Evidence Update: Biologic Plausibility of Curcumin (Turmeric) Very Low

In 2013, I wrote about the burgeoning popularity of the spice turmeric as a medicinal herb. At the time, my conclusions were:

Overall, there is no compelling clinical evidence in humans supporting any use of curcumin or other turmeric compounds…There is virtually no clinical research in companion animals, and what there is does not support claims of benefit from turmeric compounds. Finally, the limited research to date suggests a few potential risks but the significance of these is unclear.

Since then, there have been many additional in vitro or lab animal studies, but no significant clinical trials in companion animal species. The pre-clinical research continues to find interesting biological activity of curcumin and other turmeric compounds which might, or might not, lead to clinically useful effects. At this point, there isn’t much new evidence that supports altering my previous conclusions.

However, one new review has looked at the biologic plausibility of curcumin, which is one factor in assessing the potential medicinal applications. This paper, somewhat surprisingly, suggests that the basic biochemistry of curcumin makes it unlikely to be a clinically useful remedy.

Nelson KM. Dahlin JL. Bisson J. et al. The Essential Medicinal Chemistry of Curcumin J. Med. Chem. 2017;60:1620?1637.

The authors review the pre-clinical and clinical trial literature for curcumin with an eye to features that would make the compound a better or worse candidate medicine. They conclude that its basic biochemical features make it unlikely to be useful but highly likely to generate false positive results if not tested with a clear understanding of its properties:

The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead.

Curcumin…has shown excellent promise in early testing (in vitro), even though this testing may have been bedeviled by design problems that led to several misfires. The structure of 1 suggests that it might be unstable in a biological setting, and in fact, it is: both its in vitro and in vivo stabilities are abysmal…relative to commercial drugs.

To our knowledge, [curcumin] has never been shown to be conclusively effective in a randomized, placebo-controlled clinical trial for any indication. Curcumin is best typified, therefore, as a missile that continually blows up on the launch pad, never reaching the atmosphere or its intended target(s).

While these failures would normally end further research on its use as a therapeutic, they apparently have not deterred researchers interested in its development.

Given its low systemic bioavailability, we remain highly skeptical that an oral dose of 1 can ever be effective in human clinical trials that are translated from reports of in vitro activity… the lack of any observed efficacy of oral curcuminoids in clinical trials where it was given in high doses does not bode well for these alternative hypotheses of therapeutic efficacy.

Unfortunately, no form of curcumin, or its closely related analogues, appears to possess the properties required for a good drug candidate (chemical stability, high water solubility, potent and selective target activity, high bioavailability, broad tissue distribution, stable metabolism, and low toxicity). The in vitro interference properties of curcumin do, however, offer many traps that can trick unprepared researchers into misinterpreting the results of their investigations.

While such an analysis does not entirely preclude curcumin eventually being a useful remedy, it does reduce the likelihood of this, especially given the failure of any dramatic clinical trial results suggesting a significant real-world benefit.

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Evidence Update: Feline Facial Pheromone Doesn’t Reduce Stress or URIs in Shelter Cat Study

I have written numerous times about the use of pheromones to reduce stress and stress-related problems in cats and dogs (1, 2, 3). Overall, the evidence for these products is weak, and it is likely they have little to no meaningful benefit. A new study of pheromone therapy in shelter cats appears to support this conclusion.

Chadwin RM. Bain MJ. Kass PH. Effect of a synthetic feline facial pheromone product on stress scores and incidence of upper respiratory tract infection in shelter cats. J Am Vet Med Assoc. 2017 Aug 15;251(4):413-420.

In this study, several hundred shelter cats were exposed to a pheromone diffuser or a placebo diffuser and assessed in terms of behavioral indicators of stress and incidence of upper respiratory infections (URI), which appear to occur more commonly with increases stress.

The methodology was generally sound, with appropriate randomization, blind assessment, and placebo controls. The study was under-powered, which means it is possible that a small difference between the groups may have not been detected in the statistical analysis. The authors also performed a large number of statistical comparisons of many variables. This is an approach which can raise the risk of falsely positive findings.

The findings, however, were pretty consistently negative. No difference was seen in stress scores or in the occurrence of URI between cats exposed to the pheromone and those exposed to the placebo. No evidence of harm from the pheromone treatment was seen, though this was not specifically sought.

As usual, no single study should be taken as the definitive answer to any medical question. However, in light of the fact that pheromones have been in use and studied extensively for decades and strong, consistent evidence of significant benefits has not been seen, this study strengthens the argument that these products do not, in fact, provide such benefits.

 

 

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Evidence Update: Potential Associations Between Neutering and Immune System Disorders

The risks and benefits associated with neutering are a complex and active area of research and debate in veterinary medicine. I have written several extensive summaries of the literature and numerous articles here evaluating the burgeoning research evidence. One subject that has seldom come up is the potential influence of neutering on the occurrence of diseases of the immune system. Although it is well established that sex hormones have variable and significant effects on the immune system, and that there are frequently sex differences in the risk of autoimmune and immune-mediated diseases, which suggests that sex hormones influence this risk, there has not been much direct research evaluating the relationship, if any, between neutering and the occurrence of diseases involving the immune system. A retrospective study published last year attempts to add to the very limited evidence previously published on this subject.

Sundberg CR. Belanger JM. Bannasch DL. et al. Gonadectomy effects on the risk of immune disorders in the dog: a retrospective study. BMC Veterinary research. 2016;12:278.

The authors looked back at a university veterinary college database of patients seen over a 15-year period. They first identified diagnoses of a number of conditions involving the immune system an then looked for differences in the occurrence of these conditions between males and females and between intact and neutered animals. The conditions evaluated included:

Atopic dermatitis (atopy or environmental allergies)
Autoimmune Hemolytic Anemia (AIHA)
Myasthenia gravis (CMG)
Colitis
Hypoadrenocorticism (ADD or Addison’s disease)
Hypothyroidism
Immune-mediated polyarthropathy (IMPA)
Immune-mediated thrombocytopenia (ITP)
Inflammatory bowel disease (IBD)
Lupus erythematosus (systemic SLE and discoid DLE)
Pempigus complex (PEMC)

These conditions were chosen because they all occurred in at least 0.1% of the dogs in the database. These are the most common of a group of conditions which are still, as a whole, usually very uncommon. The authors also looked at the occurrence of pyometra or uterine infections, a condition known to be common in intact females and to be prevented by neutering, which served as a control condition.

The study found an association between being neutered and the occurrence of 7/11 of the autoimmune diseases evaluated: ATOP, AIHA, ADD, HYPO, ITP, IBD, and LUP. Of these and increases occurrence of LUP was only seen for females, and for females appeared to be at greater risk than males for all of the conditions except ADD.

For those animals in which the age of neutering was known, no association was found between disease occurrence and age at neutering.

As expected, pyometra was significantly more common in intact females compare to neutered females.

While these data do suggest that there may be some protective effect of sex hormones against autoimmune disease, the authors correctly identify a number of important caveats:

  1. Retrospective studies are NEVER proof of a causal relationship because there are too many variables that cannot be identified or controlled.
  2. The study population at a university hospital is often very different from the population in general, which makes it unreliable to extrapolate associations from one to the other. For example, atopic dermatitis is one of the most common conditions seen in dogs with rates up to 19% reported. This study population only had a rate of 1.8%, which is much lower than expected. In general, university patients are much sicker and have more unusual conditions than typically seen in the general pet population, so they aren’t always good examples of health and disease in more normal populations.
  3. Even if there is some causal role of neutering in the occurrence of these conditions, it is not the only or primary cause. Genetic variables and environmental triggers have been identified for many of these conditions, so any role played by neutering is just one of multiple factors to consider in the genesis of these conditions.
  4. These conditions are mostly quite uncommon, and any increase in risk that might be associated with neutering has to be balanced against the established benefits of neutering to the health of individuals and to the pet population as a whole.

Bottom Line
This paper adds some useful information to the complex and ongoing assessment of the risks and benefits of neutering. It does not establish that neutering causes autoimmune disease, and it is not justification for dramatic changes in neutering practices. However, it support continued study and consideration of the potential negative effects of neutering on the immune system.

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AVMA Policy Cautions Vets about Unproven Stem Cell Therapies

The American Veterinary Medical Association (AVMA) is the main professional organization for veterinarians in the United States. It is not a government or regulatory body, but it does sometimes promote policy statements or guidelines intended to encourage or discourage certain practices by veterinarians. In general, I have been disappointed in the unwillingness of the AVMA to confront the danger pseudoscience presents for veterinary patients, clients, and the integrity of our profession.

For example, despite the clear statement of its own Council on Research acknowledging that, “there is no clinical evidence to support the use of homeopathic remedies for treatment or prevention of diseases in domestic animals” the AVMA House of Delegates overwhelmingly rejected a resolution identifying homeopathy as an ineffective therapeutic intervention. This was a pure case of politics trumping science and of a political organization refusing to protect the public from quackery because doing so would discomfit part of its constituency.

Similarly, the AVMA House of Delegates admitted the American Holistic Veterinary Medicine Association (AHVMA), the most prominent advocacy organization for pseudoscientific medical practices, as a constituent organization in 2013. This was based solely on such criteria as having enough AHVMA members who were also AVMA members, and the move ignored the blatant promotion of pseudoscience and untested or clearly ineffective treatments that is the main reason for the AHVMA’s existence.

Given that the AVMA has not been very strong or consistent in promoting science-based standards for veterinary medicine, I was pleasantly surprised by the recent AVMA position statement on stem cell therapies. I have written about stem cell therapies frequently. It is a promising area of research that, unfortunately, has been promoted and put into widespread use far ahead of appropriate scientific evidence establishing safety and efficacy for particular methods and indications.

The FDA has essentially chosen not to exercise its regulatory authority over veterinary stem cell therapies so long as they involve cells taken from and given back to the same individual and are not used in food animals. As a result, many stem cell products are legally available that have never been properly tested to show they do more good than harm. I am quite optimistic about the potential for stem-cell-based therapies to provide useful therapeutic tools eventually, once appropriate research is done, but for now they are essentially an uncontrolled experiment on individual patients.

The AVMA, uncharacteristically, appears to largely agree with this position:

While regenerative medicine holds promise of improvements in the treatment of a variety of diseases, many of which lack adequately effective treatments, questions remain…While data continue to accumulate suggesting therapeutic benefit from regenerative medicine, published peer-reviewed studies definitively documenting benefit are still lacking for many diseases. Nor has a scientific consensus for stem cell type, stem cell origin, dosage, transfer media, or method of administration been developed for each disease being treated. Despite these scientific insufficiencies, the adoption of regenerative medicine in the veterinary profession has grown rapidly. Unfortunately, some therapies being propounded and the processes and equipment being sold have outpaced the science which supports them.

Of course, like any fundamentally political organization, the AVMA has to try to please everyone, even when that results in an internally inconsistent position. For example, the policy is quite clear about the importance of validating stem cell therapies with proper research evidence before utilizing them:

Regenerative therapy protocols should be formulated from evidence-based medicine. Veterinarians should refrain from recommending regenerative medicine protocols for which documented benefit has not been shown by clinical trials.

Regenerative therapies should utilize systems, equipment, and processes which have been adequately validated to produce therapeutic cell numbers, documented cell types, adequate cell viability, and sterility. The use of systems without such validation poses unnecessary risk to the patient, compromises treatment successes, impedes collection of therapeutic data, and exposes the attending veterinarian to potential liability.

Veterinarians engaged in the use of regenerative medicine and vendors of cell products, equipment, laboratory services, and processes should refrain from making claims in client communication, advertising, or websites that are not fully supported by peer-reviewed, published data.

Since no extant stem cell therapy can meet these criteria, effectively this should mean using stem cell treatments only as part of a clinical trial research or, perhaps, as a last-ditch treatment in desperate circumstances with full disclosure to clients that the treatment is untested and experimental. That, of course, is not at all how stem cell companies and veterinarians typically present these treatments. And the AVMA weakens its own policy by not being willing to directly discourage the use of such treatments by veterinarians. Throughout the policy it is assumed that veterinarians will continue to use these treatments despite the absence of the kind of evidence the AVMA suggests should be a prerequisite for their use:

The AVMA supports the continued scientific development of these modalities while at the same time encouraging its members to employ caution with respect to their use.

…it is incumbent upon veterinarians engaged in regenerative therapies to be well versed in the emerging science of the field in order to successfully select the specific therapeutic protocols, processes, equipment, and vendors most likely to result in clinical benefit for their patients.

Despite this equivocation, however, it is encouraging to see the AVMA clearly acknowledge that the evidence base is not yet sufficient to justify claims of safety and efficacy for veterinary stem cell therapies and that their use is not supported by adequate, appropriate science. Hopefully, this will lend some weight to the voices of caution in the profession trying to restrain the proliferation of stem cell therapies until we have sufficient reason to believe they are helpful and not harmful.

 

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Evidence Update: Music and Anxiety in Dogs

It has become quite popular to recommend music as a method of reducing the stress and anxiety of dogs in environments likely to be stressful for them, such as veterinary hospitals and shelters. I’ve reviewed the evidence concerning the effects of music in dogs (1, 2), and in general it is intriguing but not yet very convincing. Some studies show some potential effects, others don’t. Most studies have a significant degree of subjectivity to their measures of effect, and there is little consistency to what music is used and how it is presented. Overall, it is unlikely that playing music in veterinary settings does any harm, but it is unclear whether it does any good.

A new study has recently been published which adds a bit of evidence to this debate.

Engler WJ. Bain M. Effect of different types of classical music played at a veterinary hospital on dog behavior and owner satisfaction. J Amer Vet Med Assoc. 2017;251(2);195-200.

This study looked at healthy dogs and those with non-urgent medical problems seen at the community practice service of a veterinary college. In brief, the study randomly assigned dogs to be examined in rooms with classical music, the same music modified by a private company that claims to make it more appealing or effective for dogs, and no music at all. Owners and veterinarians then evaluated the level of anxiety, anxiety-related behaviors, and aggression in the dogs. Obviously, the study was not blinded since everyone participating was aware of whether or not music was playing.

The study was clearly negative, finding no differences between the three groups in any measure of anxiety or aggression. This lack of difference between the treatment groups held for both subjective behavioral measures and for objective measures such as temperature and heart rate. The only statistically significant difference identified was that owners felt their dogs were less anxious in the examination room than in the waiting room (regardless of whether music was played) and that owners were more satisfied with their visit when the original classical music was played than with the modified music or no music at all.

Certainly, no single study is ever the last word on any complex medical subject, and while this was a well-designed experiment, like all clinical research it has limitations. Direct comparison with other studies is difficult due to the differences in music choice, study population, study conditions, and many other factors. Nevertheless, this study does weaken the already tentative and inconsistent support for significant anti-anxiety benefits in dogs from the playing of music in veterinary settings.

Of course, both owners and clinicians liked the classical music, which may be reason enough to play it in this type of setting. Reducing human anxiety and improving client satisfaction are appropriate goals for environmental manipulation in the veterinary clinic. And as the authors suggest, improvement in the anxiety of canine patients could possibly be achieved through reducing the anxiety of their owners, regardless of whether the music has any direct benefits to the canine patients. Still, it is important to recognize that such intervention may effect people in one way and dogs in another (or not at all), and we have to be wary of assuming our patients will benefit simply because we like it. We also have to be mindful of the caregiver placebo effect, especially with unblinded studies of interventions with subjectively measured effects.

There were a couple of other interesting tidbits in the paper. One unsurprising finding was that owners rated their dogs’ anxiety significantly higher than the veterinarians did. Owners obviously have a more personal stake in their dogs’ reactions to the veterinary environment and are likely more sensitive and negatively affected by signs of anxiety in their pets than veterinarians, who likely view a certain amount of anxiety as normal for the situation and not a cause for concern.

The paper also illustrated how difficult it is for researchers not to put the most positive possible spin on the results of their study. This was a well-designed and reported study, and the authors deserve great credit for publishing and fully reporting negative results. Negative studies are critical to an accurate, balanced understanding of the effect of treatments, yet they are often not published, due to bias on the part of researchers and journals. As a result, the literature often presents an inaccurately positive view of medical treatments.

In this paper though the data clearly showed no difference between any of the groups (and hence no effect of the music, except on owner satisfaction), the authors still began the discussion with the claim, “Results of the present study indicated that the playing of classical music in veterinary examination rooms had some positive effects on both dogs and their owners.” Anyone reading only the discussion section (as busy clinicians often do) would come away with the misconception that the study show benefits to music in terms of reduced anxiety even though it actually showed no effect at all.

Bottom Line
This paper adds a small piece of evidence to the overall subject of the effect of music on anxiety and behavior in dogs in the veterinary setting. The existing evidence is weak and inconsistent, so no clear conclusion can be drawn. In this study, there was no sign of any effect of classical music or the same music digitally altered with the goal of reducing stress in dogs. The question remains open, and definitive claims for or against the potential effects of music in this situation are not justified.

 

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Humans are Gross!

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Colbert Takes on the Goop!

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John Oliver on Vaccines: Brilliant!!

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Evidence Update and Review for Yunnan Baiyao

Introduction
In 2010 I first evaluated the Chinese herbal remedy known as Yunnan Baiyao, and I have reviewed additional evidence repeatedly since (1, 2, 3). So far, I have found little reason to believe claims that this remedy can stop bleeding in veterinary patients.

The ingredients are poorly described and not regulated or standardized, as is always the case with Traditional Chinese Medicine (TCM) remedies, and it is unclear if they have all been disclosed since the recipe is consider a commercial secret. TCM remedies have frequently been found to contain toxins and unreported pharmaceuticals, and some YB tested has been found to contain low levels of toxic substances. The TCM theory for how it works, involving movement of blood and mystical and ill-defined entities such as Qi, is inconsistent with established scientific understanding of physiology and blood clotting mechanisms. There are a number of more scientific theories for how the many chemicals in the product might affect bleeding, but none have been properly validated, and it is recommended primarily on the basis of tradition and anecdote.

Of course, despite the implausibility and lack of a clear mechanism, some clinical research has been done. In humans, the most recent review (from a source known to be biased in favor of TCM treatments, c.f. 3, 4) found some evidence of effect but also found that 1) most of the published research was of low quality and high risk of bias, 2) for some conditions the apparent effect disappears when lower quality studies are excluded, and 3) there is evidence of publication bias, in which negative studies remain unpublished creating an inaccurate impression of the true state of the evidence.

Such weak evidence might justify further research, ideally beginning with full identification of components, basic physiologic and pharmacologic studies, and then progressing through pre-clinical studies before clinical trials, as is the appropriate and expected course of investigating new medications. However, the current evidence does not really justify routine clinical use.

There is also some research into Yunnan Baiyao in veterinary species, and I have reviewed this in my previous posts. A couple of new small studies were recently presented at the American College of Veterinary Internal Medicine (ACVIM) annual forum, so I thought it would be worth reviewing those and summarizing the evidence to date.

Recent Studies
MacRae R. Carr A. The Effect of Yunnan Baiyao on the Kinetics of Hemostasis in Healthy Dogs. ACVIM  Forum, National Harbor, MD, 2017.

The goal of this study was to evaluate the effect, if any, of Yunnan Baiyao on laboratory measures of blood clotting and to look for any obvious, short-term adverse effects. Six laboratory dogs were given the product once a day for six days and clotting measures compared before and during the treatment. No harmful effects were reported, and there was no change in any measure of blood clotting.

Adelman L. Olin S. Egger CM. Stokes JE. Effect of Oral Yunnan Baiyao on Periprocedural Hemorrhage and Coagulation in Dogs Undergoing Nasal Biopsy. ACVIM Forum, National Harbor, MD, 2017.

The abstract begins with the statement, “The hemostatic efficacy and safety of Yunnan baiyao (YB) has been demonstrated across multiple species.” This isn’t actually accurate, and it reveals a pretty clear bias on the part of the investigators, which is relevant when looking at the methods and conclusions of the study.

Nineteen dogs having nasal biopsies were randomized to Yunnan baiyao or placebo before having nasal biopsies taken, which commonly causes some bleeding. A variety of outcome measures were evaluated, including laboratory values associated with clotting and assessments of how much blood was lost and how long it took the dogs to clot after biopsy. The report indicates appropriate blinding of investigators, caretakers, and statisticians. However, not all dogs were assessed with the same measures, which introduces some inconsistency and variability into the results.

Time for bleeding to stop- Exactly how this was measured is not described. The YB group ha d a slightly shorter BMBT (300+/- 12 seconds vs 367+/- 9 seconds). Several other variables (age, history of nosebleeds, blood pressure, and number of biopsies taken) were also associated with the BMBT, though the details were not reported.

BMBT (time for bleeding to stop from a standardized cut on the gums)- There was no difference between the groups.

TEG (a lab measure of clotting)- There was no difference between the groups.

Total blood loss- It is also not clear how this was measured. There was no difference between the groups.

Despite the failure to find an effect for most measures and the questionable clinical significance of the one difference seen (a difference from 46 to 88 seconds in the time for bleeding to stop), the authors naturally conclude that the study supports using YB routinely before this type of procedure.

Veterinary Evidence Summary
The table below lists all of the actual in vivo studies in veterinary species I have found. It also lists some key features of these studies that help evaluate how reliable their results are, including the number of animals studied, the use of key methods for preventing bias, such as randomization, blinding, and a control group, and the outcomes.

Table 1. Studies of Yunnan Baiyao in veterinary species.

Of these ten studies, 5 found no effect at all, and 2 others showed mixed results, with possible effects in some measures evaluated in the studies but not in others. Of the three fully positive studies, two did not report any of the major methods for controlling for possible bias and other sources of error.

Overall, this is a very unconvincing set of data. Even clearly ineffective methods can have some positive studies due to bias and error alone, so the lack of a clear, consistent pattern of expected effects is troubling. Not all of the studies used the same measures, so it is possible the product could have some clinical effects by some mechanism that doesn’t affect the laboratory measures of clotting usually used, but that is a big stretch.

It is also worth noting that the studies showing some effect didn’t look find any benefit in terms of clinically important outcomes, such as survival, need for transfusion, etc. Even under the most optimistic assessment of the evidence, it may be that Yunnan Baiyao speeds clotting in the case of small wounds by a few minutes, but this may not necessarily have any meaningful benefit for actual patients.

Bottom Line
The TCM rationale for using Yunnan Baiyao is part of an unscientific, quasi-religious belief system and cannot be accepted as a sufficient basis for using an otherwise unproven remedy on patients, especially when the ingredients in that remedy are not fully disclosed or regulated for quality, consistency, and safety. The more plausible scientific hypotheses for how Yunnan Baiyao might work remain unproven.

The clinical research evidence is mostly negative, and even positive studies have not shown any significant effects on clinically meaningful objective outcomes.  No clear evidence of harm has yet been found, though the limited nature of the evidence does not ensure that the product is truly safe.

 

References
Ogle CW, Soter D, Cho CH (1977) The haemostatic effects of orally administered yunnan bai yao in rats and rabbits. Comparative Medicine East and West 5:2, 155-160

Ogle CW, Dai S, Ma JC. The haemostatic effects of the Chinese herbal drug Yunnan bai yao: A pilot study. Am J Chin Med (Gard City N Y) 1976;4:147–152.

Graham L, Farnsworth K, Cary J (2002) The effect of yunnan baiyao on the template bleeding times and activated clotting times in healthy ponies under halothane anesthesia. Journal of Veterinary Emergency and Critical Care 12:4; 279; 2002 (abstract only)

Epp TS, McDonough P, Padilla DJ, et al. The effect of herbal supplementation on the severity of exercise-induced pulmonary haemorrhage. Equine and Comparative Exercise Physiology 2005;2:17-25.

Fan C, Song J, White CM. A comparison of the hemostatic effects of notoginseng and yun nan baiyao to placebo control. J Herb Pharmacother 2005;5:1–5

Murphy LA, Panek CM, Bianco D, Nakamura RK. Use of Yunnan Baiyao and epsilon aminocaproic acid in dogs with right atrial masses and pericardial effusion. J Vet Emerg Crit Care (San Antonio). 2016 Sep 26. doi: 10.1111/vec.12529. [Epub ahead of print]

Frederick J, Boysen S, Wagg C, Chalhoub S. The effects of oral administration of Yunnan Baiyao on blood coagulation in beagle dogs as measured by kaolin-activated thromboelastography and buccal mucosal bleeding times. Can J Vet Res. 2017 Jan;81(1):41-45.

Lee A. Boysen SR. Sanderson J. et al. Effects of Yunnan Baiyao on blood coagulation parameters in beagles measured using kaolin activated thromboelastography and more traditional methods. International Journal of Veterinary Science and Medicine. 2017;5(1):53–56.

MacRae R. Carr A. The Effect of Yunnan Baiyao on the Kinetics of Hemostasis in Healthy Dogs. ACVIM  Forum, National Harbor, MD, 2017.

Adelman L. Olin S. Egger CM. Stokes JE. Effect of Oral Yunnan Baiyao on Periprocedural Hemorrhage and Coagulation in Dogs Undergoing Nasal Biopsy. ACVIM Forum, National Harbor, MD, 2017.

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Evidence Update: Vaccination and Autoimmune Disease

One of the potential adverse effects of vaccination is the triggering of autoimmune diseases in susceptible individuals. There is some evidence in humans, for example, that the routine MMR vaccine (which prevents measles, mumps, and rubella) can trigger an autoimmine disease, called ITP, which destroys platelets and reduces a patient’s ability to form normal blood clots. The evidence suggests this occurs in roughly 1-3 children for every 100,000 MMR vaccinations.

While this is a real and serious risk, it is important to note that not only are the diseases prevented by this vaccine a much greater risk, but it turns out that these disease can also cause ITP and at a much higher rate than the vaccine (1 child out of every 3,000-6,000 cases). Therefore, the benefit of vaccination is clearly greater than the risk in this case.

There is, as always, far less data to determine what, if any, risk of autoimmune disease there is in vaccination of dogs and cats. Both ITP and IMHA, another autoimmune disease involving destruction of red blood cells, occur in dogs, and these have been reported to follow vaccination. However, the relevant research literature is sparse, flawed, and inconsistent. The bottom line from my previous review of the literature was this:

Bottom Line

  • Little evidence vaccination causes IMHA/ITP
  • No consistent temporal association
  • Data are weak
  • Overwhelming majority of vaccinated animals do not develop these diseases
  • Infection can be a greater risk for IMHA/ITP than vaccination
  • Don’t vaccinate more than necessary
  • Don’t vaccinate less than necessary
  • Don’t avoid vaccination out of fear of IMHA/ITP

A small piece of additional evidence was recently presented at the American College of Veterinary Internal Medicine (ACVIM) 2017 Forum.

Moon, AKB. Veir, J. Vaccination Behavior and Adverse Events in Dogs Treated for Primary Immune-Mediated Hemolytic Anemia (Abstract HM17) ACVIM Forum, National Harbor, MD, 2017.

This study surveyed the owners and veterinarians of dogs who had been diagnosed with IMHA. Such dogs are frequently not vaccinated once they recover from the disease because of concerns that vaccination might trigger a relapse. This is often done even when there is no specific reason to think vaccination triggered the initial episode. It is a reasonable precaution, but since it is not clear that vaccination actually is a risk factor for ITP or IMHA, it is possible that these dogs are being left vulnerable to infectious diseases unnecessarily.

In this small study, survey results were available for 44 dogs. There were several relevant findings:

  1. The average time from most recent vaccination to the initial onset of IMHA was 351 days. Such a long period makes it unlikely that vaccination was a major trigger for IMHA in many of these dogs. It still might have been in the subset who were vaccinated closer in time to the onset of their illness. This study found no such temporal relationship, but a different study design would be necesary to confirm that.Previous studies have found only a small proportion of IMHA cases received vaccinations in the 2-4 weeks before the onset of their illness, and most found no difference in recent vaccination rates between dogs who developed these diseases and comparison dogs who did not. So far, the overall data suggests that vaccination is rarely a proximal trigger for these autoimmune disease, though whether they play a role as an overall risk factor isn’t known.
  2. About half of the dogs had not been vaccinated since their IMHA diagnosis. This is consistent with the common practice of many vets to eschew vaccination in dogs who have had a history of autoimmune disease. However, about half of these dogs did receive vaccines after their diagnosis, and almost all of these were rabies vaccines. This is likely because rabies vaccination is legally required in most of the U.S. and exceptions are not always allowed for dogs with a history of autoimmune disease.Only 2 of the 21 dogs who were vaccinated following their IMHA had any reported adverse reaction. These two reactions were typical of the acute hypersensitivity reaction seen with vaccination. No relapse of IMHA or other autoimmune disease was reported in the vaccinated dogs. This suggests that such dogs may not be more sensitive to vaccination than other dogs, though again the size and methodology of this study is not adequate to demonstrate that with any certainty.
  3. Though this is just a small bit of data, it does fit into the larger context of existing evidence in dogs, and the much more comprehensive evidence in humans, suggesting that vaccines play an extremely small role, if any, in triggering such autoimmune diseases, While caution is warranted, and certainly unnecessary vaccination should be avoided on principle, there is no justification for extreme and confident claims that vaccines are a major cause of these autoimmune diseases in our pets or that what risk may exist outweighs the benefits of appropriate vaccination.
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