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 problemwith 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 havingto 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

Leon G, et al. Toxicon; 2013

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

Snake antivenom production

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.

WHO/SEARO, Guidelines for the management of snake-bites

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

Prevalence

2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2551 2552-2553

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

MJA 2008; 188: 473–6

Pathogenic mechanisms

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 viruses2 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

Preventionantivenom 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

Leon G, et al. Toxicon; 2013

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

Heterophilic antibodies • 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

Heterophilic antibodies • 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

Heterophilic antibodies

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

Heterophilic antibodies • 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

Heterophilic antibodies • 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

Skin tests

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

• 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.

• 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 medicationuse (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

Premedications

Gawarammana I, MJA 2004;180:20-3

Silva H. PLoS Medicine, 2011:8;e1000435

ObjectivesTo assess the effects of drugs given routinely with snake antivenom to prevent adverse effects.Selection criteriaRandomized and quasi-randomized trials testing routine adrenaline (epinephrine), antihistamines, or corticosteroids.Main resultsOne 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’ conclusionsRoutine 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.

Marcopito H. BMJ: 1999

Premawardhena A. BMJ, 1999

Habib A. Drug saf 2011; 34(10)

Clinical studies have shown that pre-treatmentwith 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 riskof intracranial hemorrhage

Desensitization

• 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.

Thank you for your attention

Immediate hypersensitivity to snake antivenom

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