Immediate hypersensitivity to snake antivenom

Immediate Hypersensitivity
Reaction to Snake Antivenom
Suda Sibunruang, M.D.

Outline
• Introduction
• Prevalence
• Pathogenic mechanism
• Skin tests
• Premedication
• Desensitization

Snakebite is a global problem
with an estimated 421,000 – 1.8 million bites
and up to 94,000 deaths each year
Kasturiratne A, et al. PLoS Medicine 2008

Dealing with adverse reactions to
snake antivenom
Treating snakebite is not a pleasant experience.
Most doctors serving in countries with a high
snakebite burden dread the experience of having
to rescue patients from potentially life
threatening complications of envenomation and,
in addition, having to treat antivenom-induced
adverse reactions
I Gawarammana. Ceylon Medical Journal; 2011

Snake antivenoms
• Formulations of immunoglobulins, or
immunoglobulin fragments, purified from the
plasma of animals immunized with snake
venoms

In 2010, there were 45 public and private laboratories
that manufacture antivenoms in the world

Snake antivenom production at QSMI
80,000 Ampoules/year

Picture from www.crbdiscovery.com

Two methods of administration are
recommended:
(1) Intravenous “push” injection:
Slow intravenous injection (not more than
2 ml/minute).
Advantage
The doctor, nurse or dispenser
administering the antivenom must remain
with the patient during the time when
some early reactions may develop.
WHO/SEARO, Guidelines for the management of snake-bites

(2) Intravenous infusion:
antivenom is diluted in approximately
5-10 ml of isotonic fluid per kg body weight
(i.e. 250-500 ml of isotonic saline or
5% dextrose) and is infused at a constant
rate over a period of about one hour.

Isbister G. PLoS ONE 2012; e38739

Nomenclature of adverse reactions
In 2010, WHO classified the adverse reactions
to antivenoms as:
• Early reactions (occur within 24 hr)
• Late reactions
WHO, 2010a. Guidelines for the Production, Control and
Regulation of Snake Antivenoms Immunoglobulins

Leon G, et al. Toxicon; 2013: 63-76

0
5
10
15
20
25
30
35
40
cases
cases
Data from spontaneous report of adverse drug reaction

2526 – 2549: total 148 cases
• Anaphylactic shock 10 cases
• Anaphylactoid reaction 2 cases
• Angioedema 2 cases
• Palpitation 5 cases
• Pruritus 16 cases
• Rash 15 + cases
• Urticaria 22 cases
Data from spontaneous report of adverse drug reaction

Asian Pac J Allergy Immunol 2010;28:262-9

Low incidence of early reactions to
horse-derived F(ab)2 antivenom for
snakebites in Thailand
• The medical records of 254 cases receiving
antivenoms during 1997–2006 were reviewed.
• Most were for green pit vipers (84%) and
cobras (13%).
• Early reactions occurred in 9 (3.5%) including
3 (1.2%) with hypotension.
Thiansookon A, Rojnuckarin P. Acta Tropica 105 (2008) 203–205

PLOS Neglected Tropical Diseases, 2013:7;e2326

Malasit P, BRITISH MEDICAL JOURNAL:1986

The pathogenesis is not entirely understood.
However, it has been related to:
1. Factors depending on the manufacturing
practices
i.e., contamination of the formulation
with endotoxins or viruses
2 Factors depending on the physicochemical
characteristics of the antivenom
i.e., purity and content of protein aggregates

3. Factors depending on the immunochemical
characteristics of heterologous
immunoglobulins of antivenoms
i.e., anticomplementary activity and
immunogenicity

IgE-mediated reactions
• Rarely reported
• Occur in patients who previously exposed to
animal immunoglobulins
• Antivenoms containing traces of antibiotics
could induce early reactions in patients
presenting IgE towards antibiotics

Prevention
antivenom producers must remove the
medicated animals from the bleeding process,
until antibiotics have been cleared from blood.

Non- IgE-mediated reactions
• Vast majority of early reactions induced by
antivenoms
• hypersensitivity intradermal tests are useless
to predict their occurrence and, consequently,
are not recommended

Non- IgE-mediated reactions
• Pathogenesis is still incompletely understood
• Two mechanisms proposed to explain these
reactions are:
1. Anticomplementary Activity (ACA)
2. Natural antibodies

Anticomplementary Activity (ACA)
• It was observed that ACA is related to adverse
reactions induced by the administration of
human IVIGs
• ACA of antivenoms might have a role in the
anaphylactic reactions induced by these
immunobiologicals
• Assuming that ACA is causally related to the
pathogenesis of non IgE-mediated reactions

4 main strategies to reduce antivenom ACA have
been proposed:
• Reduction of the total amount of protein
• enzymatic digestion of immunoglobulins to
remove the Fc fragment
• reduction of IgG protein aggregates
• treatment of immunoglobulins with Beta-
propiolactone, which is known to reduce ACA

However, no difference has been observed in
the incidence of non IgE-mediated reactions
induced by the same antivenom administered at
different doses, i.e. at different protein loads

• Fc region is responsible for complement
activation by the classical pathway. So, its
removal generates products inducing lower
incidence of adverse reactions.
• However, this presumption has not been
supported by experimental and
clinical evidence

• Non IgE-mediated reactions are not associated
with consumption of components of the
complement cascade
• Equine immunoglobulins are unable to
activate the human complement system by
the classical pathway
• F(ab’)2 antivenoms have ACA despite lacking
the Fc fragment
• Several clinical trials have shown that F(ab’)2
antivenoms induce early reactions of variable
incidence depending on the product

• Thus, although pepsin digested antivenoms
have a lower ACA in vitro than equivalent
whole-IgG antivenoms, clinical studies
comparing equivalent antivenoms using IgG
and F(ab’)2 as active substance show similar
incidence of early reactions for both
formulations

• Protein aggregates in antivenoms contribute
to the development of early adverse
reactions, possibly by inducing complement
activation, although more studies are required
to further explore this hypothesis.
• Immunoglobulin aggregates can be produced
as a consequence of inadequate lyophilization,
thus affecting the physicochemical
characteristics of the antivenom.
• However, properly lyophilized antivenoms do
not induce higher incidence of adverse
reactions than their homologue liquid
formulations

• Treatment of immunoglobulins with Beta –
propiolactone is a procedure developed to
reduce ACA in IVIg preparations
• However, a clinical comparison of two
antivenoms constituted by whole IgG purified
by caprylic acid precipitation, one treated with
Beta-propiolactone and the other produced
without this treatment, showed that both
formulations induced a similar incidence of
anaphylactic reactions

• although these strategies reduce antivenom
ACA in vitro, none of them have translated
into products inducing a lower incidence of
anaphylactic reactions in clinical trials
• Despite these conflicting observations, the
ACA of antivenoms remains as the most
accepted explanation for the pathogenesis of
non IgE-mediated reactions

Natural antibodies
There are two types of natural antibodies:
• Autoantibodies (i.e. antibodies recognizing
self-antigens)
• Heterophilic antibodies (i.e. antibodies
towards molecules originating from a different
species)

Autoantibodies
• In IVIg , dimers formed by this mechanism
have been associated to hypotension
• However, the demonstration of this
phenomenon in antivenoms is pending

Heterophilic antibodies
• Heterophilic antibodies in the antivenom
• Heterophilic antibodies in human plasma

• Antibodies towards human erythrocytes,
other human cells such as mast cells,
neutrophils and endothelium are present
in the plasma of animals used as
immunoglobulin source for antivenom
production, such as equines, ovines, and
camelids

• Interestingly, it was recently found that non
IgE mediated reactions are characterized by
high levels of mast cell degranulation in
patients, a phenomenon that might be
triggered by non allergen-specific activation of
mast cells, which may be related to the quality
of antivenom preparations, as well as a
priming effect on the immune response by the
venom itself

• Production of heterophilic antibodies is
stimulated by contact with animals,
administration of vaccines, or ingestion of
food
• Therefore, heterophilic antibodies are present
in the plasma of all people
• Human plasma contains antibodies (IgG and
IgE) towards animal antigens such as albumin,
myoglobin, and immunoglobulins

• Horses are the most commonly used animals to
produce antivenoms, and human heterophilic
antibodies towards equine immunoglobulins have
been described, as well as, ovine derived antivenoms
• However, they are similarly tolerated by patients

• Other animal species used as immunoglobulin
source for the production of experimental
antivenoms are goats, hens, llamas, and
camels
• Among these, camelid immunoglobulins have
shown lower ACA and immunogenicity, when
compared with ovine or equine
immunoglobulins

Malasit P, BRITISH MEDICAL JOURNAL:1986
Sensitivity tests
• Diluted antivenom 1 in 10 in isotonic saline
• 0-02 ml was given intradermally into the left forearm of 15 patients
• One drop was instilled into the left conjunctival sac
• Plain isotonic saline (0-02 ml) was injected intradermally into the right arm
• One drop of saline instilled into the right conjunctival sac as controls

Low incidence of early reactions to
horse-derived F(ab)2 antivenom for
snakebites in Thailand
• Skin test was negative in 7/7 tested cases.
• Overall, skin test was positive in 10/211 (4.7%).
Five of them underwent desensitization.
Antivenom can be given in all 10 without
reactions.
• In conclusion, the incidence of early reactions to
antivenoms was low in Thailand and skin test is
not helpful at all in predicting this adverse
reaction.

Is skin test really useless in
predicting ADR to snake
antivenom ?

A role of snake antivenom skin test
from the allergist’s point of view
Several factors such as concurrent medication
use (antihistamines, cold remedies, tricyclic
antidepressants, and major tranquilizers) and
dermographism can interfere with wheal and
flare response and make the results unreliable.
Klaewsongkram J. Acta Tropica; 2009:84-5

A role of snake antivenom skin test
from the allergist’s point of view
• Testing concentrations need to be verified
both in healthy individuals and snake bitten
patients to ensure that they contain no irritant
effect and all confounding factors affecting the
result must be minimized.
• A well-controlled study is recommended to
optimize skin testing protocol before it can be
implemented in routine clinical practice.
Klaewsongkram J. Acta Tropica; 2009:84-5

Gawarammana I, MJA 2004;180:20-3

Silva H. PLoS Medicine, 2011:8;e1000435

Objectives
To assess the effects of drugs given routinely with snake antivenom
to prevent adverse effects.
Selection criteria
Randomized and quasi-randomized trials testing routine adrenaline (epinephrine),
antihistamines, or corticosteroids.
Main results
One trial in Sri Lanka (n = 105) giving adrenaline with polyspecific antivenom showed
fewer adverse reactions in the adrenaline group, and this effect was preserved when
stratified for severity. One trial in Brazil (n = 101) using three types of
Bothrops antivenom showed no benefit of antihistamine drugs.
Authors’ conclusions
Routine prophylactic adrenaline for polyvalent antivenom known to have high
adverse event rates seems sensible, based on this one trial. If clinicians believe local
factors do not justify routine adrenaline, then they should test their belief in
a randomized trial. Antihistamine appears to be of no obvious benefit in
preventing acute reactions from antivenoms.

Habib A. Drug saf 2011; 34(10)

Clinical studies have shown that pre-treatment
with anti-histamines or steroids do not prevent
complement activation or the appearance of
anaphylactic reactions.
In contrast, administration of low doses of
adrenaline is effective in preventing the
development of anaphylactic reactions

Nevertheless, since depending on the dose and
administration route adrenaline may induce
hypertension, caution is recommended in cases
of envenomations characterized by
hemorrhage and coagulopathy due to the risk
of intracranial hemorrhage

• Desensitization was started from 1ml of
1:100,000 dilution of antivenoms
intravenously.
• Doses were increased by 2–2.5 folds every 15
min, if there was no reaction, until reaching
undiluted antivenom.

Immediate hypersensitivity to snake antivenom

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