Dr. Yıldıran 1

ANAPHYLAXIS&

Allergic Reactions

DR. ALISAN YILDIRAN

b

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• In 1796, Jenner reported smallpox vaccine

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Von Pirquet -1905

• Defined – ALLERGY– Serum Disease– Mantoux test

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Richet-1913

• Defined Anapylaxy• Nobel laureate

IMMUNE SYSTEM

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Abbas, 2004

Abbas, 2004

Antigen presenting cell/DCPROTEIN

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IL-5

Complement activation

Mast celldegranulation

Mucosal immunity

Allergy - Atopy

Dr. Yıldıran 7Abbas, 2012

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Revised nomenclature

Anaphylaxis

ALLERGIC NON-ALLERGIC

IgE- mediated non-IgE-mediated

Johansson SGO et al JACI 2004,113:832-6

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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

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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)

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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

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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

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• 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Clinical Features

CAPILLARY LEAK

• Urticaria• Angioedema• Laryngeal edema• Hypotension/syncope

SMOOTH MUSCLE CONTRACTION

• Abdominal cramps• Nausea• Rhinitis• Conjunctivitis

MUCOSAL SECRETIONS• Bronchospasm • Diarrhoea• Vomiting

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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

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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