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Gloria module 3 allergic emergencies
GLORIA Module 3:Allergic Emergencies

Updated: June 2011


Global Resources in Allergy (GLORIA™)

Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.


World Allergy Organization (WAO)

The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.


Wao s mission

WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

WAO’s Mission


Gloria module 3 allergic emergencies1
GLORIA Module 3: the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societiesAllergic Emergencies


Allergic emergencies

Allergic emergencies the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

WAO Expert PanelAuthors:Richard F Lockey, USAConnie H Katelaris, AustraliaMichael Kaliner, USAContributors:F.Estelle R. Simons, CanadaDaniel Vervloet, France


Allergic emergencies1

Allergic Emergencies the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Section 1: Anaphylaxis


Anaphylaxis lecture objectives

After this lecture, participants will: the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Have knowledge of the different mechanisms which cause anaphylaxis and the agents which are most likely to cause it;

Be able to recognize the signs and symptoms of anaphylaxis;

Understand how to treat anaphylaxis.

Anaphylaxis lecture objectives


Definition of anaphylaxis

Anaphylaxis the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies– a syndrome with varied mechanisms,

clinical presentations, and severity.

An acute life-threatening reaction.

Usually mediated by an immunologic mechanism, allergic anaphylaxis, but not always.

Includes non-allergic anaphylaxis (formerly

referred to as an anaphylactoid reaction).

Results from the release of mast-basophil mediators.

Definition of anaphylaxis

WAO Nomenclature Review Committee JACI 2004


Gell and coombs hypersensitivity immunopathologic reactions

Type I Immediate the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Type II Cytotoxic

Type III Immune Complex

Type IV Delayed Hypersensitivity

Types I, II and III can result in

immunologically-induced or allergic anaphylaxis

Gell and Coombs’ Hypersensitivity (immunopathologic reactions)

Kemp and Lockey JACI 2002


Biochemical mediators and chemotactic substances

Degranulation of mast cells and basophils. the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Preformed granule-associated substances, e.g., histamine, tryptase, chymase, heparin, histamine-releasing factor, other cytokines.

Newly generated lipid-derived mediators, e.g., prostaglandin D2, leukotriene B4, PAF, LTC4, LTD4, and LTE4.

Eosinophils may play pro-inflammatory role (release of cytotoxic granule-associated proteins) or anti-inflammatory role (e.g., metabolism of vasoactive mediators).

Biochemical mediators and chemotactic substances

Kemp and Lockey JACI 2002


Shock organs in anaphylaxis

Guinea pig the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies– bronchial smooth muscle constriction.

Rabbit – fatal pulmonary artery vasoconstriction with right ventricular failure.

Dog– venous system of liver contracts producing hepatic congestion.

Human– shock organs are the cardiovascular system, respiratory tract, skin, and gastrointestinal tract. Laryngeal oedema, respiratory failure, and circulatory collapse are common.

Asthma is an important risk factor for death from anaphylaxis.

Shock organs in anaphylaxis

Kemp and Lockey JACI 2002

Bock, Munoz-Furlong, Sampson JACI 2001


Incidence the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Analysis of published studies of most common causes

3.3 to 4 million Americans at risk.

1,433 to 1,503 at risk for fatal reaction.

Incidence Based on Epinephrine Rx for

Out-of-Hospital Use

From Canada and Wales.

0.95% of population in Manitoba, Canada.

0.2 per 1000 in Wales.

Incidence increased in Wales between 1994 & 1999.

Neugut, Ghatak, Miller Arch Int Med 2001

Simons, Peterson, Black JACI 2002

Rangaraj, Tuthill, Burr, Alfaham JACI 2002


Incidence of anaphylaxis to specific agents 1

Antibiotics the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Most common cause of drug induced anaphylaxis.

Latex

Increased incidence last decade.

Population at risk includes multiple mucosal

exposure to latex (catheterization & surgery) and

healthcare workers.

Radiocontrast agents

Introduction of lower osmolarity agents

reduced reaction rate

Incidence of anaphylaxis to specific agents 1

Lieberman In: Allergy: Principles and Practice. Mosby, 2003


Incidence of anaphylaxis to specific agents 2

Hymenoptera stings the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Incidence ranges from 0.4% to 5%

Estimated fatalities 100 per year in U.S.A.

Food

Estimated 2% of US population has food

allergies with up to 100 deaths per year

Shellfish most common in adults; peanuts

in children

Incidence of anaphylaxis to specific agents 2

Lieberman In Allergy: Principles and Practice Mosby, 2003


Incidence of anaphylaxis to specific agents 3

Perioperative anaphylaxis the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Incidence ranges from 1 in 4500 to 1 in 2500

cases of general anaesthesia

Mortality rate can be as high as 3.4%

Most common agents responsible are

muscle relaxants, which account for 50%

to 75% of reactions.

Incidence of anaphylaxis to specific agents 3

Lieberman In Allergy: Principles and Practice Mosby, 2003


Incidence of anaphylaxis to specific agents 4

Non Steroidal Anti-Inflammatory Drugs (NSAIDs) the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Incidence varies depending on whether asthmatic subjects are included

NSAIDs probably second most common

offending drug next to antibiotics

Incidence of anaphylaxis to specific agents 4

Lieberman In Allergy: Principles and Practice Mosby, 2003


Incidence of anaphylaxis to specific agents 5

Antisera the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Heterologous antisera to treat snake bites (4.6% to 10%)

Immunosuppression, incidence for anti-lymphocyte globulin as high as 2%

Idiopathic

Estimated to be between 20,592 and 47,024 cases in USA – deaths rare

Incidence of anaphylaxis to specific agents 5

Lieberman in Allergy: Principles and Practice Mosby 2003


Allergen immunotherapy

Incidence of systemic reaction from 0.8% to the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

46.7% depending on the dose of allergen and

schedule used.

Deaths occur at a rate of 1 per 2,000,000

injections.

Allergen immunotherapy

Stewart and Lockey JACI 1992

Kemp et al In: Allergens and Allergen Immunotherapy, Marcel Dekker, 2004


Signs and symptoms of anaphylaxis

Diffuse erythema the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Diffuse pruritus

Diffuse urticaria

Angioedema

Bronchospasm

Laryngeal edema

Hyperperistalsis

Hypotension

Cardiac arrhythmias

Nausea

Vomiting

Lightheadedness

Headache

Feeling of impending doom

Unconsciousness

Flushing

Signs and symptoms of anaphylaxis

Kemp and Lockey JACI 2002


Differential diagnostic considerations in anaphylaxis

Vasovagal reactions the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Idiopathic flushing

Mastocytosis

Carcinoid syndrome

Anxiety-induced hyperventilation

Globus hystericus

Serum sickness

C-1 esterase inhibitor deficiency

Shock-associated with myocardial infarction,

blood loss, septicemia

Scombroid poisoning

Differential diagnostic considerations in anaphylaxis

Montanaro and Bardana JACI 2002


Comments about signs and symptoms of anaphylaxis

Urticaria or angioedema and flush most common the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

( > 90%)

Cutaneous manifestations may be delayed or absent

Next most common manifestations are respiratory

(40% to 60%)

Next are dizziness, unconsciousness (30% to 35%)

Gastrointestinal symptoms (20% to 30%)

More rapid onset, more likely serious

Signs and symptoms within 5 to 30 minutes, but

may not develop for hours

Comments about signs and symptoms of anaphylaxis

Lieberman In Allergy: Principles and Practice Mosby, 2003


Agents that cause anaphylaxis 1 anaphylactic ige dependent

Foods (peanut, tree nuts, and crustaceans) the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Milk, egg and fish also important, especially in children

Medications (antibiotics)

Venoms

Latex

Allergen vaccines

Hormones

Animal or human proteins

Diagnostic allergens

Muscle relaxants

Colorants

(insect-derived, such as carmine)

Enzymes

Polysaccharides

Aspirin and other non-steroidal anti-inflammatory drugs (probably)

Exercise (possibly, in food and medication-dependent events)

Agents that cause anaphylaxis 1anaphylactic (IgE-dependent)

Kemp Immunol Allergy Clin N Am 2001


Agents that cause anaphylaxis 2 allergic but not ige mediated

Immune aggregates (Type II) the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Intravenous immunoglobulin

Dextran (possibly)

Cytotoxic (Type III)

Transfusion reactions to cellular elements (IgG, IgM)

Agents that cause anaphylaxis 2 (allergic but not IgE mediated)

Kemp Immunol Allergy Clin N Am 2001


Agents that cause anaphylaxis 3 non allergic or ige independent

Multimediator complement activation/activation the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

of contact system:

Radiocontrast media

Ethylene oxide gas on dialysis tubing

Protamine (possibly)

ACE-inhibitor administered during renal dialysis with sulfonated polyacrylonitrile, cuprophane, or polymethylmethacrylate dialysis membranes

Agents that cause anaphylaxis 3 (non-allergic or IgE-independent)

Kemp Immunol Allergy Clin N Am 2001


Agents that cause anaphylaxis 4 non allergic or ige independent

Nonspecific degranulation of mast cells and basophils the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Opiates

Idiopathic

Physical factors:

Exercise

Temperature (cold, heat)

Agents that cause anaphylaxis 4(non-allergic or IgE independent)

Kemp Immunol Allergy Clin N Am 2001


Adrenergic blockade

By mouth or topically the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Paradoxical bradycardia, profound hypotension,

and severe bronchospasm

Can exacerbate disease and may impede treatment

Selective β-blockers do not produce clinically significant adverse respiratory effects in mild-moderate asthma (including COPD). Not studied in anaphylaxis

-Adrenergic blockade

Toogood CMAJ 1987

Kivity and Yarchovsky JACI 1990

Salpeter, Ormiston, Salpeter Annals Int Med 2002


Recurrent and persistent anaphylaxis

Recurrent or biphasic anaphylaxis occurs 8 to 12 the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

hours in up to 20%.

Subjects with biphasic do not differ clinically but

more epinephrine may be necessary for initial

symptoms.

Persistent anaphylaxis may last from 5 to 32 hours.

Recurrent and persistent anaphylaxis

Lee and Greenes Pediatrics, 2000

Kemp and deShazo In: Allergens and Allergen Immunotherapy to

Treat Allergic Diseases. Marcel Dekker, 2004


Physician supervised management of anaphylaxis 1

I. Immediate Intervention the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

a) Assessment of airway, breathing, circulation, and mentation.

b) Administer EPI, 1:1000 dilution, 0.3 - 0.5 ml

(0.01 mg/kg in children, max 0.3 mg dosage) IM, to control SX and BP. Repeat, as necessary.

Physician-supervised management of anaphylaxis 1

Kemp and Lockey JACI 2002

Simons et al JACI 1998

Simons, Gu, Simons JACI 2001


Physician supervised management of anaphylaxis 2

I. the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societiesImmediate Intervention - continued

c) IM into the anterolateral thigh (vastus lateralis) produces higher & more rapid peak plasma level versus SQ & IM in arm. Therefore, with moderate, severe, or progressive ANA, EPI IM into anterolateral thigh. Alternatively, an EPI autoinjector given through clothing in same manner. Repeat, as necessary.

Physician-supervised management of anaphylaxis 2

Kemp and Lockey JACI 2002

Simons et al JACI 1998

Simons, Gu, Simons JACI 2001


Physician supervised management of anaphylaxis 3

Immediate Intervention – the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societiescontinued

d) Aqueous EPI 1:1000, 0.1- 0.3ml in 10ml NS (1:100,000 to 1:33,000 dilution), IV over several minutes prn.

e) For potentially moribund subjects, tubercular syringe, EPI 1:1000, 0.1 ml, insert into vein (IV), aspirate 0.9 ml of blood (1:10,000 dilution). Give as necessary for response.

Physician-supervised management of anaphylaxis 3

Kemp and Lockey JACI 2002


Physician supervised management of anaphylaxis 4

II. General measures the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

a) Place in recumbent position and elevate lower

extremities.

b) Maintain airway (endotracheal tube or

cricothyrotomy).

c) O2, 6 - 8 liters/minute.

d) NS, IV. If severe hypotension, give volume

expanders (colloid solution).

e) Venous tourniquet above reaction site.

Question if decreases absorption of allergen.

Physician-supervised management of anaphylaxis 4

Kemp and Lockey JACI 2002


Physician supervised management of anaphylaxis 41

III. Specific Measures that Depend on Clinical Scenario the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

a) Aqueous EPI 1:1,000, ½ dose (0.1- 0.2 mg) at reaction site.

b) Diphenhydramine, 50 mg or more in divided doses orally or IV, maximum daily dose 200 mg (5 mg/kg) for children and 400 mg for adults.

c) Ranitidine, 50 mg in adults and 12.5 - 50 mg (1 mg/kg) in children, dilute in 5% G/W, total 20 ml, inject IV, over 5 minutes. (Cimetidine 4 mg/kg OK for adults, not established for pediatrics).

Physician-supervised management of anaphylaxis 4

Kemp and Lockey JACI 2002


Physician supervised management of anaphylaxis 5

III. Specific Measures that Depend on Clinical Scenario the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

d) Bronchospasm, nebulized albuterol 2.5 – 5 mg in 3 ml NS or levalbuterol 0.63 - 1.25 mg as needed.

e) Aminophylline, 5mg/kg over 30 min IV may be helpful. Adjust dose based on age, medications, disease, current use.

Refractory hypotension, give dopamine, 400 mg in

500 ml G/W IV 2 - 20 μg/kg/min more or less.

Physician-supervised management of anaphylaxis 5

Kemp and Lockey JACI 2002


Physician supervised management of anaphylaxis 6

III. Specific Measures that Depend on Clinical Scenario the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

g) Glucagon, 1- 5 mg (20 - 30 μg/kg [max 1 mg] in children), administered IV over 5 minutes followed with IV infusion 5-15 μg/min.

h) Methylprednisolone, 1- 2 mg/kg per 24 hr; prevents prolonged reactions and relapses.

Physician-supervised management of anaphylaxis 6

Kemp and Lockey JACI 2002


Vasodepressor vaso vagal

Definition the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Non-allergic reaction characterized by slow pulse nausea, pallor, sweating, clammy skin, and/or hypotension

Vasodepressor (Vaso-Vagal)

Kemp and Lockey JACI 2002


Vasodepressor vaso vagal1

Management the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

a) Place patient in supine position with elevated lower extremities

b) For severe vasodepressor reaction ONLY (i.e., bradycardia, nausea, pallor, sweating, cool clammy skin, hypotension), atropine 0.3 - 0.5 mg (0.02 mg/kg) SQ every 10 minutes (max 2 mg/adult and 1 mg/child)

c) If hypotension persists, give IV fluids

Vasodepressor (Vaso-Vagal)

Kemp and Lockey JACI 2002


Measures to reduce the incidence of drug induced anaphylaxis and anaphylactic deaths 1

General Measures the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Obtain thorough history for drug allergy

Avoid drugs with immunological or biochemical cross-reactivity with any agents to which the patient is sensitive

Administer drugs orally rather than parenterally when possible

Check all drugs for proper labeling

Keep patients in clinic for 20 to 30 minutes after injections

Measures to reduce the incidence of drug- induced anaphylaxis and anaphylactic deaths 1

Lieberman In: Allergy: Principles and Practice Mosby, 2003


Measures to reduce the incidence of anaphylaxis and anaphylactic deaths 2

Measures for Patients at Risk the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Avoid causative factor/s

Have patient wear and carry warning identification

Teach self-injection of epinephrine and caution patient to keep epinephrine kit with them.

Discontinue -adrenergic blocking agents, ACE inhibitors (controversial), monoamine oxidase inhibitors, and tricyclic antidepressants, where possible.

Measures to reduce the incidence of anaphylaxis and anaphylactic deaths 2

Lieberman In: Allergy: Principles and Practice. Mosby, 2003


Measures to reduce the incidence of anaphylaxis and anaphylactic deaths 3

Measures for Patients at Risk the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Use preventive techniques when patient is required to

undergo a procedure or take an agent which places

them at risk. Such techniques include:

Pretreatment

Provocative challenge

Desensitization

Measures to reduce the incidence of anaphylaxis and anaphylactic deaths 3

Lieberman In: Allergy: Principles and Practice. Mosby, 2003


Summary

Prognosis the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

FactorPoorGood

Dose of antigen (allergen) Large Small

Onset of symptoms Early Late

Initiation of treatment Late Early

Route of exposure Parenteral Oral*

β-adrenergic blocker use Yes No

Presence of underlying disease Yes No

* True for drugs, not foods

Summary


Allergic emergencies2

Allergic Emergencies the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Section 2: Upper Airway Oedema


Upper airway oedema lecture objectives

To understand the causes of angioedema; the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

To review the spectrum and management of hereditary angioedema;

To review Angiotensin Converting Enzyme (ACE) inhibitor related angioedema.

Upper airway oedema lecture objectives


Outline of lecture

Clinical description the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Classification

Examples of life-threatening oedema:

Hereditary angioedema

Acquired oedema

Angiotensin enzyme inhibitor-induced oedema

Clinical description

Pathophysiology

Management

Outline of lecture


Angioedema

First described by Quincke in 1882 the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Well-demarcated non-pitting oedema

Caused by same pathological factors that cause urticaria

Reaction occurs deeper in dermis and subcutaneous tissues

Face, tongue, lips, eyelids most commonly affected

May cause life-threatening respiratory distress if larynx involved

Angioedema


Classification of angioedema 1

Hereditary the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Type 1: C1 esterase inhibitor deficiency

Type 2: functional abnormality of C1 esterase inhibitor

Acquired

Idiopathic

IgE-mediated

Non-IgE-mediated

Systemic disease

Physical causes

Other

Classification of angioedema 1


Classification of angioedema 2

IgE-mediated the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Drugs

Foods

Stings

Infections (eg viral, helminthic)

Non-IgE-mediated

Cyclooxygenase inhibition (ASA and other NSAIDS)

Angiotensin converting enzyme inhibition

Classification of angioedema 2


Classification of angioedema 3

Systemic diseases the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Systemic lupus erythematosis

Hypereosinophilia

Lymphoma:

abnormal antibodies activate complement system

Classification of angioedema 3


Classification of angioedema 4

Physical causes the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

Cold

Cholinergic

Solar

Vibratory

Other

Some contact reactions

Autoantibodies to C1-esterase inhibitor

Unopposed complement activation

Classification of angioedema 4


Incidence

Chronic idiopathic urticaria/angioedema occurs in 0.1% population

65% remit within 3 years

85% remit within 5 years

95% remit within 10 years

Angioedema occurs most commonly with

urticaria (40% cases)

May occur in isolation (10% cases)

Incidence


Hereditary angioedema hae

1888 - family described by William Osler population

1963 - Donaldson and Evans described the biochemical defect responsible - absence of C1 inhibitor

Hereditary Angioedema (HAE)


Hereditary angioedema hae1

Subtypes population

Type 1*

Autosomal dominant

Markedly suppressed C1 esterase

inhibitor protein levels

* Accounts for 85% cases

Hereditary Angioedema (HAE)


Hereditary angioedema hae2

Subtypes population

Type 2*

Autosomal dominant, with a point mutation leading to synthesis of a dysfunctional protein

Functional assay required for diagnosis as level may be normal

* Accounts for 15% cases

Hereditary Angioedema (HAE)


Hereditary angioedema hae3

Epidemiology population

1:10,000 - 1:150,000 with no racial or gender

predilection

Clinical manifestations

Usually manifests in 2nd decade

May be seen in young children

Oedema may develop in one or several organs

Presentation depends upon site of swelling

Attacks last 2- 5 days before spontaneous resolution

Hereditary Angioedema (HAE)

Nzeako Arch Intern Med, 2001


Clinical manifestations 1
Clinical manifestations 1 population

  • Angioedema may develop in subcutaneous tissues of extremities, genitalia, face, trunk


Clinical manifestations 2

Oedema of wall of intestine may present as an acute abdominal emergency

Submucosal oedema of larynx or pharynx may cause asphyxiation – this may occur on first presentation

Clinical manifestations 2

Bork Mayo Clin Proc 2000


Clinical manifestations 3

Laryngeal oedema abdominal emergency

Commonest cause of mortality in HAE

Time from onset of swelling to death 1- 14 hours (mean 7 hours)

May be presenting feature

Death may occur in those with no previous laryngeal oedema episodes

Increased risk within certain families

Early symptoms - lump in throat, tightness in throat

Hoarseness, dysphagia, progressive dyspnoea

Clinical manifestations 3

Bork Mayo Clin Proc 2000


Hereditary angioedema hae4

Diagnosis abdominal emergency

Clinical presentation

For screening - quantitative and functional assays of C1 inhibitor

C4 and C2 levels reduced in acute attack

C4 persistently low in most patients

Hereditary Angioedema (HAE)

Nzeako Arch Intern Med 2001


Hereditary angioedema hae pathophysiology 1

C abdominal emergency1 inhibitor

Single chain glycoprotein; molecular weight 104,000; serine protease family

Important regulatory protein of complement cascade

Inactivates C1 esterase complex

Regulates coagulation, fibrinolytic, kinin, complement systems

Hereditary Angioedema (HAE)pathophysiology 1

Nielson Immunopharmacology 1996


Hereditary angioedema hae pathophysiology 2

Lack of C abdominal emergency1 inhibitor leads to abnormal activation of complement pathway, reduced C2 and C4 levels

Hageman factor induces formation of kallikrein from prekallikrein

Bradykinin is released from high molecular weight kininogen

All these mediators increase capillary permeability and are responsible for attacks of angioedema

Hereditary Angioedema (HAE) pathophysiology 2

Kaplan JACI 2002


Genetics

Autosomal dominant; all patients heterozygous abdominal emergency

25% no prior family history - spontaneous mutations

More than 100 different mutations reported

Varied clinical pattern may be explained by variable effect of mutations on C1 inhibitor synthesis

Genetics

Agostini Medicine (Baltimore) 1992


Hereditary angioedema hae management

Principles abdominal emergency

Action plan for acute episodes

Strategy for long term prophylaxis

Short term prophylaxis for high risk procedures

Regular follow up for education and monitoring side effects of therapy

Hereditary Angioedema (HAE)management


Management 1

Acute attacks abdominal emergency

Treatment of choice is C1 inhibitor concentrate,

500 - 1,000U intravenous infusion

Safe and effective - no long term side effects reported

Excellent and prompt response in most patients

Not available in USA, but in clinical trials

Management 1

Bork Arch Intern Med 2001


Management 2

Acute attacks when C abdominal emergency1 inhibitor concentrate not

available

Intubation and respiratory support may be necessary when laryngeal oedema present

Fresh frozen plasma (FFP) has been used successfully for acute attacks. Exacerbation of symptoms by supplying more kallikrein substrate is a theoretical consideration but is rarely seen

Management 2

Bork Arch Intern Med 2001


Management 3

Long term – adults abdominal emergency

Attenuated androgens (stanozolol, danazol, oxandrin) can prevent attacks

Increase levels of C1 inhibitor, C4 and C2

Titrate to lowest effective dose to control attacks - for danazol may be able to reduce to 200 mg/d every second day

Regular monitoring necessary

Management 3

Nzeako Arch Intern Med 2001


Management 4

Long term – children abdominal emergency

Antifibrinolytic agents have been used as first line prophylaxis

Low dose danazol

Management 4

Nzeako Arch Intern Med 2001


Management 5

Short term prophylaxis abdominal emergency

Necessary for high risk interventions,

eg, dental procedures, tonsillectomy

C1 inhibitor concentrate, where available, given before procedure

Increasing dose of attenuated androgen for a few days beforehand

Fresh frozen plasma

Management 5


Management 6

Other abdominal emergency

Avoid oral contraceptive pill, ACE inhibitor medication

Premedicate before procedures requiring radiocontrast media or streptokinase as they may decrease C1 inhibitor levels

Reassurance; address issues such as ongoing stress

Treat infections promptly

Genetic counseling and screening

Management 6


Acquired angioedema aae 1

Type 1 abdominal emergency

Associated with rheumatologic diseases, B cell lymphoproliferative disorders

Activation of complement by complexes of anti-idiotypic antibodies and surface immunoglobulins consumes C1 inhibitor so levels decline

Type 2

Development of autoantibodies against C1 inhibitor

Autoantibodies bind at active site on molecule leading to inactivation

Acquired Angioedema (AAE) 1

Markovic Ann Int Med 2000


Acquired angioedema aae 2

Decreased C abdominal emergency1q levels distinguish AAE from HAE where C1q is usually normal

Treatment of underlying condition may result in resolution

For acute attacks, C1 inhibitor concentrate, where available should be used

Attenuated androgen may be useful in Type 1

Immunosuppressive therapy for Type 2

Acquired Angioedema (AAE) 2

Laurent Clin Rev Allergy Immunol 1999


Angiotensin converting enzyme ace inhibitors and angioedema 1

Angioedema develops in 0.1% to 0.5% of those receiving the drug

Onset from 1st week of use to 2 - 3 years of use

Symptoms resolve within 24 - 48 hours of cessation of drug

Most commonly seen with captopril and enalopril but described with all in class

Genetic factors may be important

Subjects with a history of angioedema from other causes are more susceptible to ACE-induced angioedema

Angiotensin Converting Enzyme (ACE) inhibitors and angioedema 1

Slater JAMA 1988


Angiotensin converting enzyme ace inhibitors and angioedema 2

Face and lips most commonly involved drugbut laryngeal oedema reported

Risk factors include obesity, prior endotracheal intubation and face and neck surgery

ACE inhibitors will trigger attacks in those with HAE so avoid in these patients

Angiotensin Converting Enzyme (ACE) inhibitors and angioedema 2

Jain Chest 1992


Angiotensin converting enzyme ace inhibitors and angioedema 3

Pathophysiology drug

ACE inhibitors may cause bradykinin accumulation resulting in vasodilatation, capillary leakage and angioedema

Patients may have a congenital or acquired impairment of kininase 1 which degrades bradykinin leading to bradykinin accumulation once ACE is blocked

Angiotensin Converting Enzyme (ACE) inhibitors and angioedema 3


Angiotensin converting enzyme ace inhibitors and angioedema 4

Management drug

Stop drug and use other classes of antihypertensive agents

ALL ACE inhibitors are to be avoided

Management of angioedema depends on site of involvement - securing the airway by intubation may be necessary

ACE receptor antagonists are generally considered to be safe

Angiotensin Converting Enzyme (ACE) inhibitors and angioedema 4


Angioedema conclusions

Most often occurs in association with urticaria drug

When angioedema occurs alone, consider HAE, AAE

HAE is a rare disease but must be identified as it can be life-threatening

Refer to appropriate specialist for ongoing management

ACE-inhibitor induced angioedema is an important cause in older people

Angioedema - conclusions


Allergic emergencies3

Allergic Emergencies drug

Section 3: Severe Asthma Exacerbations


Lecture objectives

At the end of this lecture participants will be able to: drug

Understand the risk factors for asthma exacerbations

Identify the signs and symptoms of acute asthma

Outline appropriate treatment strategies

Lecture objectives


Features of a severe asthma exacerbation

One or more present: drug

Use of accessory muscles of respiration

Pulsus paradoxicus >25 mm Hg

Pulse > 110 BPM

Inability to speak sentences

Respiratory rate >25 - 30 breaths/min

PEFR or FEV1 < 50% predicted

SaO2 <91- 92%

Features of a severe asthma exacerbation

McFadden Am J Respir Crit Care Med 2003


Risk factors for fatal or near fatal asthma attacks

Previous episode of near-fatal asthma drug

Multiple prior ER visits or hospitalizations

Poor compliance with medical treatments

Adolescents or inner city asthmatics

(USA) African-Americans>Hispanics>Caucasians

Allergy to Alternaria

Recent use of oral CCS

Inadequate therapy:

Excessive use of β-agonists

No inhaled CCS

Concomitant β-blockers

Risk factors for fatal or near-fatal asthma attacks

Ramirez and Lockey In: Asthma, American College of Physicians, 2002


Physical findings in severe asthma exacerbations

Tachypnea drug

Tachycardia

Wheeze

Hyperinflation

Accessory muscle use

Pulsus paradoxicus

Diaphoresis

Cyanosis

Sweating

Obtundation

Physical findings in severe asthma exacerbations

Brenner, Tyndall and Crain In: Emergency Asthma. Marcel Dekker 1999


Causes of asthma exacerbations

Lower or upper respiratory infections drug

Cessation or reduction of medication

Concomitant medication, e.g. β-blocker

Allergen or pollutant exposure

Causes of asthma exacerbations


Differential diagnosis
Differential diagnosis drug

  • COPD

  • Bronchitis

  • Bronchiectasis

  • Endobronchial diseases

  • Foreign bodies

  • Extra- or intra-thoracic tracheal obstruction

  • Cardiogenic pulmonary edema

  • Non-cardiogenic pulmonary edema

  • Pneumonia

  • Pulmonary emboli

  • Chemical pneumonitis

  • Hyperventilation syndrome

  • Pulmonary embolus

  • Carcinoid syndrome

Brenner, Tyndall, Crain In: Emergency Asthma. Marcel Dekker, 1999


Peak flow meters

Use peak flow meters to monitor asthma and prevent exacerbations:

Inexpensive

Easy to use

Accurate

Provide “real life” measurements at worst and

best times of the day

Provide objective measurement of pulmonary

function

Detect early changes of asthma worsening

Peak flow meters


Patient self management

If personal best peak flow measurements: exacerbations:

Fall 10+%, double dose of inhaled CCS

Fall 20+%, use short-acting bronchodilator Q4 -6 hour, plus 2 x inhaled CCS

Call office, try to determine if infection is present

Fall 40 - 50%, add oral CCS

Fall greater than 50%, urgent visit to either

Outpatient office

Emergency room

Patient “self management”

Kaliner In: Current Review of Asthma. Curent Medicine, 2003


Stages of asthma exacerbations stage 1

Symptoms exacerbations:

Somewhat short of breath

Can lie down and sleep through the night

Cannot perform full physical activities without shortness of breath

Signs

Some wheezes on examination

Respiratory rate, 15 (normal <12)

Pulse 100

Peak flows and spirometry reduced by 10%

Stages of asthma exacerbations stage 1:


Stages of asthma exacerbations stage 2

Symptoms exacerbations:

Less able to do physical activity due to shortness of breath

Dyspnea on walking stairs

May wake up at night short of breath

Uncomfortable on lying down

Some use of accessory muscles of respiration

Signs

Wheezing

Respiratory rate 18

Pulse 111

Peak flows and spirometry reduced by 20+%

Stages of asthma exacerbations stage 2:


Stages of asthma exacerbations stage 3

Symptoms exacerbations:

Unable to perform physical activity without shortness of breath

Cannot lie down without dyspnea

Speaks in short sentences

Using accessory muscles

Signs

Wheezing

Respiratory rate 19 - 20

Pulse 120

Peak flows and spirometry reduced by 30+%

Stages of asthma exacerbations stage 3:


Stages of asthma exacerbations stage 4

Symptoms exacerbations:

Sitting bent forward

Unable to ambulate without shortness of breath

Single word sentences

Mentally-oriented and alert

Use of accessory muscles

Signs

Wheezing less pronounced than anticipated

Respiratory rate 20 - 25

Pulse 125+

Peak flows and spirometry reduced by 40+%

SaO2 91- 92%

Stages of asthma exacerbations stage 4:


Stages of asthma exacerbations stage 5

Symptoms exacerbations:

Reduced consciousness

Dyspnea

Silent chest – no wheezing

Signs

Fast, superficial respiration

Respiratory rate >25

Unable to perform peak flows or spirometry

Pulse 130 - 150+

SAO2 <90

Stages of asthma exacerbations stage 5:


Severity of asthma as graded by predicted fev1

FEV% predicted Severity exacerbations:

70 - 100 Mild

60 - 69 Moderate

50 - 59 Moderately severe

35 - 49 Severe

< 35 Very severe

(life-threatening)

Severity of asthma as graded by % predicted FEV1


Treatment of asthma exacerbations 1

Preferred treatment choices exacerbations:

β2-agonists

Inhaled by MDI or nebulizer

Injected

Anticholinergics

Inhaled by MDI or nebulizer

Corticosteroids

Parenteral, oral or inhaled

Treatment of asthma exacerbations 1


Treatment of asthma exacerbations 2

Secondary treatment choices exacerbations:

Aminophylline or theophylline (oral, parenteral)

Leukotriene receptor antagonists (oral)

Oxygen

Magnesium sulfate

Treatment of asthma exacerbations 2


Treatment of asthma exacerbations 3 beta agonists

Inhaled is preferred route exacerbations:

MDI plus spacer, 4 - 8 puffs Q 20 min x 3

Nebulizer, 2.5 - 5 mg albuterol Q 20 min x 3

Epinephrine SQ, 0.3 - 0.5ml (0.01 ml/kg children)

Levalbuterol, 0.63 - 1.25 mg Q 4 - 8 hours (if available)

Treatment of asthma exacerbations 3beta agonists


Treatment of asthma exacerbations 4 anticholinergics

Ipratropium exacerbations:

Preferred use: combined with beta agonist

MDI plus spacer, 2 - 4 puffs Q 20 min x 3

Nebulizer, 500 μg Q 20 min x 3

Treatment of asthma exacerbations 4anticholinergics


Treatment of asthma exacerbations 5 corticosteroids

No immediate effect exacerbations:

Earliest effects 6 hours after high dose

Oral is as effective as parenteral

Prednisone (equivalent), 45 - 60 mg

Higher doses have increased side effects and no appreciable increased therapeutic benefit

Methylprednisolone, 1 – 2 mg/kg/24 hours

No substantial data for usefulness in acute setting

Treatment of asthma exacerbations 5corticosteroids


Treatment of asthma exacerbations 6 aminophylline and theophylline

Controversial: exacerbations:

Added no benefit to inhaled beta agonists

Increased complications

Loading dose for aminophylline: 5 – 6 mg/kg over 20 - 30 min

Maintenance dose: 0.4 mg/kg/hr (adjust for heart and liver disease)

Try to achieve 5 - 15 μg/ml, monitor plasma levels to adjust dose

Doses for theophylline similar but slightly less

Treatment of asthma exacerbations 6 aminophylline and theophylline


Treatment of asthma exacerbations 7 leukotriene modifiers

Few studies exacerbations:

Suggest usefulness in reducing hospitalizations

Montelukast, 10 mg orally

Zafirlukast, 20 mg orally

Treatment of asthma exacerbations 7 leukotriene modifiers


Treatment of asthma exacerbations 8 magnesium sulfate

Controversial: exacerbations:

Inconsistent data

Used in very severe asthma in emergency settings:

FEV1 < 25% predicted

Other signs of severe disease

1.2 - 2 gm IV over 10 - 20 min in 50 ml saline

Minor side effects

Treatment of asthma exacerbations 8 magnesium sulfate


Preventing exacerbations 1 oral corticosteroids

Oral corticosteroids are the most powerful medications available to reduce airway inflammation

Use until attack completely abated:

PEFR and FEV1 at baseline levels

Symptoms gone

Taper to QOD and determine if patient can remain well if corticosteroids are withdrawn completely

Preventing exacerbations 1oral corticosteroids


Preventing exacerbations 2 inhaled corticosteroids

Place patient on high dose inhaled corticosteroids available to reduce airway inflammation

Fluticasone, 880 - 1760 μg

Budesonide, 800 - 1600 μg

Once oral corticosteroids are withdrawn, reduce the inhaled dose incrementally, while maintaining PEFR at personal best level

Consider combination of long acting β2-agonist and inhaled corticosteroid in order to achieve the lowest dose of corticosteroid possible

Preventing exacerbations 2 inhaled corticosteroids


Preventing exacerbations 3 underlying causes and patient education

Evaluate patient for: available to reduce airway inflammation

Allergy

Infection

Compliance

Inappropriate concomitant medications

Social factors

Tobacco, drugs, irritants, fumes

Psychiatric disorders

Patient education

Preventing exacerbations 3underlying causes and patient education


World allergy organization wao

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WAO Secretariat

555 East Wells Street, Suite 1100

Milwaukee, WI 53202

United States

Tel: +1 414 276 1791

Fax: +1 414 276 3349

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World Allergy Organization (WAO)