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Dr. Yıldıran 1
ANAPHYLAXIS&
Allergic Reactions
DR. ALISAN YILDIRAN
b
Dr. Yıldıran 2
• In 1796, Jenner reported smallpox vaccine
Dr. Yıldıran 3
Von Pirquet -1905
• Defined – ALLERGY– Serum Disease– Mantoux test
Dr. Yıldıran 4
Richet-1913
• Defined Anapylaxy• Nobel laureate
IMMUNE SYSTEM
Dr. Yıldıran 5
Abbas, 2004
Abbas, 2004
Antigen presenting cell/DCPROTEIN
Dr. Yıldıran 6
IL-5
Complement activation
Mast celldegranulation
Mucosal immunity
Allergy - Atopy
Dr. Yıldıran 7Abbas, 2012
Dr. Yıldıran 8
Revised nomenclature
Anaphylaxis
ALLERGIC NON-ALLERGIC
IgE- mediated non-IgE-mediated
Johansson SGO et al JACI 2004,113:832-6
Dr. Yıldıran 9
Hypersensitivity
Type I Immediate hypersensitivityType II Cytotoxic reactionsType III Immune complex reactionsType IV Delayed hypersensitivity
Anaphylaxis can occur through Types I, II and III immunopathologic mechanisms
Kemp SF and Lockey RF. J Allergy Clin Immunol 2002;110:341-8
Dr. Yıldıran 10
3 to 6 hours
(CysLTs, PAF,IL-5)
Mast cell
Allergen
Cellular infiltrates: 3 to 6 hours (LPR)
PGs
Return of
Symptoms
Histamine IL-4, IL-6
EosinophilCysLTs, GM-CSF, TNF-, IL-1, IL-3, PAF, ECP, MBP
Proteases
CysLTs
BasophilHistamine,CysLTs,TNF-, IL-4, IL-5, IL-6
MonocyteCysLTs, TNF-, PAF, IL-1
Lymphocyte
IL-4, IL-13, IL-5, IL-3, GM-CSFEPR 15 min
Biphasic/late-phase reaction
(Early-Phase Reaction)
Dr. Yıldıran 11
Definitions
• Anaphylaxis: a severe systemic allergic reaction involving 2 or more systems* hives/angioedema NOT universally present!
• Anaphylactic Shock: above, plus hypotension and other signs of shock
• Allergic reactions: localized reaction, involving a single system; e.g. urticaria, angioedema, contact dermatitis, rhinoconjunctivitis
Dr. Yıldıran 12
Anaphylactic vs. Anaphylactoid
• Anaphylactoid has the same clinical features as anaphylaxis but is not IgE mediated
• Instead it is due to direct mast cell degranulation and thus, does not require prior sensitization
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Differential diagnosis
• Vasovagal reactions
• Flushing
• Mastocytosis
• Carcinoid syndrome
• Hyperventilation syndrome
• Globus hystericus
• Hereditary angioedema
• Other types of shock, eg. cardiogenic, septic
• Scombroid poisoning Montanaro A and Bardana EJ Jr. J Investig Allergol Clin Immunol 2002;12:2-11
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IgE-dependent triggers
• Foods• Medications • Venoms• Latex• Allergen immunotherapy
• Diagnostic allergens
• Exercise
• Hormones
• Animal or human proteins
• Colorants (insect-derived, eg. carmine)
• Enzymes
• Polysaccharides
• Aspirin and NSAIDs (possibly through IgE)
Kemp SF and Lockey RF, J Allergy Clin Immunol 2002;110:341-8
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Hymenoptera stings
• 0.5% to 5% of the US population is allergic to
Hymenoptera venom(s)- bees- wasps- yellow jackets- hornets- fire ants
• at least 50 deaths per year
• incidence rising due to increased numbers of fire ants and
Africanized beesNeugut AI et al. Arch Intern Med 2001;161:15-21
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Immune causes other than IgE
• Cytotoxic (Type II)
- transfusion reactions to cellular elements
(IgG, IgM)
• Immune aggregates (Type III)
- Intravenous immunoglobulin
- Dextran (possibly)
Kemp SF and Lockey RF, J Allergy Clin Immunol 2002;110:341-8
Dr. Yıldıran 17
• Radiocontrast media
• Ethylene oxide gas on dialysis tubing (possibly through
IgE)
• Protamine (possibly)
• ACE-inhibitor administered during renal dialysis
MULTIMEDIATOR COMPLEMENT ACTIVATION/ACTIVATIONOF CONTACT SYSTEM
Non-immunologic causes
Kemp SF and Lockey RF, J Allergy Clin Immunol 2002;110:341-8
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Non-immunologic causes
NONSPECIFIC DEGRANULATION OF MAST CELLS AND BASOPHILS
• Opiates
• Physical factors:
- Exercise (no food or medication co-trigger)
- Temperature (cold, heat)
Kemp SF and Lockey RF, J Allergy Clin Immunol 2002;110:341-8
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Idiopathic anaphylaxis
• Common in adults
• Uncommon in children
• Negative skin tests, negative dietary history, no
associated diseases eg. Mastocytosis
• Preventive medication: oral corticosteroids, H1 & H2
antihistamines, anti-leukotrienes
• Deaths rare
• May gradually improve over time
Lieberman PL et al. J Allergy Clin Immunol 2005;115:S483-S523
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Epidemiology
• Likely under reported due to lack of recognition or self treatment in the field
• in Ontario: 4 cases/ 1 million• in Germany: 10 cases/100 000• in Minnesota, U.S.A.: 17/19,122 visits• in Brisbane, Australia: 1/440 visits
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Grading of AnaphylaxisGrad
eSkin GI tract Resp CV Neur
o1 Local
pruritus, hives, mild lip swelling
Oral “tingling”, pruritus
2 Generalized pruritus, hives, flushing, angioedema
Above plus nausea +/- emesis
Nasal congestion/sneezing
Activity change
3 Any of above Any of above + repetitive vomiting
Rhinorrhea, sensation of throat tightness
Tachy( > 15 bpm)
Above plus anxiety
4 Any of above Any of above + diarrhea
Hoarsenessdysphagia, SOB, cyanosis
Above + arrhythmia +/- dec BP
dizzinessFeeling of impending doom
5 Any of above Any above + stool incont.
Any above + resp arrest
Brady +/- card arrest
LOC
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Anaphylaxis in Infants
In infants with anaphylaxis, respiratory compromise is more likely than hypotension or shock, and shock is more likely to manifest initially as tachycardia rather than hypotension.
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Key Management of Anaphylaxis
1st line of therapy:
• AWARENESS• RECOGNITION• TREAT QUICKLY• CALL FOR BACK-UP!
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Anaphylaxis Algorithm
Anaphylaxis:(Hypotension with/without respiratory obstruction)Eg: SBP<90 +/ - stridor, tongue/ laryngeal swelling
• 0.1 mg epinephrine in 10 ml NS IV over 10 minutes! (Dilute 0.1 ml of 1:1,000 f rom 1mg/ ml amp in 10 ml NS or 1 ml of 1:10,000 f rom 1mg/ 10 ml in 10 ml NS & run @ 1 mcg/ min; total 10 mcg)
• Benadryl 50 mg IV/PO &• Ranitidine 50 mg IV or 150 mg PO &• Prednisone 50 mg PO (or Solumedrol 125 mg IV)• +/- Ventolin 2cc nebulized q 5 min X 3 prn
Systemic Allergic Reaction:(angioedema or bronchospasm)
Simple Allergic Reaction:(urticaria, GI upset, contact dermatitis)
0.3 mg (0.3 ml) 1: 1,000 epinephrine IM* (1mg/ml amp)
Cardiac Monitor + 1 L NS bolus
Repeat 1L NS bolus, if no response
Repeat IM epinephrine & add ventolin 2 cc via neb
ABCs
Least severeMost severe
All three groups of patients receive the following:
Hypotension persists No or inadequate response * never use SC due to inconsistent absorption•I n pts on Bblockersbeware of poor response to epi; use Glucagon 1 mg IV/ IM instead.CALL FOR BACK-UP!
Anita Pozgay, MD.
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Adult Epi dosing
• Epinephrine:0.3 mg (0.3 ml) 1:1000 solution IM
(NOT SC or IV)may repeat in 5 min X 1
(empirical only but safe)
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Epi: Pediatric Dosing(0.01 ml/kg)
Age (yrs) Volume ofDose (mg)
1:1000(1mg/ml)
1 0.1 ml 0.12-3 0.2 ml 0.2> 4 0.3 ml 0.3
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EPI cautions: Co-morbidities
• Thyroid disease• Cocaine addicts• CAD on BBlockers, ACEi• Depression using MAOIs or TCAs
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Mechanisms of Epinephrine
• Alpha agonist effects – increase peripheral resistance, – raise BP, – reduce vascular leakage
• Beta agonist effects– bronchodilation, – positive cardiac inotropy/chronotropy (caution
in CAD )
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Dangers of Epinephrine IV
• Only use IV Epi if patient has refractory shock not responding to fluid bolus first
• Dose 0.1 mg (10 ml) 1:100,000 dilution over 10 minutes
• Must be on cardiac monitor• Caution in elderly or those with CAD• May cause supraventricular/ventricular
dysrhythmias!
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Do all patients need Epi?
Epinephrine reverses mediator release while antihistamines (H1) do not
Epinephrine should be used for all systemic signs of allergy: airway edema (includes tongue/lips), wheezing, cyanosis, hypotension
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Do all patients need steroids?
• Corticosteroids take 4-6 hours to work• theoretically blunt the multi-phasic
reaction of anaphylaxis• the quicker the onset of anaphylaxis the
worse the reaction/quicker resolution less likely to relapse
• Caution in IV steroids esp if given in bolus doses; case reports of anaphylaxis!
• Oral form preferred if possible
Dr. Yıldıran 32
Histamine Classes• H1 receptor: stimulates – Bronchial and intestinal smooth muscle contraction, – Vascular permeability, – Coronary artery spasm
• H2 receptor: increase – Rate & force of cardiac contraction, – Gastric acid secretion, – Airway secretions, – Vascular permeability, – Bronchodilation,
• H1 and H2 combination is more helpful on urticaria
Dr. Yıldıran 33
Management Refractory Anaphylaxis
Glucagon: increases inotropy/chronotropy & causes smooth muscle relaxation independent of B receptors
Dose: 1-5 mg in adults (0.5 - 1 mg in kids) IV/IM
Dr. Yıldıran 34
Disposition & Follow-up
• Inquire about possible antigen exposure• Those with systemic reactions require a
prescription for and instruction on how to use a EpiPen
• A Medic Alert Bracelet is useful• Follow-up with an allergist for skin
testing should be arranged particularly if the allergen is unknown
Dr. Yıldıran 35
EpiPen
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Infant protocol
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Infant protocol
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Exercise Induced Anaphylaxis
• Clinical features indistinguishable from allergen induced anaphylaxis
• Food dependent or independent forms • Mechanism not fully known, but thought
exercise lowers threshold for mast cell degranulation esp after a food allergen triggers an IgE response
Dr. Yıldıran 39
Urticaria versus Angioedema
• Both characterized by transient, pruritic, red wheals on raised serpiginous borders
• Urticaria due to edema of dermis• Angioedema due to edema of
subcutaneous tissues
Dr. Yıldıran 40
Urticaria
• Other name; Hives• Raised, well-circumscribed areas of
edema and erythema involving the dermis and epidermis
• Intensely pruritic• May be acute or chronic (>6 weeks)• Multiple types: IgE-mediated, chemical-
induced, cholinergic, cold-induced, autoimmune, etc.
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Pathophysiology
• Mast cells and basophils release histamine, bradykinin, leukotrienes, prostaglandins into the dermis– Causes fluid extravasation… leads to lesion
• Pruritis is due to histamine release into the dermis
• Multiple triggers: IgE mediated, others
Dr. Yıldıran 46
Causes
• Causes: found in 40-60% of acute urticaria, and 10-20% chronic urticaria
• Include:• Infections, pregnancy, other medical
conditions• Foods, drugs, latex• Environmental factors• Stress• Cold/heat, exercise
Dr. Yıldıran 47
History
• Previous episodes/causative factors• Medical history, medications, allergies• Possible precipitants:– Recent illness or travel– New medications or IV contrast– Foods, pets, exposures– Changes in perfumes, lotions, clothes– Exercise, temperature extremes, stress
Dr. Yıldıran 48
Physical Exam
• Identify and confirm urticarial diagnosis• Dermographism?• Look for precipitants/other illnesses:• Signs of infections: e.g. URTI, fungal infection• Signs of liver/thyroid disease• Angioedema, respiratory changes (edema,
wheezes)• Joint examination
• Ensure no signs of anaphylaxis are present
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Treatment
• REMOVE ANY RELEVANT TRIGGER!
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Treatment
• H1-blockers i.e. diphenhydramine, hydroxyzine
• H2-blockers i.e. ranitidine– Act synergistically with H1 blockers
• Doxepin 10-25mg tid-qid• Glucocorticoids e.g. prednisone– Stabilize mast cells, stopping histamine
release– Anti-inflammatory effect
Dr. Yıldıran 51
Angioedema
• Deep, subcutaneous, submucosal edema due to increased vascular permeability
• May be episodic and self-limited, or recurrent
• May involve skin, buccal mucosa/tongue, larynx or GI mucosa
• Usually presents with urticaria: mast-cell mediated in these cases
Dr. Yıldıran 52
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Types
• Hereditary C1-esterase inhibitor deficiency
• Acquired: autoimmune/lymphoprolif. disorders
• Drug-induced (e.g. ACEI)• Urticaria-associated• Idiopathic (most cases)• Urticaria-associated is mast-cell mediated,
all others are kinin-mediated
Dr. Yıldıran 55
Clinical Features
CAPILLARY LEAK
• Urticaria• Angioedema• Laryngeal edema• Hypotension/syncope
SMOOTH MUSCLE CONTRACTION
• Abdominal cramps• Nausea• Rhinitis• Conjunctivitis
MUCOSAL SECRETIONS• Bronchospasm • Diarrhoea• Vomiting
Dr. Yıldıran 56
History
• Hereditary/idiopathic/drug-induced:– Episodic, self-limiting episodes of edema– Skin swelling, tongue swelling, abdominal
pain– Look for triggers
• Urticaria-associated:– Look for potential triggers: drugs, allergens,
food allergies, hymenoptera– History of atopy
Dr. Yıldıran 57
Physical Exam
• Acute onset of well-demarcated cutaneous edema of distensible tissues
• Usually face, limbs, genitals• Assess airway• Abdominal examination
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Treatment
• AIRWAY management• Intubate early if any question
• Mild Angioedema• Remove offending agent; self-limited
• Severe Angioedema• H1, H2 blockers, corticosteroids• Epinephrine