Allergy : An Overview

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 Result

source
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 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 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 IL-12
2q CD28
3p24 Bcl-6,IL3,IL4,IL5,IL13,GM—CSF,LTC4
synthase; receptor for macrophage-
CSF,2- adrenergic agonists,
corticosteroids
6p21-23
MHC,TNF,TAP-1,TAP-2, 5
Lipooxgenase,FcR1  chain
12q14-24
INF, stem cell factor, NFKB, LAT4
14q11-13 hydrolase
16p11-12 TCR/ chains, NF kappa B inhibitor
IL4 receptor
 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 alpha-tryptase.

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 . 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

 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 :

 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

 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 antigen-specific 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
 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.
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
 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. 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