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Allergy : An Overview Salwa Hassan Teama
Allergy • Allergy refers to certain diseases in which immune responses to environmental antigens cause tissue inflammation and organ dysfunction. Hypersensitivity and sensitivity are synonyms for allergy. • Allergen is any antigen that causes allergy. The allergen is either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell. It can be complete protein antigens or low molecular weight proteins capable of eliciting an Ig. E response. Pollen and animal dander represent complete protein antigens. • Atopy is the inherited propensity to respond immunologically to such common naturally occurring allergens with continuous production of Ig. E antibodies.
Allergic Reaction Its overreaction to a harmless substance (an allergen) This harmless substance that is contacted through the skin, inhaled into the lungs, swallowed, or injected.
Types of Hypersensitivity Reaction • Hypersensitivity reactions require a pre-sensitized (immune) state of the host. Hypersensitivity reactions can be divided into four types: type I, type III and type IV, based on the mechanisms involved and time taken for the reaction. Frequently, a particular clinical condition (disease) may involve more than one type of reaction.
• Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor to death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 - 12 hours). Immediate hypersensitivity is mediated by Ig. E. • The primary cellular component in this hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainly mast cells and basphil.
• Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. • e. g. Drug-induced hemolytic anemia , granulocytopenia and thrombocytopenia. • The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the Ig. M or Ig. G classes and complement. Phagocytes and K cells may also play a role (ADCC). The lesion contains antibody, complement and neutrophils.
Type III Hypersensitivity • The reaction may be general e. g. , serum sickness or may involve individual organs including: e. g. kidney (lupus nephritis), • The reaction may take 3 - 10 hours after exposure to the antigen as in Arthus reaction. It is mediated by soluble immune complexes. They are mostly of the Ig. G class, although Ig. M may also be involved. • The antigen may be exogenous or endogenous (non-organ specific autoimmunity : e. g. , systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. • Primary components are soluble immune complexes and complement (C 3 a, 4 a and 5 a). The damage is caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process.
• Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. • e. g. Tuberculin reaction which peaks 48 hours after the injection of antigen (PPD) or (old tuberculin). The lesion is characterized by induration and erythema. • Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, ……. . ) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy , chemicals, heavy metals, etc. ) in which the lesions are more papular.
Comparison of allergy with other responses Disease Mechanism Antigen source Result Allergy Immunologic Foreign Disease Immunity Immunologic Foreign Prophylaxis Autoimmunity Immunologic Self Disease Toxicity Toxic Foreign Disease
Allergy: Ig. E Mediated • Atopy; Allergic rhinitis and allergic athma are the most common manifestation of atopy. Atopic dermatitis is less common and allergic gastroenteropathy is rara. These manifestation may coexist in the same patients or at different times. Atopy can be asymptomatic. • Anaphylaxis and urticaria also caused by Ig. E antibodies, but they lack the genetically determined propensity and the target organ hyper- responsiveness of atopy. • The immunologic pathogenesis for all Ig. E mediated disease is the same, but separate consideration of atopic and a non- atopic disease is important clinically. Difference exist in the allergens, mode of exposure to allergen, genetic factor that influence etiology, diagnostic methods, prognosis and treatment.
Atopy • Atopy is a condition with certain specific immunologic and clinical features. It affect a significant portion of the general population, estimated at 10%-30% in developed countries. The cause of atopy involves complex genetic factors that are not well understood. e. g. Rhinitis, asthma and eczematous dermatitis occur in significant number of patients without atopic Ig. E mediated allergy.
Etiology of Atopy • Etiology is unknown but there is strong evidence for a complex of genes with a variable degree of expression encoding protein factors, these genes and gene clusters occupy positions on at least 11 different chromosomes in the human genome. These are that influence the propensity for atopy through the regulation of total Ig. E production and specific Ig. E antibodies to allergen epitopes, cytokines and their receptors, enzyme and receptors for mast cell mediators. • Environmental factors play a role in etiology. The initial age of exposure to a particular food or pollen determine the intensity of the subsequent Ig. E antibody response. A coexisting viral respiratory infection during allergen exposure may have an adjuvant effect on both specific and total Ig. E production. Tobacco smoking have similar effect.
Genes Identified to date in Atopy Chromosome Candidate Gene 1 p 2 q 3 p 24 IL-12 CD 28 Bcl-6, IL 3, IL 4, IL 5, IL 13, GM—CSF, LTC 4 synthase; receptor for macrophage- CSF, 2 - adrenergic agonists, corticosteroids MHC, TNF, TAP-1, TAP-2, 5 Lipooxgenase, Fc. R 1 chain INF , stem cell factor, NFKB, LAT 4 hydrolase TCR / chains, NF kappa B inhibitor IL 4 receptor 6 p 21 -23 12 q 14 -24 14 q 11 -13 16 p 11 -12
Immunopathogenesis • Both mast cells and basophils are involved in immunopathogenesis of Ig. E mediated diseases. Mast cells and basophils have a high affinity Ig. E cell membrane receptors for Ig. E (Fc RI). Mast are abundant in the mucosa of the respiratory and gastrointestinal tracts and in the skin, where atopic reaction localize. The physiologic effects of the mediator released by these cells cause the pathophysyiology of the immediate and late phases of atopic diseases. e. g. Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals. These reactions, mediated by agents without Ig. E-allergen interaction , are not hypersensitivity reactions although they produce the same symptoms. • When an allergen enters the body, it causes the body's immune system to develop an allergic reaction in a person with an allergy to it.
The major mediators: Preformed mediators: – Histamine is one well-known mediator. – Mediators have effects on local tissue and organs in addition to activating more white blood cell defenders. It is these effects that cause the symptoms of the reaction. – If the release of the mediators is sudden or extensive, the allergic reaction may also be sudden and severe. – The actions of the mediators can cause variable clinical responses depending on which organ systems affected. Histamine: This mediator acts on histamine 1 (H 1) and histamine 2 (H 2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C 3 and C 3 a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of alphatryptase. Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, cause significant tissue damage in the later phases of allergic reactions.
Common allergens include: • • Plants Pollens Animal dander Bee stings or stings from other insects Insect bites Medication Foods, especially nuts and shellfish
Mechanism • While first-time exposure may only produce a mild reaction, repeated exposures may lead to more serious reactions. Once a person is sensitized (has had a previous sensitivity reaction), even a very limited exposure to a very small amount of allergen can trigger a severe reaction. • Allergic reactions vary. They can be mild or serious. They can be confined to a small area of the body or may affect the entire body. • Most occur within seconds or minutes after exposure to the allergen, but some can occur after several hours, particularly if the allergen causes a reaction after it is partially digested. In very rare cases, reactions develop after 24 hours.
Allergic Rhinitis: Most common clinical expression of atopic hypersenstivity. Ig. E mediated allergy localized in the nasal mucosa and conjunctiva. Pollens and fungal spores, dust and animal danders usual atmospheric allergens. Allergic asthma (Ig. E mediated allergy in bronchial mucosa) Allergen exposure results in bronchoconstriction, and patients may report shortness of breath (e. g. , difficulty getting air out), wheezing, cough, and/or chest tightness. Long-term allergen exposure can cause chronic changes of increased difficulty breathing and chest tightness, and the patient may give a history of repeated rescue inhaler use or reduced peak flows. Allergic Gastroenteropathy Localized Ig. E reactions in the gut to an ingested food. Gastrointestinal loss of serum proteins and blood leading to edema and anemia. Rare in adult but more common and transient in children.
Urticaria • • • Diffuse hives or wheals may occur and cause significant purities; individual wheals resolve after minutes to hours, but new wheals can continue to form. Acute urticaria: (lasting <6 wk) can be caused by foods, drugs, or contact allergens. Chronic urticaria: lasts longer than 6 weeks.
Angioedema • • Angioedema is localized tissue swelling that can occur in soft tissues throughout the body. , which may account for a substantial volume of fluid loss from the intravascular compartment. Patients may report pain at the site of swelling instead of pruritus, which occurs with urticaria. Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or hoarseness may be present. It can be life threatening.
Anaphylaxis • • Anaphylaxis is a sudden and severe allergic reaction that occurs within minutes of exposure. Immediate medical attention is needed for this condition. It can get worse very, very fast and lead to death within 15 minutes if treatment is not received. Anaphylaxis is a severe allergic reaction marked by swelling of the throat or tongue, hives, and trouble breathing. life is at risk. And time is critical. Patients may not be able to identify the allergen either because they are unaware of the allergy (e. g. , first reaction to insect sting) or because they were unaware of exposure to the allergen (e. g. , a patient who is allergic to peanuts who eats a processed food containing peanut protein). Particular attention should be given to: – New or recently changed medications. – – – – A history specific for insect stings or New environmental exposures should be obtained. Food history should also be obtained. Symptoms usually begin within minutes of allergen exposure Drug administration, Insect sting, and Food ingestion But can recur hours after the initial exposure (late-phase
The causes of anaphylaxis are divided into two major groups: • Ig. E mediated : This form is the true anaphylaxis that requires an initial sensitizing exposure, the coating of mast cells and basophils by Ig. E, and the explosive release of chemical mediators upon re–exposure. • Non–Ig. E mediated : These reactions, the so called "anaphylactoid" reactions, are similar to those of true anaphylaxis, but do not require an Ig. E immune reaction. They are usually caused by the direct stimulation of the mast cells and basophils. The same mediators as occur with true anaphylaxis are released and the same effects are produced. This reaction can happen, and often does, on initial as well as subsequent exposures, since no sensitization is required.
Symptoms – Patients may report dizziness, faintness, diaphoresis, and pruritus. Difficulty breathing can result from angioedema of the pharyngeal tissue and from bronchoconstriction. – Patients may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. – Patients may experience uterine cramping or urinary urgency. – Patients can have a sudden onset of respiratory and/or circulatory collapse and go into anaphylactic shock.
Food Allergy may be defined as a complex of clinical syndromes (sick all over) resulting from the sensitization of the patient to one or more foods, in which symptoms manifest locally in the GI tract or in other remote organs. Any symptom can be associated with food allergy or intolerance. By identifying and eliminating or treating food allergies, many of our insolvable chronic health problems can be improved or eradicated. Some reactions are classically allergic (immediate reactions alone), or may reflect delayed Ig. E-mediated mechanisms.
Immunologic response to a food protein. This overreaction cause symptoms from the mild (hives) to the severe (anaphylactic shock) upon subsequent exposure to the substance. An actual food allergy, as opposed to simple intolerance due to the lack of digesting enzymes, is indicated by the production of antibodies to the food allergen, and by the release of histamines and other chemicals into the blood.
Many medical conditions are thought to be associated with food allergies. These conditions can be: Respiratory (hay fever, asthma, bronchitis, recurring ear infections, sinus conditions, rhinitis, laryngitis, allergic sore throat, hoarseness); digestive (gastroenteritis, irritable bowel syndrome, celiac disease, inflammatory bowel disease, diarrhea, constipation, colic, malabsorption); cerebral (headaches, dizziness, sleep disorders, learning disorders, tension-fatigue syndrome, foggy thinking, irritability, depression); skin-related (dermatitis, eczema, angioedema, hives, rashes); or related to other body systems (arthritis, myalgia, urinary irritation, conjunctivitis, edema, hypoglycemia, diabetes, overweight, underweight, premenstrual syndrome, and fatigue.
Symptoms Respiratory symptoms: Sneezing, runny nose , stuffy nose wheezing, watery eyes, persistent cough, bronchitis, itchy feeling in the mouth or throat. Skin affection: Red, sandpaper-like facial rash, dry scaly, itchy skin (mostly on face), swelling in hands and feet, puffy eyelids, dark circles under eye, tongue soreness and cracks, sore throat. Behavior changes: fatigue, migraine, headaches, hyperactivity, crying, irritability, anxiety, crankiness, sore muscles and joints. GIT Symptoms: burn like rash around anus, vomiting, constipation , abdominal discomfort, mucous diarrhea, intestinal bleeding poor weight gain, bloating, gassiness, excessive spitting up.
The 6 most common food allergens are peanuts, shellfish, eggs, milk, soy, and wheat. the most common food allergies present in children are milk, eggs , and peanuts Certain foods can cross-react with latex allergens. These foods include banana, kiwi, chestnut, avocado, pineapple, passion fruit, apricot, and grape.
Food Intolerances Many adverse reactions to foods do not involve Ig. E antibodies. They are often called food “sensitivities” or “intolerances. ” The absence of Ig. E does not make them any less real; other immune mechanisms, such as Ig. G antibodies, immune complexes, or cell-mediated reactions are involved instead. These reactions can happen quickly or can be delayed for two to seventy-two hours or longer. About 95% of Ig. G-mediated reactions are not fixed. Therefore, after several months of avoidance, problem foods can be reintroduced into the diet in moderate amounts without causing symptoms as long as they are not eaten too frequently.
Diagnosis Ig. E-mediated allergies are easily detected by standard blood or skin tests. The reactions happen rapidly, usually within a few minutes of exposure to inhaled substances or eating a food. The cutaneous and intradermal allergy testing The cutaneous test (prick test, puncture test epicutaneous test) is used routine diagnosis in atopic or anaphylactic diseases. A single drop of concentrated aqueous allergen extract placed on the skin which is then pricked lightly with a needle point at the center of the drop. After 20 minutes the reaction is graded and recorded. Negative and positive control should be included. Negative results should be repeated using the intradermal skin test (intracutaneous test). Food skin tests have a higher false-positive rate than skin tests for aeroallergens, but negative food skin test results can be helpful in excluding Ig. E-mediated allergies.
Laboratory Tests • Laboratory tests may be helpful in determining whether a reaction is truly allergic in nature. Obtaining a tryptase level soon after the onset of symptoms can be helpful in differentiating anaphylaxis from other forms of shock and from other symptom complexes that may be confused with anaphylaxis. The tryptase level can be elevated, which is indicative of mast cell degranulation. False-negative results can occur. Ideally, the tryptase level should be drawn within 4 hours after the event, but it can be drawn up to 15 hours later.
– An elevated eosinophil count may be observed in patients with atopic disease. – Ig. E levels may be elevated in patients who are atopic, but the level does not necessarily correlate with clinical symptoms. – The radioallergosorbent test (RAST) measures antigenspecific Ig. E and can be useful in identifying which allergens are causing symptoms for the patient. A more sensitive type of RAST is known as the CAP-RAST and has a greater positive predictive value.
Nasal Smear Tests – – A nasal smear can be performed to look for eosinophils. Elevated eosinophil levels can be consistent with allergic rhinitis. Test For Drugs – – – Standardized diagnostic allergens are not available for drugs. Penicillin is the only drug for which a standardized diagnostic allergen exists. While nonstandardized skin tests can be performed for the minor determinants in penicillin or for other drugs (ie, by pricking the skin where drug solution has been placed), these tests are only useful if findings are positive. Spirometry or pulmonary function tests offer an objective means of assessing asthma. Peak-flow meters can also be used for this and can be used by patients at home to monitor their status.
Prevention • Avoid triggers such as foods and medications, …… that have caused an allergic reaction, even a mild one. This includes detailed questioning about ingredients when eating away from home. Ingredient labels should also be carefully examined. • A medical ID tag should be worn by people who know that they have serious allergic reaction. • If any history of a serious allergic reactions, carry emergency medications (such as diphenihydramine and injectable epinephrine. • Do not use your injectable epinephrine on anyone else. They may have a condition (such as a heart problem) that could be affected by this drug.
Food Allergy: Treatment • Treatment consists of avoidance diets, where the allergic person avoids any and all forms of the food to which they are allergic. For people who are extremely sensitive, this may involve the total avoidance of any exposure with the allergen, including touching or inhaling the problematic food as well as any surfaces that may have come into contact with it.
Food Allergy Treatment Trial • • • The only hope for patients is to resolve these problems is to take charge of their own management. The diagnosis should be based on elimination and reintroduction trials. For the nutritionally important foods (milk and wheat in young children) more formalelimination--challenge test should be carried out. The suspected food(s) are eliminated from the diet totally (for 1 -2 weeks). The onset/disappearance of symptoms is recorded in a symptom diary. Reduction or disappearance of symptoms supports food allergy, but is not diagnostic. The food needs to be reintroduced (challenge). A small amount of the food is reintroduced to the diet and, the amount is increased gradually to the normal.
References & Online Further Reading • Atopic diseases: in Medical Immunology. eds ( Tristram G. Parslow, Daniel P. A Stites, Abba I. Terr. and John B. Imboden), tenth edition. • Anaphylaxis and Urticaria: in Medical Immunology. eds ( Tristram G. Parslow, Daniel P. A Stites, Abba I. Terr. and John B. Imboden), tenth edition. Brostoff J and Challacombe, S. Food Allergy and Intolerance. Bailliere Tindall, London. 1987. pp 431 -794 Shapiro, RS, Isenberg, BC. Allergic Headache. Annals of Allergy. 23 (3): 1965 Monroe J, Brostoff, J. Food Allergy and Migraine. Lancet. July 5, 1980 Egger J, Will J, Carter CM. Is Migraine Food Allergy? A Double-Blind Control Trial of Oligoantigenic Diet Treatment. Lancet. 865, 1983 Mansfield L, Vaughn R, et al. Food Allergy and Adult Migraine: Double-Blind Mediator Confirmation of an Allergic Etiology. Annals of Allergy. 55: 126 -129, . Nsouli TM, et al. Serous Otitis Media and Food Allergy. Annals of Allergy, 73: 215 -219 Sandberg, DH. Gastrointestinal complaints related to diet. Intern Pediatrics, 5(1): 23 -29, 1990 Hill, DJ. A low allergy diet is a significant intervention in infantile colic: results of a community based study. J of Allergy and Clinical Immunology, 1995 (Dec): 886 -890 Randolph TG. Allergy as a Causative Factor of Fatigue, Irritability, and Behavioral Problems of Children J Pediatrics. 31: 560 -572, 1947. Boris M and Mandel FS. Foods and additives are common causes of the attention deficit hyperactive disorder in children. Annals of Allergy. 72(5): 462 -468, 1994 Adkinson NF Jr. Middleton’s Allergy: Principles and Practice. 6 th ed. Philadelphia, Pa: Mosby; 2003. Rakel RE. Textbook of Family Medicine. 7 th ed. Philadelphia, Pa: WB Saunders; 2007. American Gastroenterological Association medical position statement: guidelines for the evaluation of food allergies. Gastroenterology 2001. Mar; 120(4): 1023 -5. American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol 2006. Mar; 96(3 Suppl 2): S 1 -68. Adkinson NF Jr. Middleton’s Allergy: Principles and Practice 6. th ed. Philadelphia, Pa: Mosby; 2003 • • •