Hypersensitivity reactions for Medical Students

Hypersensivity Reactions
Allergies Greek = altered reactivity
1906 – von Pirquet coined term:
hypersensitivity

Immunreaktionen der Haut 2
HYPERSENSITIVITY
adverse clinical reaction by the host or,
“when the immune system does something bad
to the host, i.e. tissue damage”

POINTS TO BE DISCUSSED
1. Definition of hypersensitivity
2. Four types of hypersensitivity
3. Type I – anaphylactic
4. Type II – cytotoxic
5. Type III – immune complex mediated
6. Type IV – contact, tuberculin and
granulomatous

Definition
 Hypersensitivity refers to undesirable
(damaging, discomfort-producing and
sometimes fatal) reactions produced by the
normal immune system.
 Hypersensitivity reactions require a pre-
sensitized state of the host.

Hypersensitivity reaction depends on:
1) chemical nature of allergen.
2) route involved in sensitization ie. inhalation,
ingestion, injection.
3) physiological state of individual / genetic
potential.

Classification
 Immediate
 Delayed

 Coombs and Gel (1963) classified
hypersensitivity reactions into five major
types:
 Type I (Anaphylactic, IgE or Reagin depandent)
 Type II (Cytotoxic)
 Type III (Immune complex disease)
 Type IV (Dealyed or Cell mediated )
 Type V (Stimulatory)

TYPE I (Anaphylactic)
• Immediate
hypersensitivity reaction.
• IgE antibodies mediated
• Occurs within minutes to
4-6 hours of drug
exposure

• Immediate
•IgE (or rarely IgM)
antibodies mediated
•Antibody-drug interaction
on the cell surface results
in destruction of the cell.
TYPE II( CYTOTOXIC)

• Immediate
•Antigen- Antibody
complex mediated.
•Onset: 2 days up to 4
weeks
• penicillin commonest
cause
TYPE III( Immune complex)

• Delayed hypersensitivity
reaction.
•Cell mediated.
•Antigen activates
specifically sensitised
CD4 and CD8 T cells,
leads to secretions of
lymphokines and
phagocyte accumulation.
TYPE IV (cell mediated)

• Modified form of Type II Hypersensitivity
reaction.
•In this type of reaction, instead of binding
to cell surface components, the antibodies
recognize and binds to the cell surface
receptors.
TYPE V (Stimulatory Hypersensitivity)

Coombs and Gell’s Classification of Hypersensitivity

INTRODUCTION
 Anaphylaxis is defined as a life-threatening allergic reaction set in
action by a wide range of antigens and involving multiple organ
systems.
 The true incidence is difficult to estimate, but in 1973 the Boston
Collaborative Drug Surveillance Program reported six
anaphylactic reactions and 0.87 deaths from anaphylaxis per 10,000
patients.
 Reactions to insect stings alone are responsible for at least 50
deaths in the United States each year.
 These figures reveal the importance of continued research into the
biology of anaphylaxis along with developing new (and improving
existing) therapies.

Type I Hypersensitivity
These occurs in two forms:
 Atopy – any chronic, recurrent, non fatal,
local allergy such as hay fever or asthma
 Anaphylaxis – a systemic, often explosive
reaction that involves airway obstruction and
circulatory collapse

 Common among population in developed
nations
 Prerequisite: need prior sensitization to
antigen
 the binding of antigen to antigen specific IgE
bound on mast cells
 Rapid liberation of active chemicals such as
histamine and serotonin

TYPE I HYPERSENSITIVITY
 A Type I Hypersensitive
reaction is mediated by IgE
antibodies whose Fc region
binds to receptors on the mast
cells or blood basophils.
 Crosslinkage of the fixed IgE
by allergen leads to mast cell
or basophil degranulation with
release of pharmologically
active mediators.
 The primary effects of these
mediators are smooth-muscle
contraction and vasodilation.
www-immuno.path.cam.ac.uk/.../lec13/type2a.gif

Sensitization

Type-I Hypersensitivity: Animation I
Production of IgE in Response to an Allergen

Type-I Hypersensitivity: Animation II
Allergen Interaction with IgE on the Surface of Mast
Cells triggers the Release of Inflammatory Mediators

Mast cells and Basophils
Mast cell
basophills

Anaphylactic-type Degranulation of a Mast Cell

Granule proteins
MBP, ECP, EPO
Cytokines
IL-3, IL-4, IL-5, GM-CSF,
IL-6, IL-12, TGF-b
LTC4, PAF Chemokines
Eotaxin, RANTES
Epithelial damage / loss
Muscarinic M2 dysfunction/ AHR
Attract/activate eosinophils
Airway remodelling, IgE,
Th2 polarisation
Attract/activate eosinophils
Mucus hypersecretion,
Airway narrowing
Attract/activate
pro-inflammatory cells
Products of Human Mast Cells

 The allergic response
Figure 43.20
IgE antibodies produced in
response to initial exposure
to an allergen bind to
receptors or mast cells.
1 On subsequent exposure to the
same allergen, IgE molecules
attached to a mast cell recog-
nize and bind the allergen.
2 Degranulation of the cell,
triggered by cross-linking of
adjacent IgE molecules,
releases histamine and other
chemicals, leading to allergy
symptoms.
3
1
2
3
Allergen
IgE
Histamine
Granule
Mast cell

BIOLOGY OF ANAPHYLAXIS
 Anaphylaxic symptoms can occur
within seconds of antigen
exposure. With fatal reactions, the
respiratory and cardiovascular
systems are affected.
 Upper airway obstruction caused
by angioedema usually lead to
asphyxia. Lower airway obstruction
with wheezing and chest tightness
is caused by bronchospasm.
 Hypotension is caused by a shift of
fluid from the intravascular to the
extravascular space.
 Losses of intravascular volume can
occur quickly as a result of
increased vascular permeability.
 Patients normally compensate
through maximal vasoconstriction
initiated by the release of
catecholamines and angiotensin.
www.pennhealth.com...allergyimages19320.jpg

Typical responses to
these chemicals:
 Increased capillary permeability
Urticaria [hives]
 Excessive mucus production
 Allergic rhinitis [hay fever]
 Diarrhea or vomiting
 Asthma

Causes of anaphylaxis
 Exercise-induced
 food-dependent, exercise-induced
 cold-induced
 idiopathic

32
Allergic reactions on skin
 Stevens-Johnson Syndrome (SJS) and Toxic
Epidermal Necrolysis (TEN)
-A manifestation of acute graft versus host
disease
-Medications with longer half-lives are more
likely than those with shorter half-lives to
pose a risk for SJS and TEN

33
Stevens Johnson’s syndrome

36
SJS & TEN
 SJS & TEN develop 1-3 weeks after the
culprit medication is initiated
 Sulphonamides, other antibiotics, NSAIDs,
anticonvulsant and antiretroviral agents are
the most common causative medications.

37
Signs and Symptoms of SJS & TEN
 Mucosal erosions
 Asymmetric skin
involvement with
blisters
 Widespread of skin
distribution
 <10% total body
surface area
affected
 Mucosal erosions
 Flaccid blisters and
denuded skin
 Widespread of skin
distribution
 > 30% total body
surface area
affected

Frequency of symptoms in
Anaphylaxis
Urticaria/angioedema 88%
Upper airway edema 56%
Dyspnea or wheeze 47%
Flush 46%
Dizziness,
hypotension, syncope
33%
Gastrointestinal sx 30%
Rhinitis 16%

Vasculature
Skin
Upper
respiratory
Lower
respiratory
GI Tract
TYPES:

Anaphylaxis
 Onset of symptoms of anaphylaxis: usually
in 5 to 30 minutes; can be hours later
 A more prolonged latent period has been
thought to be associated with a more benign
course.
 Mortality: due to respiratory events (70%),
cardiovascular events (24%)

43
Strategies for circumventing allergic
attacks

Methods of diagnosis
1) History taking for determining the allergen involved
2) Skin tests:
Intradermal injection of battery of different allergens
A wheal and flare (erythema) develop at the site of
allergen to which the person is allergic
3) Determination of total serum Ig E level
4) Determination of specific Ig E levels to the different allergens

Skin Prick Test
In this test a small needle is used to
gently prick the skin through a drop of
fluid containing a known allergen. It is
usually done on the forearm, although
with young children it may be done on
the back so they don't have to see what
is happening.
A negative reaction means that you do
not have an allergy to that particular
allergen.
Your clinical symptoms should correlate
with the allergens to which you test
positive, only then can an allergy be
confidently diagnosed.

Immediate and Delayed Phases of Type I Hypersensitivity
Immediate Delayed

Prevention of anaphylaxis
 Avoid the responsible allergen (e.g. food,
drug, latex, etc.).
 Keep an adrenaline kit (e.g. Epipen) and
Benadryl on hand at all times.
 Medic Alert bracelets should be worn.
 Venom immunotherapy is highly effective in
protecting insect-allergic individuals.

Treatment of anaphylaxis
 Place patient in Trendelenburg position.
 Establish and maintain airway.
 Give oxygen via nasal cannula as needed.
 Place a tourniquet above the reaction site
(insect sting or injection site).
 Epinephrine (1:1000) 0.1-0.3 ml at the site of
antigen injection
 Start IV with normal saline.

Ch. 15
Therapies
Avoidance of Ag
Hyposensitization
Drugs
antihistamines (block receptors)
epinephrine (maintain high cAMP and
prevent degranulation
cromolyn sodium block calcium flux
and more (p. 388)

Intervention for Type I Hypersensitivity
Animation: Treatment with monoclonal anti-IgE antibody

Ch. 15
Type II: antibody-mediated cytotoxic reactions:
Antibodies bind to cells and mediate their
destruction
Transfusion reactions (ABO blood group Ags)
Drug-induced hemolytic anemia
drugs absorb to RBCs, like hapten-carrier
Hemolytic disease of the newborn

Type II Hypersensitivity
Antibody-Complement Dependent Mediated Lysis
Animation: IgG or IgM reacts with epitopes on the host cell membrane and
activates the classical complement pathway. Membrane attack complex (MAC)
then causes lysis of the cell.

Antibody-Complement Dependent Mediated Lysis
Example: Autoimmune Hemolytic Anemia

Antibody Dependent Cell Mediated Cytotoxicity
Animation: Antibodies react with epitopes on the host cell membrane and NK
cells bind to the Fc of the antibodies. The NK cells then lyse the cell with pore-
forming perforins and cytotoxic granzymes

Antibody-Mediated Cell Disfunction
Example: Myasthenia Gravis

Ch. 15
Type III: Immune complex disease:
Sometimes antibody- (soluble) antigen complexes
are not cleared like they should be
When deposited in tissue, they cause damage
complement activation- produces
inflammatory mediators
neutrophils are attracted
Arthus reaction - sensitized person develops
a reaction at site of exposure (slower than
type I)

70
Autoimmunity
 In certain type I & II hypersensitivities, the
immune system has lost tolerance to self
molecules and forms autoantibodies and
sensitized T cells against them.
 More common in females
 Disruption of function can be systemic or
organic specific
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Endocrine autoimmunities
 Myasthenia gravis
 Multiple sclerosis

Clinical conditions of Type III Hypersensitivity
Diseases produced by immune complexes are those in
which antigens persists without being eliminated as:
a- Repeated exposure to extrinsic antigen
b- injection of large amounts of antigens
c- Persistent infections
d- Autoimmunity to self components

1- Arthus Reaction
* This is a local immune complex deposition phenomenon
e.g. diabetic patients receiving insulin subcutaneously
edema
* Local reactions in the form of erythema
necrosis
deposited
* Immune complexes in small blood vessels
vasculitis
leading to microthrombi formation
vascular occlusion
necrosis

2- Serum Sickness
* A systemic immune complex phenomenon
* Injection of large doses of foreign serum
* Antigen is slowly cleared from circulation
* Immune complexes are deposited in various sites
fever
urticaria
* 10 days after injection arthralgia
lymphadenopathy
splenomegaly
glomerulonephritis
antidiphtheritic serum
e.g. treatment with penicillin
sulphonamides

Type III Hypersensitivity Clinical Conditions
3- Post-streptococcal glomerulonephritis
glomerulitis associated with infective endocarditis
4- Hypersensitive pneumonitis (farmer lung)
immune complexes depositition in lung after repeated
inhalation of dust , mould spores
5- Endogenous antigen antibody complexes involved in
autoimmune diseases
e.g. SLE, rheumatoid arthritis

 Repeated antigenic exposure
 Chronic infection
 Autoimmunity
 Cancer
Predisposing Conditions

Ch. 15
Generalized reaction- large amounts of antigen
enter bloodstream
Immune complexes form
Serum sickness- immunization with foreign serum
Complexes tend to accumulate in kidneys,
arteries, joints
Autoimmune disease
Infectious disease (malaria, parasitic disease)
Cross-reactivity with bacterial or viral antigens

Ch. 15
Type IV (TDTH and TC, or delayed-type):
Detected with skin test (e.g., tuberculin or PPD
skin test for tuberculosis)
Contact dermatitis- when small molecules
complex with skin proteins (poison ivy,
poison oak, cheap jewelery)
Internalized and presented by Langerhans
cells; TH1 response; influx of macrophages
Can lead to granuloma formation

THE VARIANTS OF TYPE IV
(DELAYED) HYPERSENSITIVITY
 Contact one – eczematous reaction at the point of
contact with allergen, usually hapten, occurs within
72 hours of antigen challenge
 Tuberculin one – an area of red firm swelling of the
skin, 48-72 hrs after injection
 Granulomatous one – formation of granuloma at 21-
28 days following antigen exposure

DISEASES WITH TYPE IV
GRANULOMATOUS
HYPERSENSITIVITY
 Chronic pulmonary tuberculosis
 Borderline leprosy
 Sarcoidosis
 Crohn’s disease
 Schistosomiasis
 Some fungal diseases

Type IV: Cell Mediated
Delayed Type Hypersensitivity
triggering DTH reactions by TH1
* T-cells cause tissue injury by or
directly killing target cells by CD8
* TH1 and CD8 T cells secrete cytokines (IFN-γ and TNF)
attract lymphocytes
* Cytokines activate macrophages
induce inflammation
* Tissue damage results from products of activated macrophages

Tuberculin –Type Hypersensitivity
* When PPD is injected intradermally in sensitized person
* Local indurated area appears injection site (48-72 hs)
* Indurations due to accumulation Of:
macrophages and lymphocytes
* Similar reactions observed in diseases
e.g. brucellosis, lepromin test in leprosy, Frei’s test in
lymphogranuloma venereum

Granulomatous lesions
* In chronic diseases : T.B., Leprosy, schistosomiases
* Intracellular organisms resist destruction by macrophag.
* Persistent antigen in tissues stimulate local DTH reaction
* Continuous release of cytokines leads to accumulation of
macrophages which give rise to epitheloidal and giant cell
granuloma

Contact Dermatitis
* Contact of skin with chemical substances or drugs
e.g. poison, hair dyes, cosmetics, soaps, neomycin
* These substances enter skin in small molecules
* They are haptens that attached to body proteins, form
immunogenic substances
* DTH reaction to these immunogenic subst. lead to:
eczema
inflammtory reaction of skin in rash
vesicular eruption

Type IV (TDTH and TC, or delayed-type)
Can lead to granuloma formation
Detected with skin test (e.g., skin test for
tuberculosis)
Contact dermatitis- when small molecules
complex with skin proteins
Internalized and presented by Langerhans
cells
TH1 response; elicitation of macrophages

Helps protect against intracellular pathogens
Granulomas form in chronic reactions
DTH response declines in immune deficient
people (with T cell deficiency)

Ch. 15
Helps protect against intracellular pathogens
Granulomas form in chronic reactions
DTH response declines in immunodeficient
people (with T cell deficiency), like AIDS

CONCLUSION
 Anaphylaxis is a potentially fatal
allergic reaction. Causes can range
from bee stings to drugs, foods, and
exercise.
 Onset is usually sudden, and a
delayed reaction can occur several
hours after the first reaction.
 Treatment consists of airway
maintenance and support of the
blood pressure with fluid expanders,
epinephrine, and oxygen.
 Additional medicines, such as
corticosteroids, antihistamines,
vasopressors, glucagon, atropine
sulfate, and isoproterenol
hydrochloride, may be beneficial.
 Prevention is the most important
part of anaphylaxis management.1
health.yahoo.commediahealthwiseh9991075.jpg

A 22 year old medical student presents to the Dermatology Clinic
with an itchy rash on the trunk and extremities that
started to appear two days after a camping trip to the Texas hill
country.
Scenario:contact hypersensitivity

Calor (heat)
Rubor (redness)
Dolor (pain)
Tumor (swelling)
Results of increased blood flow to the irritated area.
Leads to edema from increased capillary filtration and
leakage of plasma proteins out of capillary.
Increased flow pushes lymphocytes out of vessel into tissue
Clinical Presentation

Allergic Contact Dermatitis (Acute Eczematous Dermatitis)
Red papulovesicular oozing and lesions
Edema localized to perivasuclar spaces in epidermis

 Immunologic mechanisms
IgE-mediated
- drugs
- foods
- hymenoptera (stinging insects)
- latex
Non-IgE mediated
- anaphylotoxins-mediated
e.g. mismatched blood

 Direct activation of mast cells
- opiates, tubocurare, dextran,
radiocontrast dyes
 Mediators of arachidonic acid metabolism
- Aspirin (ASA)
- Nonsteroidal anti-inflammatory
drugs (NSAIDs)
 Mechanism unknown
- Sulphites

Risk of anaphylaxis
 Yocum etal. (Rochester Epidemiology
Project) 1983-1987:
incidence: 21/100,000 patient-years
 food allergy 36%, medications 17%,
insect sting 15%

 EPINEPHRINE (1:1000) SC or IM
- 0.01 mg/kg (maximal dose 0.3-0.5
ml)- administer in a proximal extremity
- may repeat every 10-15 min, p.r.n.
 EPINEPHRINE intravenously (IV)
- used for anaphylactic shock not
responding to therapy
- monitor for cardiac arrhythmias
 EPINEPHRINE via endotracheal tube

 Benadryl (diphenhydramine)
- H1 antagonist
 Tagamet (cimetidine)
- H2 antagonist
 Corticosteroid therapy: hydrocortisone IV or
prednisone po

 Biphasic courses in some cases of
anaphylaxis:
- Recurrence of symptoms: 1-8 hrs later
- In those with severe anaphylaxis,
observe for 6 hours or longer.
- In milder cases, treat with prednisone;
Benadryl every 4 to 6 hours; advise to return
immediately for recurrent symptoms

Treatment of Anaphylaxis in Beta
Blocked Patients
 Give epinephrine initially.
 If patient does not respond to epinephrine
and other usual therapy:
- Isoproterenol (a pure beta-agonist)
1 mg in 500 ml D5W starting at
0.1 mcg/kg/min
- Glucagon 1 mg IV over 2 minutes

Fatal Food-induced Anaphylaxis
SERIES YUNGINGER
(n=7)
SAMPSON
(n=6)
Ages 16-43 years 2-16 years
Atopy All asthmatics
Locale 1/7 at home 1/6 at home
Allergen Peanut- 4
Tree nut- 1
Seafood- 2
Peanut- 3
Tree nut- 2
Egg- 1

Use of epinephrine in
Food Allergy
 Epinephrine should be used immediately
after accidental ingestion of foods that
have caused anaphylactic reactions in the
past.
 An individual who is allergic to peanut,
nuts**, shellfish, and fish should
immediately take epinephrine if they
consume one of these foods.
 A mild allergic reaction to other foods (e.g.
minor hives,vomiting) may be treated with
an antihistamine

Exercise-induced anaphylaxis
 Exercise induces warmth, pruritus, urticaria.
 Hypotension and upper airway obstruction
may follow.
 Some types: associated with food allergies
(e.g. celery, nuts, shellfish, wheat)
 In other patients, anaphylaxis may occur after
eating any meal (mechanism has not been
identified)

Cold-induced anaphylaxis
 Cold exposure leads to urticaria.
 Drastic lowering of the whole body
temperature (e.g. swimming in a cold lake):
hypotensive event in addition to urticaria
 mechanism: unknown

DRUG ALLERGY
 Adverse drug reactions
- majority of iatrogenic illnesses
- 1% to 15% of drug courses
 Non-immunologic (90-95%): side effects,
toxic reactions, drug interactions, secondary
or indirect effects (eg. bacterial overgrowth)
pseudoallergic drug rx (e.g. opiate reactions,
ASA/NSAID reactions)
 Immunologic (5-10%)

Drugs as immunogens
 Complete antigens
- insulin, ACTH, PTH
- enzymes: chymopapain,
streptokinase - foreign antisera e.g.
tetanus antitoxin
 Incomplete antigens
- drugs with MW < 1000
- drugs acting as haptens bind to
macromolecules (e.g. proteins,
polysaccharides, cell membranes)

Factors that influence the
development of drug allergy
 Route of administration:
- parenteral route more likely than oral
route to cause sensitization and
anaphylaxis - inhalational route:
respiratory or conjunctival manifestations
only - topical: high
incidence of sensitization
 Scheduling of administration:
-intermittent courses: predispose
to sensitization

Factors that influence the
development of drug allergy
 Nature of the drug:
- 80% of allergic drug reactions due to:
- penicillin
- cephalosporins
- sulphonamides (sulpha drugs)
- ASA/NSAIDs

Penicillin Allergy
 beta lactam antibiotic
 Type 1 reactions: 2% of penicillin courses
 Penicillin metabolites:
- 95%: benzylpenicilloyl moiety (the
“major determinant”)
- 5%: benzyl penicillin G, penilloates,
penicilloates (the “minor determinants”)

Penicillin Allergy
 Skin tests: Penicillin G, Prepen (benzyl-
penicilloyl-polylysine): false negative rate of
up to 7%
 Resolution of penicillin allergy
- 50% lose penicillin allergy in 5 yr
- 80-90% lose penicillin allergy in 10 yr

Cephalosporin allergy
 beta-lactam ring and amide side chain
similar to penicillin
 degree of cross-reactivity in those with
penicillin allergy: 5% to 16%
 skin testing with penicillin determinants
detects most but not all patients with
cephalsporin allergy

“Ampicillin rash”
 non-immunologic rash
 maculopapular, non-pruritic rash
 onsets 3 to 8 days into the antibiotic
course
 incidence: 5% to 9% of ampicillin or
amoxicillin courses; 69% to 100% in those
with infectious mononucleosis or acute
lymphocytic leukemia
 must be distinguished from hives
secondary to ampicillin or amoxicillin

Sulphonamide hypersensitivity
 sulpha drugs more antigenic than beta
lactam antibiotics
 common reactions: drug eruptions (e.g.
maculopapular or morbilliform rashes,
erythema multiforme, etc.)
Type 1 reactions:
urticaria, anaphylaxis, etc.
 no reliable skin tests for sulpha drugs
 re-exposure: may cause exfoliative
dermatitis, Stevens-Johnson syndrome

ASA and NSAID sensitivity
 Pseudoallergic reactions
- urticaria/angioedema
- asthma
- anaphylactoid reaction
 prevalence: 0.2% general population
8-19% asthmatics
30-40% polyps & sinusitis
 ASA quatrad: Asthma, Sinuitis, ASA
sensitivity, nasal Polyps (ASAP syndrome)

ASA & NSAID sensitivity
 ASA sensitivity: cross-reactive with all
NSAIDs that inhibit cyclo-oxygenase

ASA & NSAID sensitivity
 no skin test or in vitro test to detect ASA or
NSAID sensitivity
 to prove or disprove ASA sensitivity: oral
challenge to ASA (in hospital setting)
 ASA desensitization: highly successful with
ASA-induced asthma; less successful with
ASA-induced urticaria

Allergy skin testing
 Skin tests to detect IgE-mediated drug
reactions is limited to:
Complete antigens
- insulin, ACTH, PTH
- chymopapain, streptokinase
- foreign antisera
Incomplete antigens (drugs acting as
haptens) - penicillins
- local anesthetics
- general anesthetics

Management of drug allergy
 Identify most likely drugs (based on
history).
 Perform allergy skin tests (if available).
 Avoidance of identified drug or suspected
drug(s) is essential.
 Avoid potential cross-reacting drugs (e.g.
avoid cephalosporins in penicillin-allergic
individuals).

Management of drug allergy
 A Medic-Alert bracelet is recommended.
 Use alternative medications, if at all possible.
 Desensitize to implicated drug, if this drug is
deemed essential.

Desensitization to medications
 Basic approach: administer gradually
increasing doses of the drug over a period of
hours to days, typically beginning with one
ten-thousandth of a conventional dose

Hypersensitivity reactions for Medical Students

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