into the skin and watching for a reaction. A test is considered positive if a wheal and a flare reaction occurs (wheal diameter 3 to 5 mm greater than that of the control after 15 to 20 minutes). The most common antigens used are those for pollens, molds, dust, animal dander, insect venoms, foods, and certain antibiotics. Depending on the environment in which the patient lives and based on possible allergic reactions in the past determines which antigens are used. There are two methods for performing skin tests, percutaneous (where the antigen is placed on the skin and the skin is pricked slightly), and intradermal (where the antigen is injected into the dermis). Although the intradermal test is more sensitive, it is less specific and is often done to confirm allergic reactions after a positive skin prick test is positive. In conditions such as dermatographism (where the skin wheals and flares after simple stroking or scratching of the skin), false positive results can occur (Merck, 2007; Wikipedia, 2008).

Radioallergosorbent testing (RAST) testing is done when skin testing cannot be performed accurately or when otherwise contraindicated. It detects the presence of allergen-specific serum IgE in the serum and is quantified by measuring the amount of antibody present in serum (Merck, 2007; Haith, 2005; Wikipedia, 2008).

Provocative testing is done by exposing the patient directly to the allergen source in order to document reaction for various reasons. Food allergies and some other allergens are not easily measured with skin testing due to lack of antigen availability in that form and are more accurately documented in this way (Merck, 2007; Haith, 2005).

When to Seek Medical Care

Medical attention is recommended in all cases of allergic reactions except those that are very minor and localized. If the symptoms progress over days, a physician should be notified. Of course, sudden and severe reactions require immediate emergency care. If any of the following occur, a medical professional should be notified as the reaction could progress towards anaphylactic shock
(Haith, 2005):

1. Sudden and severe symptoms.
   
2. Exposure to an allergen that has previously caused sudden or severe reaction.
   
3. Swelling of the lips, tongue, throat, or face.
   
4. Wheezing, chest tightness, stridor, trouble breathing, etc.
   
5. Nausea or vomiting, confusion, unconsciousness.
   
6. Widespread rash.

Treatment

The treatment of allergic reactions begins with avoidance of triggering stimuli and then medical treatment after exposure to an allergen. Removal of certain items that can collect allergen material (soft pillows, stuffed animals, etc.), frequent washing/cleaning to remove allergens from the environment (and use of HEPA filters) and removal of irritants such as perfumes, smoke, odors, etc. can all help to avoid allergic reaction. Severe reactions should not be attempted to be cared for at home (Merck, 2007; Haith, 2005).

There are several medications that are used to block the action of allergenic mediators (called antagonistic drugs) to prevent the activation of cells and to prevent them from degranulating. Included in these are antihistamines, corticosteroids, epinephrine, theophylline, and cromolyn sodium. Anti-leukotrienes are also used. Anti-cholinergics, decongestants, mast cell stabilizers, and others may help to prevent the movement of eosinophils in response to allergens. These only treat the acute phases of an allergic reaction, and are not for the chronic treatment of allergy (Wikipedia, 2008).

Antihistamines are used to block histamine receptors in the body. Histamine-1 (H1) blockers are widely used for allergic disorders, histamine-2 (H2) blockers are most effective the in gastrointestinal tract for acid suppression and are not usually used in the treatment of atopic disorders. H1 blockers are most effective in the treatment of atopic disorders and are less effective in treating bronchoconstriction (in asthma) and vasodilation. Antihistamines can be used intranasally and ocularly as well. The most common side effect from oral antihistamines is drowsiness (Merck, 2007; Haith, 2005).

Mast cell stabilizers can be used to block the release of mediators from mast cells and their subsequent effects. These are usually used when antihistamines and corticosteroids are not available or are contraindicated (Merck, 2007).

Antiinflammatories are used to treat symptoms of allergic reaction due to swelling. NSAIDs are not effective enough to do this, and thus, corticosteroids are the drugs of choice. Corticosteroids reverse the effect of systemic mediators. Nasal corticosteroids are most often prescribed and have few side effects as compared to corticosteroids taken orally or via injection (Merck, 2007; Haith, 2005).

Leukotriene modifiers are used in the treatment of asthma and seasonal allergic rhinitis to prevent the side effects from leukotriene production by the body (Merck, 2007).

Anti-IgE antibody is used for more severe cases of asthma that do not respond to other treatments and may also be helpful in cases of rhinitis that are refractory to other treatments (Merck, 2007).

Decongestants can be given to reduce sinus drainage and relieve nasal congestion and swelling, and sinus pain (Haith, 2005).

Treatment by immunotherapy is based on the theory of hyposensitization/desensitization via injection of the allergen to the patient. This does not treat the symptoms of an allergic reaction, but alters the immune response to prevent further reactions by increasing IgG production which in turn blocks excessive IgE production. This form of treatment is indicated when the patient cannot avoid allergen exposure and medical treatment is not otherwise available. This is done by giving an injection of the allergen monthly. The dose of the allergen is increased until a maximum tolerated concentration is reached, meanwhile observing the patient to ensure no serious reaction takes place. This maximum dose is then given every 4 to 6 weeks year round. This can be done for most allergens including pollen, dust, mold, and insect venom. It can be done for animal dander in those who cannot avoid exposure and for certain antibiotics such as penicillin. Food desensitization is not performed (Merck, 2007; Haith, 2005; Wikipedia, 2008). A second type of immunotherapy is performed in which monoclonal anti-IgE antibodies are injected into the bloodstream which bind to free IgE and destroys them. (It does not affect IgE that are already bound to the FcεRI receptor-if it did, it would signal a response instead.) Sublingual immunotherapy is a third form which is orally administered and uses oral immune tolerance to antigens such as foods and resident bacteria. Oral tolerance refers to specific suppression of cellular and/or humoral immune reactivity to an antigen by administration of the antigen orally (Wikipedia, 2008).

In the event that a patient has an anaphylactic reaction, evaluation in the emergency department is performed on the basis of stabilizing the patient by monitoring blood pressure, respiratory sufficiency, history of what possibly caused the reaction, and an IV line is often placed in case of further/continued emergency. Epinephrine is given in anaphylaxis and works by dilating the bronchioles (bronchodilator) and constricts blood vessels (to increase blood pressure) (Haith, 2005).

Prevention

Primary prevention of allergic reaction centers around avoidance of known triggers. Desensitization or immune therapy can help to prevent future allergic attacks, especially for those that cannot be readily avoided. For patients who are allergic to IV dye, they should avoid exposure if at all possible. When it is not possible, administration of prednisone and diphenhydramine before the procedure may help to prevent complications from IV dye administration (Merck, 2007). For those patients who have anaphylactic reactions to certain triggers, carrying a prefilled epinephrine syringe to be injected at the time of exposure may prevent reaction and the need for hospitalization (Merck, 2007; Haith, 2005).

Common Allergic Reactions

Some of the most common allergens are listed below. Some people have cross reactions to items that are similar in protein structure. For instance, children can be allergic to birch pollen and have the same reaction with eating apples because the protein construction in each is similar. It is important to know associated allergic classes as to potentially prevent other reactions from occurring. This scenario is common with medication allergies, and the most common classes of medication allergies are listed below as well (ACENTA, 2003; Geimeier, 2007, and More, 2009):

Common Airborne allergens:

1. Dust mites.
   
2. Pollen.
   
3. Molds.
   
4. Pet dander.
   
5. Cockroaches.

Common Food Allergens:

1. Cow’s milk (protein).
   
2. Eggs.
   
3. Seafood/shellfish (can be associated with allergy to iodine or IV contrast dye).
   
4. Peanuts/tree nuts (associated with allergies to legumes, grass, wheat, corn).
   
5. Soy.
   
6. Wheat.

Other Common Allergens:

1. Insect stings.
   
2. Chemicals (detergents, perfumes, etc.)
   
3. Grass (can be associated with allergy to potato, melon, tomato, watermelon, orange, cherry, peanut)
   
4. Latex (can be associated with allergy to avocado, potato, banana, tomato, chestnut, kiwi fruit, herbs, carrot).
   
5. Medications.
  
a. Penicillin (and associated antibiotics, the "-cillins").
   
b. Cephalosporins (also associated with allergy to penicillin derivatives).
   
c. Sulfonamides.
   
d. Non-steroidal anti-inflammatory drugs (NSAIDs).
   
e. IV contrast dye.
   
f. Local anesthetics (often the preservatives in the preparations are the source of the reaction to these medications).
   
g. General anesthesia.
   
h. Anti-seizure medications.

Other Common Cross Reactions:

1. Birch: Apple, carrot, cherry, pear, peach, plum, fennel, walnut, potato, spinach, wheat, buckwheat, peanut, honey, celery, kiwi fruit, hazelnut, anise, fennel, coriander, cumin.
   
2. Mugwort Sage: Celery, carrot, spices, melon, watermelon, apple, chamomile, hazelnut, anise, fennel, coriander, cumin.
   
3. Ragweed: Melon, chamomile, honey, banana, sunflower seeds
   
4. Plantains: Melon

Nursing Interventions

Nurses in the hospital setting can help identify existing allergies by taking a history from patients regarding past reactions to medications, foods, or environmental factors. Accurate documentation of these previous reactions may help to prevent an inadvertent reaction while the patient is in the hospital setting, during a potentially vulnerable time. Accurate assessments of patients in the hospital may help the nurse to identify an allergic reaction a patient may be having to something introduced within the hospital. In this instance, it is important for the nurse to accurately document the findings and notify the appropriate personnel to initiate/prescribe treatment for the reaction, if necessary. An anaphylactic reaction within the hospital setting may require advanced cardiac support skills and would require the nurse to accurately assess the situation and initiate appropriate care. Any allergies discovered in the hospital setting should be explained to the patient along with how to avoid such triggering factors and potential reactions in the future. Knowledge of the different classes of medications and potential cross reactions helps the nurse to educate the patient to identify not only the particular medication/allergen to avoid, but also class(es) of medications/allergens to which a patient may have similar reactions.

Nurses who work in the community setting can be instrumental working with patients with allergies by educating them about particular signs and symptoms of an allergic reaction and when a reaction is serious enough to warrant emergency intervention. Teaching can be undertaken for patients with known allergies regarding usage of medications for mild allergic reactions and severe reactions including how to use epinephrine injectional systems for patients who have potential or known anaphylactic reactions to certain triggers. Often hyposensitization shots are administered by nurses in the community setting. It is important to monitor response to all therapies, and this can be done by the nurse directly while the patient is in his/her care, or by taking a verbal history from the patient. If a response is noted, the nurse may need to notify the patient’s physician about the reaction, and may administer care to the patient, depending on the severity and type of reaction. The nurse can help the patient identify triggering factors by encouraging them to keep a log of reactions and all potential triggers. Once the triggers are known, nurses can help patients learn ways to avoid these triggering factors and potential further reaction.

Conclusion

Allergic reactions are usual responses to any number of various potential triggers and can become very serious and life threatening. Careful notice of reaction to which triggers, when, and under which circumstances can help a patient to identify their specific triggering factors. Skin testing can also be of help in identifying triggering factors. Once the factors are identified, they can more readily be avoided, and if not able to be avoided, medical therapy can be utilized to prevent future reaction. Of course, in the event of any major reaction, emergency medical attention should always be sought for the patient.

References

AAAAI (American Academy of Allergy, Asthma, and Immunology) (2007), ‘Tips to Remember: What is an allergic reaction?’, [Online] http://www.aaaai.org/patients/publicedmat/tips/whatisallergicreaction.stm, [Accessed 7/29/2008].

ACENTA (Arkansas Center for Ear, Nose, and Throat and Allergy) (2003), ‘Food Allergy & Cross-Reactivity’, [Online] http://www.acenta.com/allergy.foodallergy.asp, [Accessed 1/31/2009].

Geimeier, William J. (2007), ‘Kids’ Health for Parents: All About Allergies’, [Online] http://kidshealth.org/parent/medical/allergies/allergy.html, [Accessed 1/31/2009].

Haith, W.L. (2005), eMedicineHealth, copyright by WebMD, ‘Allergic Reaction,’ [Online] http://www.emedicinehealth.com/allergic_reaction/page16_em.htm, [Accessed 7/29/2008].

Merck Manual, The, (2005), ‘Allergic and Other Hypersensitivity Disorders’, [Online], http://www.merck.com/mmpe/sec13/ch165/ch165a.html, [Accessed 7/29/2008].

Merck Manual, The, (2007), ‘Atopic and Allergic Disorders’, [Online], http://www.merck.com/mmpe/sec13/ch165/ch165c.html, [Accessed 7/29/2008].

More, Daniel, (2009), ‘About.com: Allergies: Drug Allergy: Medication Allergies: Allergic Reactions to Medications – A Common Problem’, [Online] http://allergies.about.com/od/medicationallergies/a/drugallergy101.htm, [Accessed 1/31/2009].

Thomas, C., (1997) ‘Taber’s Cyclopedic Medical Dictionary,’ copyright by F.A. Davis Company, Philadelphia, pp. 67-68.

Wikipedia, (2008), Wikipedia, The Free Encyclopedia, ‘Allergy,’ [Online], http://en.wikipedia.org/wiki/Allergy, [Accessed 7/29/2008].

Wikipedia, (2008), Wikipedia, The Free Encyclopedia, ‘Immune Tolerance,’ [Online], http://en.wikipedia.org/wiki/Immune_tolerance#Acquired_tolerance, [Accessed 8/4/2008].