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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