Division of Allergy-Immunology

Department of Internal Medicine, Faculty Medicine of

Udayana University
Denpasar
Definition
Anaphylaxis is an acute severe, life-threatening, generalized or systemic
hypersensitivity reactions

Why we should know ?

• Anaphylaxis can be fatal
• Unpredictable and suddenly
• Can happen anywhere
• It’s prevalence increased

• Medico legal ?
Mechanisms underlying anaphylaxis
ANAPHYLAXIS
(Anaphylactoid) (Anaphylactic) (Anaphylactoid)
Complement activity IgE Substance for histamine release

Classic Alternative
pathway pathway Arachidonic acid modulation

Mastocyte
C3a, C5a Physical factor
Anafilaktoksin
Idiopathic

Mediator

•  vascular permeability
• vasodilatation
• Smooth muscle constraction
• Mucosal gland hypersecretion
• peripheral nerve stimulation

• Erythema, urtica, pruritus (the skin & subcutaneous tissues)

• Nasal congestion, broncho spasm / dyspnea, larynx edema
(respiratory system)
• Nausea, vomiting, abd. cramp, diarrhea (gastrointestinal system)
• Palpitation, hypotention, shock ( cardiovascular system)
EPIDEMIOLOGY

Severe anaphylaxis : 1 - 3/104 people

(Moneret-Vautrin et al; Oct 2005)
Incidece rising in parallel with incidence of food allergy
2.5 x rise in Britain l995 - 1999
(Sheik A et al. Clin Exp Allergy 2001)
AETIOLOGY

The aetiology of Anaphylactic and anaphylactoid :

1. Drugs :
- antibiotic : penicilin most frequens
- aspirin, NSAID
2. Foods :
- Most commonly : fish / sea food, lobster, eggs,
cow milk, nuts.
3. Venoms :
- Heminoptera insects
4. Radiographic contrast media
5. Idiopathic
6. Others :
- Blood products
- Physical factors ( cold & exercise – induced )
PATHOPHYSIOLOGY
• Anaphylactic reaction (IgE mediated reaction)

Anaphylactic reaction / IgE mediated reaction3

• Anaphylactoid reaction (Non IgE mediated)
- Complement activation - Physical factors
- Substance for Histamine released - Idiopathic
- Arachidonic acid modulation
PATTERN OF MEDIATOR (HISTAMINE)
RELEASE ON ANAPHYLAXIS

Histamine released by Mast Cell

Histamine levels

Histamine released by Basophyl

Hour 0 ½ 1 2 3 4 5 6 48-72

Figure 5. Pattern of histamine release on anaphylaxis

Clinical Criteria for Diagnosing Anaphylaxis
(Sampson HA, et al. JACI 2006)

1. Acute onset of an illness ( minutes to several hours)

with involvement of the skin, mucosal tissues, or both
( eg, generalized hives, pruritus or flushing, swollen
lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm,
stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction
(eg, hypotonia /collapse, syncope,
incontinence)
Clinical Criteria for Diagnosing Anaphylaxis (con’t)
(Sampson HA, et al. JACI 2006)

2. Two or more of the following that occur rapidly after exposure to a

likely allergen for that patient (minutes to several hours) :
a. Involvement of the skin-mucosal tissue (eg, generalized hives,
itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm,
stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia collapse,
syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal
pain, vomiting)
Clinical Criteria for Diagnosing Anaphylaxis (con’t)
(Sampson HA, et al. JACI 2006)

3. Reduced BP after exposure to known allergen for that patient

( minutes to several hours ) :

a. Infants and children: low systolic BP (age specific) or greater

than 30% decrease in systolic BP

b. Adults: systolic BP of less than 90 mm Hg or greater than 30%

decrease from that person's baseline
CLINICAL FEATURES
Grading system for generalised hypersensitivity
/ anaphylaxis
( Brown SGA . Clinical features and severity grading 0f anaphylaxis
J. Allergy Clin Immunol 2004, 114(2) : 371-6 )

1.Mild (involvement of the skin-mucosal tissues) :

generalised erythema , urtica, periorbital edema or angioedema

2.Moderate (involvment of Respiratory, Cardiovascular, GI syst) :

SOB, Stridor, wheezing, nausea, vomiting, dizziness
(presyncope),diaphoresis, chest / throat tightness, abd. pain /
abd. cramp

3.Severe (hypoxia, hypotention, neurological compromise) :

cyanosis(SpO2  92%), hypotention(adults ;SBP < 90 mmHg),
confusion, collapse, LOC / Loss of Consciousness,
incontinence.

(1 = acute hypersensitivity reaction) (2 &3 = anaphylaxis)

Angioedema
Clinical Criteria for Diagnosing Anaphylaxis
(Sampson HA, et al. JACI 2006)

• Acute onset + 2 / more involvement of the system/ organs

Respiratory
compromise anaphylaxis
The Skin
1 mucosal

Cardiovascular anaphylaxis

anaphylaxis
The Skin Respiratory
mucosal compromise anaphylaxis
anaphylaxis
2
anaphylaxis
G I Tract Cardiovascular anaphylaxis
anaphylaxis
Clinical Criteria for Diagnosing Anaphylaxis
(Sampson HA, et al. JACI 2006)

Acute onset of Cardiovascular

( Reduced BP )
3 anaphylaxis
after exposure to known allergen
for that patient

Acute onset of the Skin &

Acute hypersensitivity / Acute
4 Subcutaneous tissues only
allergic reaction
( Urtica & Angioedema )
• Laboratory Findings
Laboratory test are seldom necessary or helpful initially, although certain
test may be used later to assess and monitor treatment and to detect
complications.
• Blood cell counts ( haemoconcentration ? )
• Eosinophil counts, stool examination
• IgE total
• ECG
• Chest X – ray
• Others : dou to progress note ( eg ; Electrolyte,
Blood Gas Analyse, Blood Suger )
Differential diagnosis
Clinical Features Differential Diagnosis
Shock Septic shock
Hypovolemic shock
Cardiogenic shock
Vasovagal reaction
Respiratory distress Corpus alienum in Resp.
with wheezing or tract
stridor Asthma bronchiale
COPD
Vocal cord disfunction
FACTORS ASSOCIATED WITH
SEVERITY REACTIONS
• Age
• Allergen
• Atopy
• CVD (Cardiovascular Disease)
• COPD (Chronic Obstructive Pulmonary Disease)
• Bronchial asthma
• Acid base and electrolyte inbalance
• Drugs ( eg, beta-blocker, ACE-inhibitor)
• Interval of epinephrine injection after exposure
MANAGEMENT OF ANAPHYLAXIS
History of severe allergic reaction with respiratory difficulty or hypotension,
especially if skin changes present

Stop administration of precipitant

Oxygen high flow

Adrenalin / epinephrine (1 : 1000) 0,3 – 0,5 ml IM (0,01 mg/kg BW)

Repeat in 5-15 minutes if no clinical improvement

Antihistamine 10-20 mg IM or slowly Intravenously

In addition
 Give 1-2 l of fluid intravenously if clinical manifestation of shock do not respond to drug
treatment
 Corticosteroid for all severe or recurrent reactions & patients with asthma.
- Methyl prednisolone 125-250 mg IV
- Dexamethasone 20 mg IV
- Hydrocortisone 100-500 mg IV slowly
continue by maintenance dose
 Inhaled short acting -2 agonist may used if bronchospasm severe
 Vasopressor (dopamine, dobutamine) with titration dose
Observation for 2 - 3 x 24 horus, for mild case just need 6 hours
Give Corticosteroid and antihistamine orally for 3 x 24 horus
Elderly ( 60 y.o), CVD  adrenalin dose 0,1-0,2cc IM with interval 5-10 mnt
Adrenaline / epinephrine

• A quick-acting hormone

• Secreted by Suprarenal gland

• A direct-acting sympathomimetic
(-adrenergic, -adrenergic agonist)

• A narrow toxic-therapeutic index (risk-to-benefit ratio)

• No absolute contra indications

• The first-aid treatment of anaphylaxis

Epinephrine

1-receptor 2-receptor 1-adrenergic 2-adrenergic

receptor receptor

•  vasoconstriction •  insulin release •  inotropic •  bronchodilator

•  peripheral vascular •  noreepinephrine •  chronotropic •  vasodilatation
resistance release
•  glycogenolysis
•  mucosal edema
•  mediator release

Pharmacology of epinephrine
 Dosage and route of injection
• Dose epinephrine and route of injection :
• 0,3-0,5 ml inj SC/IM lateral thigh / deltoid
(North American Guidelines, Indonesia)
• 0,5-1 ml inj SC/IM lateral thigh / deltoid
(European Literature)
• Pharmacokinetic and pharmacodynamic epinephrine

Intramuscular inj
8 ± 2 minutes

Subcutaneus inj.
34 ± 14 (5-120) minutes

5 10 15 20 25 30 35

Time of Cmax after injection (minutes)

Absorption of epinephrine
PREVENTION
a. Explore the major risk factors for anaphylaxis include a prior history of
such reactions, -adregenric blocker or possibly ACE inhibitor therapy,
and the multiple antibiotic sensitivity syndrome, atopic background.
b. Application the rationale therapy
c. Informed consent
d. Patients & their families education maybe the most important
preventive strategy; be carefully instructed about hidden allergens,
cross-reactions to various allergens, unforeseen risk during medical
procedures, when and how to use self-administration epinephrine (if
available).
e. In a future; injection anti IgE antibody with regular interval could be
prevent the risk or the severity of anaphylaxis reactions
 Why, follow up is needed ?
 Anaphylaxis can occur repeatedly / episodics
 The trigger need to be confirmed

 Long term preventive strategies

need to be implemented
 Allergen exposure

(drugs, food, insect sting)

second - 6 hours

Clinical Features

• Mild
• Age
(acute hypersensitivity reaction)
• Allergen
• Moderate, severe (anaphylaxis) • Atopy
• CVD
• COPD
• Bronchial Asthma
• Acid base, electrolyte inbalance
Management • Drugs (-blocker, ACE-inhibitor)
• Interval injection adrenaline after
exposure
- Antihistamines ( AH-1 & AH-2 )
- ABC, Adrenalin, Anti-histamine,
Corticosteroid, fluid, others)

48-72 hours
Outcome (?)
Drug allergy or hypersensitivity is a form of
Adverse Drug Reaction (ADR)
DEFINITION
An ADR is
any undesirable effect of drug
that is administered in standard doses
by the proper route for the purpose of
prophylaxis, diagnosis, or treatment.
Drug allergy
an immunologically mediated reaction,
occur in a susceptible populations,
characterised by specificity,
transferability by antibodies or lymphocytes,
and recurrence on re-exposure
Epidemiology

 ADR is estimated that up to 15% of drug

administrations
 The risk is roughly doubled in the hospital
setting
 Fatal drug reactions occur in approximately
0.1% of medical in patients
 0.01% of surgical inpatients
 Drug allergy account for only 5-10% of all ADRs
Diagnostic tests
SPT may be helpful for diagnosing IgE mediated
drug reactions (in vivo)
RAST may detect serum IgE antibodies to certain
drugs (e.g : penicillin and succinyl choline)
(in vitro)
Provocation tests
Oral provocation tests, may be as a gold
standard
They must be performed under strict medical
supervision with resuscitative equipment
available
Classification of ADRs
 Reactions that may occur in anyone
* Drug overdose ; toxic reactions linked to
excess dose or impaired excretion, or to
both
* Drug side effect ; undesirable
pharmacological effect at recommended
doses
* Drug interaction ; action of a drug
on the effectiveness or toxicity of another
drug.
 Reactions that occur only in susceptible
subjects
• Drug intolerance ; a low threshold to the normal
pharmacological action of drug
• Drug idiosyncrasy ; a genetically determined,
qualitatively abnormal reaction to a drug related to
a metabolic or enzyme deficiency
• Drug allergy
• Pseudoallergic reaction ; a reaction with the same
clinical manifestations as an allergic reaction, but
lacking immunological specificity.
Pathophysiology
Allergic drug reactions are usually defined as ;
 reaction caused by suspected immunologic
mechanisms
 result from the production of antibodies and / or
cytotoxic T cells directed against the drug,
its metabolite, a soluble / cell-bound carrier
protein
 as a responses to prior or continuous exposure to
a drug
Clinical history
A precise and detailed history, including ;
- clinical symptoms and their timing, duration in relation to drug
exposure.a
- the onset may be ;
- immediate (onset second to minutes / < 6 hrs) :
e.g : anaphylaxis,urticaria,angioedema,bronchospasm
- accelerated ( > 6 hrs to 72 hrs ) :
e.g : urticaria,bronchospasm, erythema multiforme,
maculopapular rash, Serum sickness
- delayed ( > 72 hrs ) :
e.g : maculopapular rash, fever, serum sickness, recurrent
urticaria
- The past history
- The family history
Diagnosis
Diagnosis of drug allergy based on ;
 Clinical history
 Clinical manifestations
 Diagnostic test
Management
 Avoidance

 Premedication

 Desensitisation
Classification of ADR ADR

Type A reaction Type B reaction

• Dose dependent • Dose independent
• Predictable • Unpredictable
• More common • Less common

Overdose Intolerance

Side effect Idiosyncrasy

(pharmacogenetics)
Drug interaction Drug allergy

Immunologic reaction
Pseudoallergic reaction
(Gell and Coombs classification

Type I reaction Type II reaction Type III reaction Type IV reaction

• IgE mediated • Antibody dependent • Immune complex • T-cell mediated
• Anaphylactic cytotoxicity damage damage (CD8)
Urticaria • IgG/IgM bind to antigens • Antibody binding to • Delayed Type
Angioedema on cells antigens in large Hypersensitivity
Bronchospasm • Complement quantiles (CD4)
Hypotension Phagocyte
Complete Antigens
High-molecular weight (HMW) drugs
can induce the production of anti-drug
antibodies without the need to couple to
a carrier protein.

HMW drugs are more likely to provoke

an allergic reaction than Low molecular
weight (LMW).
Haptens
Most drugs are LMW agents
and cannot induce an immune response
Must covalently combine with carrier proteins
in the body to elicit an immune response
The actual allergen may be ;
- the hapten itself
- the hapten-protein complex
- a tissue protein that has been altered
by interaction with the drug
(recognized as foreign)
Immunologic mechanisms
(The Gell & Coombs classification)
Type I Immediate hypersensitivity, IgE mediated Anaphylaxis ;
the onset ; seconds to minutes for drugs urticaria/
parenterally, up to 1 hr for drugs taken orally Angioedema,
bronchospasm,
shock,
hypotension
Type II Antibody-dependent cytotoxic Hemolytic anemia,
hypersensitivity / vasculitis, rashes,
IgG & IgM-dependent complement mediated interstitial nephritis
cytolysis
Type III Immune complex-mediated hypersensitivity Serum sickness,
rashes, fever,
vasculitis
Type IV Delayed type hypersensitivity, T cell Contact dermatitis,
mediated Granulomatous
reaction

Mechanism unknown ; Stevens-Johnson syndrome (SJS), toxic epidermal

Necrolysis (TEN), Drug fever, acute interstitial nephritis, pulmonary infiltrates
with eosinophilia
Risk factors
 Patient related
Age, sex, genetics, atopy, AIDS

 Drug related
Macromolecular size ; bivalency, haptens,
route, dose, duration of treatment

 Aggravating factors
β Blockers, asthma, pregnancy
Clinical manifestations
Manifestation Clinical features Examples of drugs
Anaphylaxis Urticaria, angioedema, rhinitis, Penicillin, neuromuscular blocking drugs
asthma, abd. pain, CV collaps

Pulmonary Interstitial pneumonitis Amiodarone, nitrofurantoin, chemotherapiutic

agent
asthma Aspirin, NSAID, β blockers
Hepatic Acute or chronic hepatitis Halothane, chlorpromazine,carbamazepine
Haematological Haemolytic anaemia Penicillin, -methyldopa, mephenamicacid
Thrombocytopenia Furosemide,thiazide, gold salts
Neutropenia Penicillin
Agranulocytosis Phenylbutazone, Chlorampenicol
Aplastic anaemia NSAID, sulphonamides
Renal Interstitial nephritis, NS Cimetidine
Cardiac Eosinophylic myocarditis -methyldopa

Other Serum Sickness, drug fever, Anticonvulsants,diuretics,antibiotics,hydralasine

vasculitis, lymphadenopathy procainamide, penicillamine
Avoidance

As a general rule,
a drug responsible for an allergic reaction
should not be reused
Unless there is an absolute need
and no alternative drug is available.
Premedication
Pretreatment with H1 antihistamines
should not be used
as they do not prevent anaphylactic shock
And may mask early signs.
However, in association with H1 antihistamines,
corticosteroids have been shown to be effective
in reducing reactions to radiocontrast media
Desensitisation
Desensitisation should be considered in patients
who have experienced IgE mediated allergic reactions to Penicillin
and who require penicillin for treatment of serious infections
(e.g ; bacterial endocarditis and meningitis)
Protocol using oral and parenteral routes have been proposed.
Should be performed under specialist supervision.
Oral administration is preferred because it is less likely to provoke
a life threatening reaction.
Desensitisation may occasionally be indicated for other antibiotics,
such as ;
sulphonamides, cephalosporins
 Management acute hypersensitivity / anaphylaxis

Acute hypersensitivity reaction Anaphylaxis reaction

(involvement of the skin, mucosal tissues, (involvement of 2 or more system /
or both only) organ)

Dipenhydramine inj (10-20 mg) IM Management of anaphylaxis

Observation for 4-6 hours Observation

No Response
Good Response No worsening (be worsen)
(no clinical response
manifestation) Explore the
prognostic factors

In patient
Another treatment
Ambulatory  IVFD (due to the problem)
Oral AH1 inj i.m
antihistamie
for 3 days AH2 inj i.v
Steroid inj No Response
Good Response
(be worsen)