Download Allergy : An Overview

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 IgE 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 IgE 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 II, 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 IgE .
•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 IgM or IgG 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 IgG class, although IgM 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 (C3a, 4a and 5a). 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: IgE 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 IgE antibodies,
but they lack the genetically determined propensity and the
target organ hyper- responsiveness of atopy.
• The immunologic pathogenesis for all IgE mediated disease
is the same, but separate consideration of atopic and a nonatopic 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 IgE 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 IgE production and
specific IgE 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 IgE antibody response. A
coexisting viral respiratory infection during allergen
exposure may have an adjuvant effect on both specific and
total IgE production. Tobacco smoking have similar effect.
Genes Identified to date in Atopy
Chromosome
Candidate Gene
1p
2q
3p24
IL-12
CD28
Bcl-6,IL3,IL4,IL5,IL13,GM—CSF,LTC4
synthase; receptor for macrophageCSF,2- adrenergic agonists,
corticosteroids
MHC,TNF,TAP-1,TAP-2, 5
Lipooxgenase,FcR1  chain
INF, stem cell factor, NFKB, LAT4
hydrolase
TCR/ chains, NF kappa B inhibitor
IL4 receptor
6p21-23
12q14-24
14q11-13
16p11-12
Immunopathogenesis
•
Both mast cells and basophils are involved in immunopathogenesis of
IgE mediated diseases. Mast cells and basophils have a high affinity
IgE cell membrane receptors for IgE (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 IgE-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 (H1) and histamine 2
(H2) 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 C3 and C3a. 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:
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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 . IgE mediated
allergy localized in the nasal
mucosa and conjunctiva. Pollens
and fungal spores, dust and
animal danders usual atmospheric
allergens.
Allergic asthma (IgE 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 IgE 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
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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
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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.
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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
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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.
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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 :
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IgE mediated :This form is the true anaphylaxis that requires an initial
sensitizing exposure, the coating of mast cells and basophils by IgE,
and the explosive release of chemical mediators upon re–exposure.
•
Non–IgE mediated :These reactions, the so called "anaphylactoid"
reactions, are similar to those of true anaphylaxis, but do not require
an IgE 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
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 IgE-mediated mechanisms.
Immunologic response to a food protein.This
overreaction can 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, fish, 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 IgE antibodies. They
are often called food “sensitivities” or “intolerances.” The absence of
IgE does not make them any less real; other immune mechanisms,
such as IgG 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 IgG-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
IgE-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 IgE-mediated allergies.
Laboratory Tests
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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.
– IgE 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 IgE 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
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A nasal smear can be performed to look for eosinophils.
Elevated eosinophil levels can be consistent with allergic rhinitis.
Test For Drugs
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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.
Treatment
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
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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.
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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. 6th ed. Philadelphia, Pa: Mosby;
2003.
Rakel RE. Textbook of Family Medicine. 7th 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):S1-68.
Adkinson NF Jr .Middleton’s Allergy: Principles and Practice6 .th ed. Philadelphia, Pa: Mosby;
2003
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