Antivenom

11 Mar 2017
Sticky Post By Posted in Antivenom Permalink

Solving Snakebite in Sub-Saharan Africa

Sticky Post By On March 11, 2017

For a long time now, South Asia — and India in particular — has been cited as the world’s epicenter of snakebite mortality and morbidity, but the region is not alone. The problem of snakebite in Africa is comparable in scale to that in India. And while reliable epidemiological data are hard to come by, the best estimates are that Africa may have as many as 30,000 snakebite deaths per year (with some estimates closer to 50,000), plus hundreds of thousands of permanent injuries and amputations. Both deaths and disabilities exact terrible economic and social costs.

So it was big news when Sanofi Pasteur ceased production of Fav-Afrique, probably the most important antivenom used in Sub-Saharan Africa, due to its being unprofitable to produce. News of the crisis grew more urgent when they later announced that supplies would soon run out. Africa became increasingly desperate for a solution to its snakebite problem.

Understanding the Problem, and Solving It

Without a doubt, the hardest part of solving the snakebite problem in Africa is the fact that it isn’t just one problem; it’s a collection of problems:

  • Antivenom is the definitive treatment for snake envenomation, but the areas with the worst snakebite problems have continual shortages.
  • When antivenom is not available, medical professionals may not be trained to use it. If snakebite victims do not expect antivenom to be available, they often won’t go to a hospital for treatment, but resort to traditional remedies, which fail to help or make things worse.
  • Where the right antivenom is available, it usually costs more than people can pay.
  • Making antivenom cost-effective means making a lot of it, and you can’t make a lot if nobody is buying it.

All of these problems interact with each other, so the real challenge is addressing all of them, all at the same time, which means:

  • Antivenom manufacturers have to made high-quality antivenom, against the right species, in huge quantities.
  • Someone needs to buy that antivenom and get it to hospitals where it’s needed.
  • Medical professionals need to be trained to use it.
  • Snakebite victims need to go to the hospital to get antivenom.

Addressing all of these problems in parallel appears intimidating, but it’s been done. Success stories in countries like Mexico and Burkina Faso have demonstrated that it’s possible.

La Société Africaine de Venimologie (the African Society of Venimology, “ASV”) is an association of African physicians and experts in related fields around the world, who specialize in the treatment of snakebite and train healthcare professionals throughout Africa to do the same. Last summer, Dr. Leslie Boyer and I began a project in cooperation with ASV to produce a series of videos to help them deliver training to doctors and nurses throughout the continent. We’re fortunate to be working with many of the most respected experts in the field, including Dr. Jean-Philippe Chippaux and Dr. Alejandro Alagón, whom many readers will know of in connection with their work related to venom, snakebite treatment and antivenom production.

The training modules will be available in French, Spanish and English, with versions subtitled in all three languages. They will cover general topics, like public health, sourcing and policy, as well as specific clinical topics like patient assessment, administering antivenom, symptomatic management, and post-hospital follow-up care. There will also be modules on the medically important snakes of Africa and the manufacturing of antivenom. We hope to release one module each month (maybe two, if we can work that quickly!), from now through this coming summer.

The modules will be distributed online (first on Vimeo, and then later on YouTube), and they will be available free to everyone in the world.

Preview: “Snakebite and Treatment in Sub-Saharan Africa”

Direct links to all languages

Other Links

05 Jul 2016
Sticky Post By Posted in Antivenom, Self-immunization Permalink

Response to “Self-immunization with Snake Venom”

Sticky Post By On July 5, 2016

This post is a response by Dr. Sean Bush of East Carolina University’s Brody School of Medicine to the preceding article, “Self-immunization with Snake Venom”

Republished with permission.

July 4, 2016 – 7:30pm

Dear Ray,

Thank you for an intelligent summary of the state of the art of self-immunization with snake venom. Your insights apply to many snakebite interventions, from The Extractor to Fab antivenoms.

I concur that self-immunization has never been properly subjected to the Scientific Method. In short, the Scientific Method involves these steps: (1) Ask a question (2) Find out what is known (3) Develop a hypothesis (4) Test it (5) Analyze results (6) Draw conclusions – i.e., accept or reject hypothesis (7) Report your study (especially the methods. The methods must be reported in a way that the experiment can be reproduced by another scientist).

Many theories seem to make sense but when hypothesis tested, turn out wrong. For example, “The Extractor,” once recommended by the Wilderness Medical Society, was subjected to hypothesis testing. Two concomitant experiments concluded, “Snakebite suction devices don’t remove venom—they just suck.” [Bush SP. Annals of Emergency Medicine. 2004. 43(2): 187-188.]

Another long-term debate just got resolved through a properly done experiment in human subjects. Fab antivenom is efficacious for copperhead envenomation. [Gerardo CJ, et al. The efficacy of early fab antivenom versus placebo plus optional rescue therapy on recovery from copperhead snake envenomation (abstract). Toxicon. 2016. 117: 102.] I enrolled patients into this multi-center clinical trial. The most interesting thing about this study is that it was PLACEBO-CONTROLLED.

Here is another multi-center placebo-controlled trial involving a venomous animal: “Dart RC, Heard K, Bush SP, et al. A Phase III Clinical Trial of Analatro® [Antivenin Latrodectus (Black Widow) Equine Immune F(ab’)2] in Patients with Systemic Latrodectism (abstract)” to be presented at the North American Congress of Clinical Toxicology in September.

The gold standard in clinical science is the prospective, double blind, placebo-controlled Randomized Clinical Trial (RCT).

Why is the fact that these studies were placebo-controlled so interesting in the context of self-immunization with snake venom? It means a placebo-controlled study could be ethically done in a group of volunteers consenting to participate in an experiment on self-immunization.

There are a lot of things to consider…

For one thing, the aforementioned RCTs used venomous species with very low mortality rates. That’s likely how they got ethics approval. It also required the investigators use clinically important endpoints, such as pain scales or limb function at specific time intervals. So far, that’s all easy enough to do for self-immunization.

For another thing, there were clinically important questions to answer. Was antivenom effective for copperhead or black widow spider envenomation? This is important because antivenom has side effects and costs. On the other hand, envenomation can cause residual disability or refractory pain. Sometimes envenomation can cause death, but sometimes anaphylaxis to antivenom can, too.

Further, there is presently an epidemic of opiate/opioid (pain-killer) over-prescription and use in the US. If antivenom reduces the opiate requirement and chance of addiction, then that’s a good thing.

A gold standard experiment is not always necessary to change clinical practice. It only takes a few bad outcomes to kill a drug or first-aid intervention. Sometimes it only requires one case. For example, there was a case of fatal anaphylaxis to black widow spider antivenom in the early 1990’s. At that same time, the medical community knew of no fatal cases of black widow spider envenomation. Therefore, the majority of clinicians simply did not use antivenom for black widow spider envenomation. They felt the treatment was worse than the disease.

Some things seem so counter-intuitive that you shouldn’t even have to do the experiment, such as cutting and sucking, electric shock, cryotherapy… Yet all have been considered for treatment of snakebite.

Bryan Fry’s quote is great: “The plural of anecdote is anecdotes, not data.”

However, after enough anecdotal cases, you do obtain data. First you have a case series. Some of these get published in the peer-reviewed medical and scientific literature. It’s not the gold standard, nor does it utilize the scientific method (unless you are able to somehow compare to historical controls). If you see many anecdotal cases, let’s say dozens or hundreds, eventually you might do a retrospective analysis. Still retrospective studies are not the top tier of scientific rigor. However, retrospective studies can be helpful in developing a hypothesis for testing. Now we are getting closer to answering a question using the Scientific Method!

Even an anecdote is an observation. Case reports can change clinical practice (as above). The converse is also true: RCTs do not always change clinical practice. I am still shocked at what happened to Anavip. In the venomous world, business decisions and legal proceedings sometimes supersede the best medicine. [Bush SP, Ruha A-M, Seifert SA…et al…Boyer LV. Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial. Clinical Toxicology. 2015. 53(1): 37-45. http://dx.doi.org/10.3109/15563650.2014.974263]

These are just some of the challenges anyone who wants to explore self-immunization with snake venom is up against. Keepers of hots generally do not trust physicians, and physicians generally do not trust keepers of hots. There are good reasons on both sides. I know because I am one of both: a physician keeper of hots.

I am also an established clinical scientist with a well-established publication record. Search PubMed for Bush SP if you want to get an idea.

If we are going to answer Ray Morgan’s questions, we are going to have to “science the shit out of it.” [The Martian] We are also going to have to medically manage the fuck out of it.

Let’s take a few steps through the Scientific method. Suppose we want to do an experiment involving self-immunization with snake venom (SISV). One must enter into an experiment with an open mind, as free from bias as possible. We will need ethics approval (e.g., via an Institutional Review Board). We need to get approval to use venom as an Investigational New Drug. We will need to select a venom. There should be good reasons for the venom we select. I believe a monovalent immunity is best to start with (i.e., a single species). We would want to use the simplest venom possible. We will need to come up with a research question to answer and a meaningful hypothesis. We need to sort out a sample size. There needs to be an experimental group and a control group. The groups should be similar at baseline. Anyone with a significant exposure to the venom chosen would have to be excluded, although there could be caveats to this. For example, someone bitten by a Viperidae may still be eligible to participate in a study that involves Elapidae. Or maybe someone bitten by a garter snake could still be included. We will need to define what “exposure” means. Does it mean natural or artificial injection of venom? Or could it mean snake handling? For the record, a dangerously venomous snake has never bitten me. We will try to be blind to which group is getting venom versus placebo. That may be hard to achieve if the venom causes an easily detectable difference at low doses. In that case, it will be a limitation. All scientific experiments have limitations. Nevertheless, we will conduct the experiment with as much rigor as possible. We will collect data meticulously, analyze it, and draw conclusions. We will want to publish in a peer-reviewed medical journal.

Some experiments are not possible. For example, for rare conditions it is hard to enroll enough subjects (i.e., insufficient sample size). That’s a challenge for coral snake studies. More on that later…

There is another challenge unique to snake envenomation that makes it hard to develop active immunity against. With certain vaccinations, take viral for instance, the immune system has a chance to respond while the virus replicates. It’s a relatively slow process. Envenomation, in contrast, can bolus a large venom load very quickly. There is no time for the immune system to “remember.” It has to be ready for a full load immediately. Essentially, the self-immunizer has to be constantly and fully immune to be ready for the big bite. This requires frequent boosters, possibly on the order of every 2 to 4 weeks.

Methods for immunizing animals to make antivenom are proprietary. SIers aren’t willing or able to share their methods. These are added challenges, but I believe I am getting a good idea how to do it. For example, I think it’s going to take about 6 months.

I welcome constructive suggestions. The only way I can find the holes in my theory is through the critique of others. When I find the holes, I can patch them or ditch the experiment (if convinced).

Now let’s take a few steps through the medicine of it. Naturally, we would want to monitor the experiment closely. All preparations for any worst-case scenario would need to be immediately at hand (including but not limited to): appropriate antivenom, epinephrine, airway and alternative airway equipment, diphenhydramine, a doctor, and nurse. Any emergency physician worth his or her board certification and any stethoscope-wielding nurse worth his or her RN can manage anaphylaxis if it happens right in front of them with all medications and equipment readily accessible.

The practice of medicine is part science, part art. Add in committees, administrators, insurance companies, attorneys, and you get the most bizarre “dance” imaginable. And then there are the patients… Many of you know how hard it is to be a patient with an exotic venomous bite. Physicians often have little clue how to help you. Should they trust the medical advice (even if it is spot-on) of a patient, who would keep an illegal hot?

What does a physician do in absence of evidence? What is known about the cross-protectivity of crotaline Fab antivenom against a Bothrops sp. envenomation? Precious little. The experiments have not been done. There are anecdotal cases. I have been involved in the treatment of a few. Recently I helped a toxicologist manage a Brazilian lancehead (Bothrops moojeni) envenomation with Crotalidae Polyvalent Immune Fab (ovine) in Illinois. I coauthored a case report involving management of a Brazilian lancehead envenomation in Nebraska. That was about the extent of my experience with that species. I had also served as expert witness in a legal case involving the unsuccessful treatment of an urutu envenomation with Fab antivenom in Ohio. As I reviewed that case, I began to wonder if that was a failure of efficacy or dosing. Years later, an urutu bite presented to my ER – you know, “Venom ER.” The real Venom ER. I treated that patient with the antivenom I had in my ER: CroFab. Meanwhile, I looked for more specific antivenom and was able to find none in a timely fashion, not even expired Antivenin (Crotalidae) Polyvalent. Even if I had found some, would I (should I) have used it? Anyway, I presented the case at Venom Week in Hawaii, and the abstract is published [Bush SP, Phan TH: Experience with Crotalidae Polyvalent Immune Fab (Ovine) for a non-North American Rattlesnake Envenomation. Presented at Venom Week, Honolulu HI, 2012. Toxicon 2012. 60, 224.] So now there are two bits of data. Can we draw any firm conclusions? No. However, if more cases occur, eventually we will have a series. Maybe a meta-analysis can be done and serve as the foundation for a study.

My biggest criticism of the most prominent self-immunizers (with few exceptions) is that they do not publish or even share their methods in a manner that is reproducible. That’s not science, and it’s not helping anyone but yourself (if even that). There are a lot of reasons SI could just appear to be effective. Some bites are dry. Rates vary by snake family and even species. (E.g., Australian elapids have a high dry bite rate whereas rattlesnakes have a low dry bite rate – less than 10 percent in my experience and studies). Also, in a clinically significant proportion of bites, only a minimal or moderate amount of venom is introduced. Who knows how many of those folks would do just fine with or without SI. Further, SIers often use captive specimens and apply the “bite” in an artificial way. They may press the snake’s fangs to their skin, and this may restrict the flow of venom in some way.

One would expect self-immunization to mitigate some effects of envenomation. Animals develop immunity to venom. Why wouldn’t humans? However, even modern crotaline fab antivenom doesn’t mitigate all effects of envenomation (e.g., myokymia). Perhaps this is because antibodies do not recognize certain components for some reason or the species is not used to develop the antivenom or theories, theories, ad nausea. I have wondered why crotaline fab antivenom is not as effective for C. helleri as it is for C. scutulatus and come up with some theories of my own. [Bush SP, et al: Crotalidae Polyvalent Immune Fab (Ovine) Antivenom is Efficacious for Envenomations by Southern Pacific Rattlesnakes (Crotalus helleri). Annals of Emergency Medicine. 2002; 40(6): 619-624.]

Occasionally science moves my leaps and bounds, but more often it moves in increments. I would not suggest start with a Bitis sp. It would be hard to obtain ethics approval to do a prospective, interventional experiment in human subjects in which the outcome measured is mortality or digit loss.

Ray also brings up a good question about “resistance” versus “immunity” and “self-inoculation” versus “self-immunization.” When we give antivenom to a patient with a snakebite, are we merely giving that patient resistance or are we giving passive immunity? Or something else, like tolerance? What is the proper term for it? I believe it is passive immunity. When self-immunizers use snake venom to build immunity, I believe they intend to develop active immunity. There are issues with that, which I will expand on shortly…

Certain animals have protease inhibitors, which give them a sort of resistance to venom. Are self-immunizers developing protease inhibitors? I doubt it.

Inoculation is a fine word, but so is immunization or vaccination. It might be appropriate to call it sub-clinical envenoming. I just threw the UK term in there to say it is partly a matter of semantics. It’s also partly a matter of what is really going on.

Whatever we call it (i.e., “self-whatever”), we might consider having a hot nurse administer the venom, toxin, immunogen, or whatever you want to call that. We could have an entire debate on semantics, but we want to do an experiment, right? By “hot nurse,” I am being “genderist” – I am talking about my wife (of course). She really is a nurse, and she really is hot. Some of you may prefer a hot nurse (male or female – whatever your preference). Sorry, no trans-gendered nurses though – only because they might find it hard to use a public bathroom in North Carolina. Isn’t politics embarrassing?

A little more medicine for Ray and others: if we choose an appropriate species, kidney injury can be avoided. We will give extra fluids to our subjects to be sure. Livers are surprisingly resilient, and few act directly on brain tissue (although secondary injury through bleeding or clotting or hypotension are very real risks). There are two sides to the “thinning” effect of venom on blood. More on that in just a bit…

Still more medicine: Aseptic technique could be used to reduce the risk of bacterial infection, and venom is bacteriostatic. Risk of viral transmission from a snakebite is not known to occur (e.g., you can’t get rabies from a snakebite). However, if you go a step further and start talking about transfusing the self-immunizer’s serum to others’ with snakebites, there are heaps of viruses to consider (HIV, hepatitis, and many, many more). Plus there are issues of blood compatibility. I’m not even going to go any further into that right now. This is where it starts to sound like quackery.

I was most surprised to learn from Ray that self-immunization with snake venom “…has not yet landed any in a grave…” Really? That’s interesting. Antivenom has. Legit snakebites have.

It is notable that no one in private labs self-immunizes. Is that because allergy is so common in this population? That would be a good reason. Or is it because self-immunization is considered quackery? Well, that could be sorted out through science. Allergy to venom or developing an allergy to venom through the process of self-immunization is a real risk. Allergy is a form of immune response. Anaphylaxis, or Type 1 hypersensitivity, is a like an immune response on steroids. Actually that’s a bad choice of words. Steroids are used to treat allergic reactions.

If you come to my ER with a snakebite, you will get rapid, well-rehearsed emergency response. Sadly, that is not true for all ERs, and even less so for an exotic bite. Not everyone goes to the trouble to learn, rehearse, stock, etc.

As for obtaining the venom for self-immunization, one does not have to extract the venom oneself. There are resources, like the National Natural Toxins Research Center, who can supply you with the venom of your choice.

I can imagine problems for which self-immunization is the best available solution or preferable to passive immunization with antivenom. For example, the only commercially available coral snake antivenom in the U.S. is no longer manufactured and is running out. No one has been able to replace it at the time of this writing. So what does the Food & Drug Administration (FDA) do? Extends the expiration date for over 10 years. What medicine would you want to take that is over 10 years expired? Would you even drink bottled water that was 10 years expired? Coral snake antivenoms are being developed, but snakebite medications slither slowly, at a snail’s (or more apropos, at a snake’s pace) through the FDA. I hearsay Coralmyn may not be effective for Micrurus fulvius because M. nigrocinctus was used. I don’t believe this has been experimentally tested, and I have offered to help test it. At least one other coral snake antivenom is in development, [https://www.clinicaltrials.gov/ct2/show/NCT01337245?term=coral+snake&rank=1], but the investigators are not talking yet. I get the impression that enrollment is slow. That means this study will take a very long time to complete. Maybe I need to move to Florida to help with enrollment? Or maybe I should consider self-immunization. For curators of zoos who keep eastern coral snakes or for keepers of a “Native Snake Display,” who likes to show it at Venom Week V WITH A CORAL SNAKE, perhaps active immunity to eastern coral snake venom might be prudent. As it is, I can only say I have all vipers native to North Carolina in my display. I would like to say I have all venomous snakes of North Carolina in my display. It’s important to get antivenom administered before paralysis begins because of way the venom affects the synapse. What better way than to have continuous active immunity? Still there is a lot to work out in terms of experimental design, like how do you measure outcome? Pulmonary function studies? Historical fatality rates? Other ideas?

Here’s another idea. Compare self-immunizers with copperhead venom to “self-immunizers” with placebo. Increasing doses of venom would be used until the venom effects were intolerable in the control arm. There would, of course, be an antivenom rescue arm.

Still…why are we doing this? Consider the following. In the U.S. a course of antivenom costs a minimum of $15,000 (even for a copperhead bite, which has a survival rate with or without antivenom of 99.96 percent) and can easily exceed $100,000 for a rattlesnake bite. Just for the antivenom. Sometimes insurance doesn’t pay or only partially pays. We know antivenoms are safe and effective, but the cost is off the snake hook. These extreme costs drive people to go to extreme measures. I told one of my patients, who had a bill in excess of a quarter of a million dollars, “Just don’t pay it.” Couldn’t self-immunization, if properly done be much less costly? Many venoms are cheap. Just check the price list at NNTRC. Wouldn’t it be nice to circumnavigate Big Pharma, Big Money, et cetera?

There is substantial evidence that venom contains many pharmacologically beneficial properties to humans. For one thing, whole venom is used to make antivenom. Further, there are many pharmaceuticals originally derived from venom: ACE-inhibitors, used to lower blood pressure in patients with high blood pressure, was discovered in Bothrops jararaca. Eptifibatide (Integrilin), used to keep heart arteries open after a heart attack is stopped using balloon angioplasty, was discovered in Sistrurus miliarius (Pigmy rattlesnake). So a medicine derived from Pigmy rattlesnake venom prevents post-procedure heart attacks. This excites me because this is a snake native to North Carolina! How cool is that? I am 50 and take a baby aspirin a day because that’s what my doctor told me to do. Class I evidence supports it. What if I just use a little Pigmy rattlesnake venom each day? It’s a helluva lot more exciting than taking a baby aspirin. There are others, look on PubMed for Markland FS. If you are too lazy to do that, just look up this one article [http://www.ncbi.nlm.nih.gov/pubmed/16707922]. In short, this guy has been researching Contortrostatin (from copperhead venom) for its activity against breast and ovarian cancer.

Wouldn’t it be cool if a bunch of women self-immunized with copperhead venom were found to have a lower rate of cancer than the general population? Now I am dreaming…

Whatever has gone on before, published or not, has not resolved the debate. I agree with Ray that as it’s being done today, it makes no progress toward answering the questions it raises.

Let’s do the experiment and do it right!

I have a lot more thoughts on the topic, but right now I’d better get out and see some fireworks!

To be continued. Hopefully!

Sean

—
Sean P. Bush, MD, FACEP
Professor of Emergency Medicine, with Tenure
Department of Emergency Medicine
Brody School of Medicine
East Carolina University
3 ED 342
Vidant Medical Center
600 Moye Blvd
Greenville, NC 27834
Mailstop #625
(252) 917-9311 – mobile
seanbushmd@gmail.com

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03 Jul 2016
Sticky Post By Posted in Antivenom, Mythbusting, Self-immunization With 1 Comment Permalink

Self-immunization with Snake Venom

Sticky Post By On July 3, 2016 With 1 Comment

Few topics in venomous herpetology generate debate as contentious as that around self-immunization. The subject is so divisive and the opposing opinions hurled with such ferocity that it’s the only topic I specifically called out as having “worn out its welcome” in the posting guidelines for The Venom Interviews group on Facebook. (There’s an exception for peer-reviewed research published in credible journals, but I’m not sure that exception has ever been used.) This rule arose as a practical necessity in response to the certainty with which self-immunization discussions descend into loud, angry bar fights that monopolize the group for days at a time. I suppose it’s ironic to have written an article that’s off-limits for discussion in my own group.

I don’t expect this article will change the mind of anyone already invested in an opinion about self-immunization. But since there are a lot of people who are just hearing about it for the first time and are unsure what to believe amidst all the noise, I thought it might be helpful to try to examine the subject objectively, with as little prejudice as possible.

Here are the topics I’ll try to cover:

  • What is self-immunization?
  • Why is the debate so nasty?
  • Does it work?
  • Is there any application for it?
  • Has it produced new discoveries?

What is self-immunization?

In the context of this article, “self-immunization” (“SI” for short) is the practice of injecting snake venom in an attempt to cause one’s body to produce a titer of antibodies sufficient to at least partially mitigate the effects of envenomation by the chosen species.

Some of those who practice SI do so outside the public eye for practical reasons. Others see themselves as scientific pioneers, blazing new trails for science in the tradition of medical self-experimenters like Walter Reed,  Albert Hofmann, Stubbins Ffirth, August Bier, Marie Curie, Barry Marshall, Elizabeth Parrish, and, of course, Bill Haast. There’s also a small subset of practitioners for whom self-immunization is a public spectacle.

Medical self-experimentation has a fascinating and colorful history. Its track record is mixed, producing both important advancements and catastrophic failures, and it has always been contentious. The flaws in evidence collected by self-experimentation are nicely summarized in Wikipedia’s article on the subject:

“Self-experimentation has value in rapidly obtaining the first results. In some cases, such as with Forssmann’s experiments done in defiance of official permission, results may be obtained that would never otherwise have come to light. However, self-experiment lacks the statistical validity of a larger experiment. It is not possible to generalise from an experiment on a single person. For instance, a single successful blood transfusion does not indicate, as we now know from the work of Karl Landsteiner, that all such transfusions between any two random people will also be successful. Likewise, a single failure does not absolutely prove that a procedure is worthless. Psychological issues such as confirmation bias and the placebo effect are unavoidable in a single-person self-experiment where it is not possible to put scientific controls in place.”

Self-immunization differs from most other instances of medical self-experimentation in that it is not performed by medical professionals. At present, SI is performed, apparently exclusively, by people without formal education in medicine or immunology, and this is evident in some fundamental flaws in their approach — the absence of things like baseline measurements, controls, double-blind trials, etc. The seriousness of these flaws seems to be underestimated or ignored by practitioners, and there appears to be little clarity around how hypotheses are formed and tested, how data are collected and interpreted, and how conclusions are drawn. By any measure, it’s a stretch to characterize current SI practices as “citizen science.”

Why is the debate so… venomous?

Aside from the issues related to SI directly, the nature of the debate itself is fascinating. While many scientists and most herpers seem to have shallow reservoirs of diplomacy, SI is a uniquely potent catalyst for dooming virtually any discussion to vitriolic ad hominem attacks, straw man arguments, and general mayhem.

What is it about this particular topic that makes it seemingly impossible to discuss rationally? After years of observing people argue over SI, it’s often possible to see the triggers that send the discussion off the rails. Opponents of the practice mock its proponents the moment they display some egregious misunderstanding of the science they believe they’re doing. Proponents often invite this ridicule with credulous, uncritical acceptance of half-baked hypotheses until they are disproved — the exact opposite of evidence-based skepticism. Proponents respond with anecdotes, and they deride the opponents as purists, elitists and “haters” (for those still using tween vocabulary), who are impeding progress and stifling discoveries with their silly, uncompromising insistence on rigor.

Each side is openly suspicious the other’s motives. Opponents dismiss the proponents’ claims of “doing science” as a disingenuous cover for desperate, reckless bids to feed their egos with the amazement of admirers who don’t know any better. They are accused of trying to emulate Bill Haast, who had a medical necessity to protect himself 70 years ago, while that medical requirement isn’t the same today.

Meanwhile, proponents reflexively reject these criticisms, claiming that they are nothing but petty jealousy, that the naysayers are secretly bitter than they cannot exhibit such impressive feats of immunity. Skepticism is interpreted as attacks against the practitioner personally or against a personal hero (i.e., Haast). Inevitably, the argument deteriorates into explicit challenges to the opponents’ bravery, masculinity, or general badassery, and all hope for rational dialogue is lost. (Prediction: Responses to this article will follow the same trajectory.)

While the personalities involved and the scientific potential should be two distinct issues, from a practical standpoint, they are hard to separate. The discussion of SI is often overshadowed by the behavior of some (but certainly not all!) who practice it. It’s hard to be a credible public face of something that claims to be a scientific endeavor while, for example, conflating facts and opinions, being unclear what peer review means, misunderstanding what constitutes an experiment or observation, or — and I’m not kidding — challenging people to fights for disagreeing. (Since this article is about the practice and not the personalities involved, I’ve opted not to name names.)

Does it work?

Short answer: It depends.

Whether self-immunization works depends on how you define works. For any sufficiently specific definition of working, it should be possible to let data answer the question. Therein lies a central problem with SI today: As of the time of this writing, objective data on the subject are conspicuously thin, and this is especially remarkable given the extraordinary claims made in its absence. Not only are data lacking, but there’s not much to indicate that data-collection is getting any better.

However, it’s not necessary to abandon skepticism to concede that self-immunization appears to mitigate the effects of some at least some components of at least some venoms to a point where symptoms are reduced, perhaps even greatly reduced, possibly even to a degree that an otherwise potentially fatal bite is survived without antivenom. In the absence of real data, these are bold assertions, but they don’t conflict, in principle, with what’s known about immunochemistry: venom is introduced, B cells make antibodies against it, and those antibodies neutralize the toxins to which they’ve been raised.

Yes, it would be possible to fake the claimed results. For example, one could use venomoid snakes or snakes that were so unhealthy that their venom production was severely compromised. A more rigorous science observer might not be so generous, but I’ll take the risk of saying that I don’t think that outright deception like that is generally what’s happening.

Aside from the anecdotes of individual practitioners, belief in the potential protective capability of self-immunization is bolstered by various studies by the US military, including programs that tested immunization against the venom of Naja naja in humans (1963) and toxoids of Deinagkistrodon acutus, Bungarus multicinctus, Protobothrops mucrosquamatus, P. elegans and Trimeresurus stejnegeri in rabbits and mice (Yoshio Sawai, 1968), often cited as the “habu studies” along with its predecessors involving Protobothrops flavoviridis and Gloydius halys. (Taxons made current for clarity.) Each of these studies reported that immunization had some prophylactic value.

Not all venom toxins are created equal. Perhaps counter-intuitively, the simple toxicity (murine LD50) of a venom is almost certainly less important than what that venom does and how much of it there is. At least some neurotoxins seem to be mitigated by SI, and some toxins that affect blood coagulation might be as well. On the other hand, it seems highly improbable that even a high titer of antibodies would be a match for a massive dose of ferociously cytotoxic (tissue-destroying) venom from a large viperid like Bothrops or Bitis, which would completely overwhelm any antibodies in the tissue at the bite site.

At best, resistance is a better descriptor than immunity, and self-inoculation is a better use of the “SI” acronym than self-immunization.

So the interesting discussion is not so much around the century-old science of whether SI works, but rather whether there’s any legitimate application for it.

Is there any application for it?

Without dismissing it outright, the fact that hyper-immunity might be possible does not automatically make it the best option for protection against envenomation. Whether self-immunization is a good idea should be more a matter of data than opinion, but the dearth of data leaves opinions to fight for themselves.

Is it possible to construct hypothetical scenarios in which hyper-immunity might be useful? Are there situations in which the potential benefits outweigh the risks? Much of the difficulty in answering that question is that there is too little consensus on risks and too little high-quality data on the benefits.

The known risks are not trivial. They include the things we know venom can do, like cause kidney, liver and brain damage. How much damage can it do in tiny doses? Unknown.

There’s certainly the risk of miscalculating the dose, and this error has landed a handful of aspiring self-immunizers in the ER. As far as I am aware, it has not yet landed any in a grave, but that’s more a testament to their doctors’ heroics than to the safety or predictability of the practice.

There’s a risk of taking a more-severe-than-expected bite, overestimating one’s immunity, delaying treatment, and realizing too late how bad the bite was. Delays in treatment could easily lead to more complicated treatment, a longer recovery, and a higher probability of permanent injury, like loss of digits or worse.

There are other risks, like allergy, abscess, and bacterial or viral infection, and quantifying those risks is essentially impossible.

So is there any scenario where self-immunization is worth the risks, the pain, and the general unpleasantness of regular self-inoculation?

I know of several cases of venom-collection professionals who work with species for which there is no antivenom available, and in some of these cases, they work with species that can be extremely dangerous. The small handful of people who actually make a living extracting venom have, on average, about one accident every 30,000 to 50,000 extractions. In these cases, I could understand if these people reasoned that the potential benefit might outweigh the risk. However it is notable that none of those in the major private labs have chosen to self-immunize. All of the major private venom labs in the US — those with a statistical certainty of being bitten — opt for rapid antivenom rather than self-inoculation. Even in those instances where envenomation does happen, there is no clear evidence that the risk:benefit of SI is superior to rapid, well-rehearsed emergency response.

The situation Joe Slowinski faced on expedition in Myanmar is also cited as a possible application. Joe was surveying a remote area, days from medical care, when he was bitten by a small krait (Bungarus multicinctus). The team’s plan to equip themselves to manage such an accident fell apart on arrival in the country, and they decided to press on with the expedition regardless. Despite their heroic efforts, Joe’s team were not able to save his life, and he died the next day. Would self-immunization have saved him? There’s no way to answer that with any certainty. Some have cited Complete and Spontaneous Recovery from the Bite of a Blue Krait Snake (Bungarus Caeruleus) (1955) about Bill Haast’s survival of envenomation by a blue krait to suggest that it could have. But even if that were true, Slowinski’s situation was exceptional in every conceivable way, and it would be difficult to argue that self-immunization under his unique circumstances is a basis for more general application.

There are also cases where antivenom exists, but the person is allergic to it. Is self-immunization a solution in these cases? Again, that’s hard to say, but hospitals are equipped to manage anaphylaxis, and they are infinitely more rehearsed at doing that than they are at treating envenomation, especially exotic envenomation, deliberate or otherwise. It’s tough to make the case that self-immunization is the best way to manage these cases.

Each of these scenarios is highly unusual, and even for those cases, at the very least it would be reasonable to involve an immunologist with the training and expertise to direct and monitor the process.

So while there might be some theoretical application under some truly exceptional circumstances, in practice that’s not how SI is being used. More often than not, it’s being done to facilitate unnecessarily risky handling and demonstrate the ability to withstand intentional bites rather than protect against accidental ones.

There is a fatalistic — but patently wrong — saying among some amateur herp enthusiasts about being bitten that “it’s not a matter of if, but when.” This is simply false. There are well-established tools and techniques for safe, hands-off maintenance of venomous collections that reduce the risk of envenomation to nearly zero. There are plenty of examples of people who have worked with venomous snakes for 30 or 40 years (and more) without ever being bitten. There is no reason to consider accidents inevitable. They’re not. Therefore, SI as protection in the context of general husbandry is insurance against risk-taking that isn’t necessary to begin with. It is the herpetological equivalent of buying expensive, unnecessary insurance against your own drunk driving.

Dr. Bryan Fry summed it up nicely: “Indeed for most of the people self-immunising, a significant portion of their risk of envenomation comes when milking the snakes to obtain venom for self-immunisation. Circular logic at its finest.”

Ultimately, it’s hard to imagine any problem for which self-immunization is the best available solution or preferable to passive immunization with antivenom. The practice boils down to taking significant risks for benefits that are almost certainly unnecessary.

Are there other benefits?

Short answer: None have been demonstrated.

“The plural of anecdote is anecdotes, not data.”
— Dr. Bryan G. Fry

Beyond resistance to envenomation, SI discussions are riddled with wishful thinking and questionable claims about the supposed health effects of injecting venom. It’s easier to be unequivocal about these claims: There is no evidence whatsoever that the human body can somehow accept whole venom — a biocidal cocktail that evolved to kill things — and by some unknown mechanism, magically transform it for its own benefit. There is no support for the assertion that whole venom provides any health benefits whatsoever, either generally or as a treatment for any specific condition. (Immunotherapy with bee venom is beyond the scope of this article, but it’s a whole different process with different objectives.)

A popular response to this objection is something like, “But you can’t prove it doesn’t work!” Sorry, that’s not how evidence works. It’s actually the opposite of how evidence works. It is nonsensical to assert that venom might have <whatever> effect unless there’s some evidence that it actually does. This is critical-thinking 101: Absence of contradictory evidence is not evidence that all hypotheses are possible. It has not been proved that I cannot dead-lift 10x my own weight, but it’s not reasonable to assume that I might be able to do it just because ants can.

“But it did <whatever> for that guy!”

First of all, it probably didn’t do <whatever> for that guy. It’s more probable that <whatever> was a coincidence, a wrong observation, or an effect of some other cause that was wrongly attributed to venom. These stories don’t even make good anecdotes, let alone compelling evidence.

The fact that Bill Haast lived to be 100 years old (and reportedly was rarely ill) is frequently cited as anecdotal evidence that self-immunization could contribute to long life and all-around good health, but that’s a tenuous conclusion. Lots of people live to be 100, and none of them inject snake venom. The 2010 US Census reported more than 53,000 centenarians, and it’s probable that their longevity is attributable to well-understood factors like heredity, general health, weight, diet, activity and exercise, lifestyle, hygiene, stress, and community. The fact that one of these lucky, long-lived folks happened to inject himself with snake venom is not compelling evidence that the venom deserves the credit. This is confirmation bias. There are even occasional smokers who live to be 100, but nobody is in a hurry to credit tobacco for their longevity.

Still, there are adherents with unshakable belief that training (or “boosting!”) the immune system with venoms might have beneficial effects, despite the absence of any evidence to support this. Various other ideas — the notion that you can use venom to exercise the immune system like a muscle (a bad analogy), preserve youth, and boost your energy — have no scientific support whatsoever.

Has SI produced any new discoveries?

Short answer: No.

Long answer: Still no. The modern idea of using antibodies to deal with toxins and pathogens dates back well over a century, at least to the pioneering work of scientists like Edward Jenner (1749–1823), Albert Calmette (1863–1933), Vital Brazil (1865–1950), Clodomiro Picado Twight (1887-1944). While antivenoms have been improved and refined over the decades since they were conceived, the basic idea hasn’t changed: challenge an immune system with venom, allow it to produce antibodies, and then use them to treat someone poisoned with a venom those antibodies can deal with. Whether the antibodies are raised in a horse, a sheep, or a person, the basic idea is the same. SI today is doing little beyond re-creating immunologic effects that have been understood for over a century. It has not, thus far, contributed anything really new to the body of knowledge on the subject, and it appears unlikely to do so.

But could it? Possibly. Maybe. Who knows? SI raises some interesting questions. However, as it’s being done today, it makes no progress toward answering the questions it raises.

29 May 2016
Sticky Post By Posted in Antivenom, Herpetoculture Permalink

Antivenom Should be Required for Private Keepers

Sticky Post By On May 29, 2016
(This article was originally published by Kristen Wiley of Kentucky Reptile Zoo and is reproduced here with permission.)

In light of recent events and conversations here on Facebook and elsewhere, Jim and I decided it was time to make a post about private individuals keeping venomous snakes. In general, neither of us have a problem with it — it is certainly possible for private keepers to do a great job and be safe and responsible — however we do have a big problem with the fact that most private keepers do not have their own antivenom. Please note that we are talking here about private keeping in the US — we are aware that in some other countries, especially some in Europe, the government actually does have foreign antivenom to treat private individuals. That is not the case in the US.

Antivenom is not a luxury. It is the necessary safety net that should be REQUIRED to keep venomous snakes, especially those not native to the place where they are being kept. It is not a mystical potion that is unobtainable by mere mortals. I am going to address several excuses why people say they can’t get it here.

1. It costs too much.

Wrong. It is not prohibitively expensive, and if the cost of it is prohibitive, guess what, you can’t afford to keep venomous snakes. Here are some real prices: Thai Red Cross neuro or hemato polyvalent — $60/ vial. Only keep Naja kaouthia and don’t need the polyvalent? The monovalents are $40/vial. South African Polyvalent: $315/vial. Costa Rican Polyvalent I haven’t bought in a while because we’ve had Bioclon, but maybe $100-150/vial these days. In general you need 10 vials to be safe. 20 for a king cobra. Maybe you will need more in a very bad bite, but if you have at least that you can at least get started, and that will be enough for the vast majority of bites. Between those three companies you can cover the vast vast majority of snakes kept in private hands. So the most expensive one is SAVP — that’s a little over $3000. I bet most people with serious collections have more than that in cages alone. Keep in mind that antivenom does not need to be replaced every year — all the ones I listed above have 3- to 5-year expiry dates, so that is not an annual expense.

2. I can’t get it.

Wrong. YOU CAN! The problem is it is a pain in the ass because you have to deal with the FDA, a government agency, and there are forms to fill out and it is intimidating. However, in my experience the FDA is not interested in making things hard for people trying to keep antivenom for emergency use, which is what this is. I have called them and gotten help when I needed it or had questions. You can too! I will be happy to send anyone who asks the pdf we have that gives some guidance on how to get your own antivenom. I know a couple of private keepers who have done this and now keep their own stock.

3. Even if I get it, the hospital won’t use it.

Nope. If you have an IND, the Dr. is obligated to use it. Sure they may be worried- I myself have had one who was very hesitant. But if you are keeping a bunch of exotic venomous snakes, you have to send a letter to the hospital and let them know what you have and that you have the antivenom legally. Give them some notice so you don’t seem like a Yahoo with a snake fetish when you show up. Develop a relationship if at all possible. You’ll have to have a sponsor anyway for the IND- you can use that physician as a contact to get in touch with the hospital ED folks. You also need a written protocol that can be handed to the ED when you arrive. Joe has some! If you expect expired antivenom to be used on you, you MUST also have a signed release stating you want it used on you. No doctor is going to risk his/her medical license by giving expired product.

4. I don’t need it because I will never get bit.

Yeah, but what if you do? There is a reason car insurance is required even if you are a very safe driver. Things happen. People make mistakes — even you. Idiots could distract you. Equipment could malfunction. I personally have had both a hook and a grabstick break during use. The hook breaking was interesting. Not in a good way. The point is everyone makes mistakes, and shit happens. Be prepared for it.

5. It’s my life. I’m not affecting anyone else if I get bit.

Unless you are a hermit with no living family or friends this is not true. If you die or are severely injured, who is going to take care of you during your rehab? Won’t your mother be sad? Do you support kids? Who is going to do that if you can’t work for a period of time? Also, if you use a zoo’s antivenom, YOU ARE AFFECTING THE PEOPLE AND ANIMALS AT THAT ZOO. I do not keep antivenom for you. I keep it for myself, my husband, and my hard-working employees. If any of us make a mistake (see above about everyone making mistakes) it is MY responsibility to make sure we are ok. When you use our antivenom, you are making us choose between working the animals without our safety net, or letting the animals languish because we really shouldn’t be working them without antivenom. Last year we provided some Echis antivenom to an idiot who was freehandling his Chlorechis. At that time we were working on an order of Echis venom. So should we put our business on hold so someone can play with their pet? Should the researcher have to wait a few months to conduct their research so someone can think they are ‘one’ with their venomous snake?

6. Venom One will take care of me!

This is only true if you are in Florida, preferably south of Tampa. Venom One does an admirable job, but they can’t get antivenom to you in Pennsylvania or Arizona or Ohio very quickly. Plus, if you are in one of those states, your tax dollars are not supporting them. I don’t want this to happen, but it seems to me that sooner or later the taxpayers in Miami-Dade county are going to realize their tax funds are going out of state or to people who are behaving dangerously on purpose, and the funding is going to go away. At the very first Venom Week, a quite prominent doctor was very adamant to Jim and I that he did not believe they could cover any place but south and maybe central FL. Antivenom should be administered in two hours to be its most effective. It takes that long to get admitted, have the ED call them, and for them to get on their way. If you are more than maybe an hour by helicopter, you are too far away to rely on them.

Keeping an animal that can kill you is a great responsibility. If you choose to keep without antivenom, know that in my opinion you are irresponsible, reckless, and have no respect for those of us who endeavor to do it properly. I don’t care how long you have been keeping or how knowledgeable you think you are, or how many people in the community support you. We as a group are looking at this wrong, we have developed a culture of recklessness and I for one am tired of it.

Questions? Comments?

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