The 12-year-old boy was stung by a bee and began experiencing symptoms of anaphylaxis including shortness of breath, wheezing, weakness, and dizziness. At the emergency department, he was found to have low blood pressure, rapid heart rate, respiratory distress, urticaria, and pale appearance. He was treated with epinephrine, antihistamines, steroids, and fluids, which resolved his symptoms. He was discharged with oral medications and instructed to follow up. Anaphylaxis is a severe, potentially life-threatening allergic reaction caused by the release of chemicals from mast cells and basophils.

1. ANAPHYLAXIS
Intern Manish Uprety
Department of Internal Medicine

2. A 12-year-old boy is brought to the emergency department after
being stung by a bee. He had been well until he was stung on his
right forearm, while playing in the yard. He initially complained of
localized pain and swelling. Fifteen minutes later, he began to
complain of shortness of breath. His parents observed him to be
wheezing. He also said that he felt very weak and dizzy. His parents
brought him immediately to the local emergency department
CASE

3.  On Examination:
Vital sign: T 37.1, P 120, R 39, BP 69/45.
He is in mild respiratory distress.
He is drowsy and pale, but awakens when you talk to him.
He has generalized urticaria.
He has no conjunctival edema.
His lips and tongue are not swollen.
His voice sounds normal.
Heart tachycardic without murmurs.
His lung examination shows mild wheezing and fair aeration with
minimal retractions.
His abdomen is soft and non-tender.
His face is moderately pale.
The bee sting site on his right forearm is unremarkable with no
foreign body seen.

4. IV line is opened
He is immediately given IM epinephrine and an albuterol
updraft with improvement of his symptoms.
He is given diphenhydramine IV, cimetidine IV,
methylprednisolone IV, and an IV fluid bolus of normal saline.
His urticaria resolves, his blood pressure normalizes and his
lungs sound clear.
After being observed in the ER for three hours, he feels as if he
is back to normal.
He is discharged from the ER on oral diphenhydramine and
prednisone.
Treatment

5. Basic concepts
 Hypersensitivity (also called hypersensitivity reaction or intolerance) is
a set of undesirable reactions produced by the normal immune system,
including allergies and autoimmunity.
Allergen: The antigens that give rise to immediate hypersensitivity
 Atopy：The genetic predisposition to synthesize inappropriate levels of IgE
specific for external allergens
 Hypersensitivity reaction depends on:
 chemical nature of allergen
 route involved in sensitization i.e inhalation, ingestion, injection
 physiological state of individual / genetic potential

6. •Hypersensitivity reactions – originally divided into 2 categories:
•Immediate type
•Delayed type
•Hypersensitivity reactions may be either Humoral or Cell-
mediated
•In 1968 Coombs & Gell defined the 4 types used today:
Type I: classical immediate hypersensitivity
Type II: cytotoxic hypersensitivity
Type III: immune-complex mediated hypersensitivity
Type IV: cell mediated or delayed hypersensitivity

7. IgE-MEDIATED HYPERSENSITIVITY (type I)
Exposure to antigen(allergens) in susceptible
individual
Activates TH2 cells which secrete several cytokines like IL-4, IL-5 and IL-13
IL-4 simulates B cell to undergo heavy chain class switching to IgE
IL-5 activates Eosinophils that are recruited to the reaction
IL-13 acts on epithelial cells and stimulate Mucus secretion.

8. Mast cells express a high affinity receptor for Fc portion of ε heavy chain of IgE called FcεRI
IgE produced bind to these FcεRI present in Mast cells
Reexposure to allergens in an susceptible individual
Allergens bind to multiple specific IgE molecule on mast cells
IgE molecules get cross linked and series of biochemical signal is triggered
The signal culminate in secretion of various mediators from the mast cell

9. Secretion of Mediators from Mast cell
Vasoactive amines released from
granule stores
Histamine- Vasodilation, Increased
Vascular permeability, Smooth muscle
contraction and increased mucus
secretion
Adenosine- Bronchoconstriction and
inhibit platelets aggregation
Chemotactic factors( ECF and NCF)
Proteases- Damage tissue and generate
kinins and cleave complement
component to produce additional
chemotactic and inflammatory factor
Newly synthesized lipid
mediators
Prostaglandins D2- Intense
bronchospasm, increase
mucus secretion
Leukotrienes B4- Chemotactic
for Neutrophils, Eosinophils
and Monocytes
Leukotrienes C4 and D4-
Increased Vascular
permeability, Smooth muscle
contraction
Cytokines
TNF and chemokines- Recurit and activates
leukocytes
IL-4 and IL-5- Amplify Th2 initiated immune
reaction
IL-13- stimulates epithelial cell mucus
secretion
IMMEDIATE RESPONSE LATE RESPONSE

11. ALLERGENS ASSOCIATED WITH IgE-MEDIATED
HYPERSENSITIVITY
• Proteins – Foreign serum, vaccines
• Plant pollens – Rye grass, Ragweed
• Foods– Nuts, Seafoods, Eggs, Beans
• Insect products – Bee, Ant & Wasp venom,Dust mites
• Drugs – Penicillin, Sulfonamides, Local anesthetics
• Animal hairs, latex etc.

12. ANTIBODY-MEDIATED CYTOTOXIC
(type II) HYPERSENSITIVITY
Antibody mediated destruction of cells (IgG, rarely IgM)
Antibody bound to a cell
surface antigen can
activate complement
system, creating pores in
the membrane of a
foreign cell
Cell can also be destroyed
by another mechanism
called antibody dependent
cell-mediated cytotoxicity
(ADCC). In this process
cytotoxic cells with Fc
receptors bind to the Fc
region of antibodies on
target cells and promote
killing of the cells.
Antibody bound to a
foreign cell also can
serve as an opsonin,
enabling phagocytic cells
with Fc or C3b receptors
to bind and phagocytose
the antibody-coated cell.

13. • Examples of type II hypersensitivity reactions:
Transfusion reactions
Hemolytic disease of new born
Drug induced hemolytic anemia

14. IMMUNE COMPLEX MEDIATED
(type III) HYPERSENSITIVITY
The reaction of antibody with antigen generates immune complexes and
the damage is because of deposition of these complexes in and around
small blood vessels, joint membranes, glomerular basement membrane of
kidney, choroid plexus of the brain.
The deposition of immune complexes initiates a reaction that results
recruitment of neutrophils to the site.
The tissue injury is due to lytic enzymes of the neutrophil.
The immune complex can also activate complement system and destroy
tissue.
The activation of complement can also induce platelet aggregation
resulting release of clotting factors and formation of microthrombi.

15. Examples of type III hypersensitivity reactions:
 Serum sickness
 Arthrus reaction
 Autoimmune diseases
 Rheumatoid arthritis
 Systemic Lupus erythematosus
 Goodpasture’s syndrome
 Infectious diseases
 Poststreptococcal glomerulonephritis
 Meningitis
 Hepatitis
 Malaria

16. DELAYED TYPE HYPERSENSTIVITY (type IV)
It is cell mediated immune response and consists of mixed
cellular reaction involving T lymphocytes(TH1,TH2 and Tc)
and macrophages.
Typically provoked by intracellular microbial infections or
haptens like simple chemicals applied on skin.

17. DELAYED TYPE HYPERSENSTIVITY (type IV)
Mechanism:
1. Sensitization phase
Initial contact with antigen
Proliferate TH cells
Differentiate into TH1cells

18. 2) Effector Phase
Sensitized TH1 Cells
Secrete cytokine and chemokines
Activate Macrophage and inflammatory cells
Perpetuating DTH response

20. DEFINATION
• Anaphylaxis is an acute, potentially fatal, multiorgan system reaction
caused by the release of chemical mediators from mast cells and
basophils.
• The classic form involves prior sensitization to an allergen with later re-
exposure, producing symptoms via an immunologic mechanism.
• Anaphylaxis has no universally accepted clinical definition.
• It is a clinical diagnosis based on typical systemic manifestations, often
with a history of acute exposure to a causative agent.

21. BACKGROUND
• Portier and Richet first coined the term anaphylaxis in 1902 when a
second vaccinating dose of sea anemone toxin caused a dog’s death.
• The term is derived from the Greek words ana - (“up, back, again”)
and phylaxis(“guarding, protection, immunity”).

22. CLASSIFICATION
• IMMUNOLOGIC ANAPHYLAXIS
 Allergic IgE- mediated anaphylaxis (Type I Hypersensitivity)
Immune complex- complement-mediated anaphylaxis
Cytotoxic mediated anaphylaxis
• NON IMMUNOLOGIC ANAPHYLAXIS
 Non allergic anaphylaxis ( Anaphylactoid)
 Idiopathic

23. EPIDEMIOLOGY
• 50 TO 2000 Episodes per 100000 person-year
• Life time Prevelence 0.05-2%
• Fatality 0.7-2% per case
0
1
2
3
4
5 Hymenoptera
Food Product
Medication/Blood
Products
Chronic Allergic
Asthma
Alberta Fatalities Due to Anaphylaxis 1984-2004

24. ETIOLOGY
• IMMUNOLOGIC CAUSE
 Food
Hymenoptera sting
Medication
Latex Rubber
Blood products
• NON - IMMUNOLOGIC CAUSE
 Radiocontrast media
Medication ( Vancomycin,
opiates, Muscle relaxant,
NSAIDS, ACE-I and sulfating
agent
Hemodialysis
Physical factor( Cold/Exercise)
Idiopathic

26. Drug Hypersensitivity Reactions
• Anaphylaxis
• Angioedema
• Urticaria
• Serum
Sickness
• SJS
• TEN
How drugs stimulate the immune system
1. Drugs (or their metabolites) can bind to
native proteins and change their shape
so that they become immunogenic and
induce cell-mediated or humoral
immune responses
2. Drugs can directly stimulate the
immune system by binding to T-cells
that have receptors able to recognize
the drug

27. Antibiotics Allergy
• The most common allergic type reactions to antibiotics are maculopapular
skin eruptions, urticaria, and pruritus and are typically delayed*
• Not all of these reactions are IgE mediated
• Three classes of reactions
1. Immediate
2. Accelerated
3. Delayed
• May take >72 hours to occur
• TEN
• Interstitial nephritis
• Serum sickness
• Maculopapular rashes (most common)

28. • Penicillin is most common cause of drug induced anaphylaxis.
• Only 15% of patients with a history of allergy to penicillin have positive
skin tests and, of those, 98% will tolerate a cephalosporin. However, those
patients who react (less than 1%) may have fatal anaphylaxis (Ann allergy
Asthma Immunol 1999; 83:655-700)
• Patient with history of penicillin allergy who have negative penicillin skin
test response might safely receive Cephalosporin.
• Patient with history of penicillin allergy who have positive penicillin skin
test response might 1) Receive an alternate (non B lactum) antibiotics 2)
Receive cephalosporin through graded challenge 3) Receive cephalosporin
through rapid desensitization
• Carbopenems should be considered cross reactive with penicillin.
Penicillin

30. Sulfur Medication Allergies
• Actually consists of three different classes
• Sulfonylarylamines (Antibiotics)
• Non-arylamine sulfonamides (Thiazides, loop diuretics)
• Sulfones (Dapsone)

31. • 8% of patients treated with Sulfamethoxazole (SMX) have an adverse
reaction
• 3% reaction represent hypersensitivity.
• Largest % antibiotics induced cases of TEN and SJS
• Sulfonamide antibiotics differ from other sulfonamide containing
medications (have an extra amine group)
• Despite drug label warnings it would be safe to give lasix in a patient
with a Sulfamethoxazole allergy (NEJM 2006; 354: 601-609)
• Other non antimicrobial sulfur containing drug can cause allergic
reactions but much less frequently than SMX.
• Treatment for other non-antimicrobial sulfur containing medication
warrants graded dose challenges or alternative drug choice

32. PATHOPHYSIOLOGY
• IMMUNOLOGICAL • NON IMMUNOLOGICAL
• Direct degranulation of mast
cell in absence of
immunoglobulin

33. RISK FACTOR
• IMMUNOLOGICAL
Previous sensitization and
formation of antigen-specific
IgE with history of
anaphylaxis
• NON IMMUNOLOGICAL
Mastocytosis
Radiocontrast sensitivity
reaction
 Age>50
Preexisting Renal or CVS
disease
History of allergy
History of previous reaction to
contrast media

34. CLINICAL PRESENTATION
• HISTORY – Recent
consumption of food,
antibiotics or Stung
• Followed by appearances
of symptoms
• Symptoms usually begin
within 5-30 minutes from
the time the culprit
antigen is injected but
can occur within seconds.
• If the antigen is ingested,
symptoms usually occur
within minutes to 2 hours
• Symptoms:
Cutaneous/ocular - Flushing, urticaria, angioedema,
cutaneous and/or conjunctival pruritus, warmth, and
swelling
Respiratory - Nasal congestion, rhinorrhea, throat
tightness, wheezing, shortness of breath, cough,
hoarseness
Cardiovascular - Dizziness, weakness, syncope, chest
pain, palpitations
Gastrointestinal - Dysphagia, nausea, vomiting,
diarrhea, bloating, cramps
Neurologic - Headache, dizziness, blurred vision, and
seizure (very rare and often associated with
hypotension)
Other - Metallic taste, feeling of impending doom

35. PHYSICAL EXAMINATION
• GENERAL CONDITION AND VITALS
General appearance and vital signs vary according to the severity of the
anaphylactic episode and the organ system(s) affected.
 Vital signs may be normal or significantly disordered with tachypnea,
tachycardia, and/or hypotension.
Patients commonly are restless due to severe pruritus from urticaria.
 Anxiety, tremor, and a sensation of cold may result from compensatory
endogenous catecholamine release.

36. • SYSTEMIC FINDING
RESPIRATORY SYSTEM
 Laryngeal edema may manifest as stridor .
Loss of voice, hoarseness, and/or dysphonia may occur.
 Bronchospasm, airway edema, and mucus hypersecretion may manifest as
wheezing.
In the surgical setting, increased pressure of ventilation can be the only
manifestation of bronchospasm.
CARDIOVASCULAR SYSTEM
 Tachycardia as a compensatory response to reduced intravascular volume or to
stress from compensatory catecholamine release.
Bradycardia, in contrast, is more suggestive of a vasodepressor (vasovagal) reaction.
Hypotension (and resultant loss of consciousness) may be observed secondary to
capillary leak, vasodilation, and hypoxic myocardial depression.

37. NEUROLOGICAL EXAMINATION
If hypoperfusion or hypoxia occurs, it can cause altered mentation.
 The patient may exhibit a depressed level of consciousness or may be agitated.
CUTANEOUS EXAMINATION
The classic skin manifestation is urticaria ..
In a local reaction, lesions occur near the site of a cutaneous exposure (eg,
insect bite).
Angioedema (soft-tissue swelling) is also commonly observed..
Generalized (whole-body) erythema (or flushing) without urticaria or
angioedema is also occasionally observed.
Cutaneous findings may be delayed or absent in rapidly progressive anaphylaxis.
GASTROINTESTINAL EXAMINATION
Vomiting, diarrhea, and abdominal distension are frequently observed.

39. WORK UP
• Anaphylaxis is clinical diagnosis. Usually lab studies are not required
• Lab studies done if diagnosis is unclear or with recurrent syndrome or other disease
need to be ruled out.
• HISTAMINE AND TRYPTASE ASSESSMENT
• Plasma Histamine level rises within 10 min of onset but fall again in 30 min.
• Urinary Histamine metabolites measurement is better test.
• SERUM MATURE TRYPTASE
• Level peak after 60-90 min of episode and persist for as long as 5 hours
• In systemic mastocytosis alpha tryptase is produced in large quantity
• Ratio of total tryptase to mature tryptase if >20- Mastocytosis, if <10- Anaphylaxis of
another etiology

40. URINARY 5-HYDROXYINDOLEACTEIC ACID LEVEL: R/O CARCINOID SYNDROME
SKIN TESTING
INVITRO IgE TEST
TESTING FOR FOOD ALLERGY
TESTING FOR MEDICATION ALLERGY
TESTING FOR SUSCPECTED INSECT BITE AND STING
TESTING FOR CAUSE OF IgE INDEPENDENT REACTION

43. TREATMENT AND MANAGEMENT
Remove the allergens ( If still persistent)
Airway management (eg, ventilator support with bag/valve/mask, endotracheal
intubation)
High-flow oxygen
Cardiac monitoring and/or pulse oximetry
Intravenous access (large bore)
Fluid resuscitation with isotonic crystalloid solution
Supine position (or position of comfort if dyspneic or vomiting) with legs elevated

44. Epinephrine
Stimulation of α-adrenoceptors increases peripheral vascular
resistance thus improving blood pressure and coronary perfusion,
reversing peripheral vasodilation, and decreasing angioedema.
Stimulation of β1 adrenoceptors has both positive inotropic and
chronotropic cardiac effects.
Stimulation of β2 receptors causes bronchodilation as well as
increasing intracellular cyclic adenosine monophosphate
production in mast cells and basophils, reducing release of
inflammatory mediators.

45. • Epinephrine
• When do we give it?
More LikelyLess Likely
• Known CAD
• Presence of CAD Risk Factor’s
• Advancing Age
• Absence of cardio-respiratory
symptoms
• Airway symptoms
• Cardiovascular instability
• Acuity of Onset
• Hx of previous severe allergic rxns

46. • Epinephrine
• Available in two dilutions:
• 1:10 000 (0.1 mg/mL or 100 mcg per mL)
• 1:10 000 is the crash cart epi and used for IV administration
• 1:1000 (1 mg/mL)
• 1:1000 is used for IM
• Epinephrine
• Adult dosing
• 0.3-0.5 mL (0.3-0.5 mg) of 1:1000 IM in the vastus lateralis (thigh),repeated at 10-15 min interval if
necessary
• Pediatric dosing
• 0.01 mg/kg of 1:1000 IM in the vastus lateralis (thigh),repeated at 10-15 min interval if necessary
• In case of Major airway compromise or hypotension
• 0.5 mL (0.5 mg) of 1:1000 solution sublingually.
• 3 to 5 ml of 1:10000 solution via central line
• 3 to 5 ml of 1:10000 solution diluted with 10ml of NS via endotracheal tube

47. • Antihistamines: Relieve skin symptoms but have no immediate effect on the
reaction. They may shortens duration of the reaction
Diphenhydramine (Benadryl)  H1 antihistamine ( 12.5 -50 mg IM/IV)
Hydroxyzine ( Visatril)  H1 antihistamine
Ranitidine (Zantac)  H2 antihistamine
• Glucocorticoids: No significant immediate effect. However they may prevent
relapse of severe reaction
Methylprednisolone: Prevent late phase allergic reaction ( Biphasic anaphylaxis)
 IV methylprednisolone 125mg; then PO prednisone for one week (practice varies)
Hydrocortisone: 25-200mg IM/IV

48.  A biphasic reaction is a two phase anaphylactic event.
 This means that after anaphylaxis is treated and the
symptoms go away, they return without you being re-exposed
to the allergen. The second reaction can be less severe,
equal to or more severe than the first reaction.
 This makes them dangerous as some people may think that
they are fully recovered and they may not have their
adrenaline auto-injector as they will have used it to treat their
first reaction.
 A second reaction can occur as little as 2 hours and as
much as 72 hours after the first reaction.
 The average length between reactions is 6-10 hours.

49. • Glucagon: To provide inotrophic support for patient taking B- blocker
• Dosing 1-5 mg (20-30 mcg/kg in pediatrics) IV over 5 minutes; then infusion of 1mg/hr
can be used
• Side Effect: Vomiting! Give ondansetron prophylactically
• Inhaled B2- adrenergic agonists: Treat resistant bronchospasm
• Albuterol 0.5ml( 2.5mg) or Metaproterenol 0.3ml( 15mg) in 2.5ml of NS

50. PREVENTION
• Recognition of potential triggers and avoidance
• Short term De sensitization Procedure
• Anti- IgE administration: Omalizumab
• Premedication in case of radiosensitivity reaction:
Prednisone 50mg PO given 13,7,1 hrs before procedure
Diphenhydramine 50mg PO given 1 hrs before procedure
H2 blocker also given 1 hrs before procedure
• Consultation with allergist-immunologist
• Wearing MedicAlert bracelet
• Providing prescription for epinephrine autoinjector( EpiPen)