Medical Reasoning vs. A Diagnostic Manual

 

I taught a course on medical decision making and how not to mistake a physical illness for a psychiatric disorder from about 1990 to 2002. The main theorists at the time were all internists – Stephen Pauker, Jerome Kassirer, Richard Kopelman, David Eddy, and Harold Sox.  I read their papers and attended their courses.  State-of-the-art in those days involved extensive differential diagnosis, Bayesian analysis, and an awareness of an extensive list of potential cognitive biases. I had been impressed with the need for pattern matching and pattern completion and incorporated all those elements into my course.  I eventually pared it down to about 9 sections in the lecture notes illustrated with case vignettes.

My original emphasis was to recognize that there are several considerations when assessing the medical aspects of psychiatric care.  The first is the medical stability of the patient.  Can they be cared for on a psychiatric unit or do their medical needs require medicine or in some cases surgery?  Do they need referral to a generalist of specialist?  This is more complicated than it sounds because the patient is there seeing a psychiatrist for what is supposed to be a psychiatric problem.  But that presentation is complicated by several factors including most patients have no primary care physician and no routine health care maintenance. Many will come into the emergency department concerned about a medical problem but get sent to psychiatry. In that situation, people still get all of the acute medical illnesses including heart attacks, strokes, asthma attacks, pulmonary emboli, seizures, pneumonia, meningitis, encephalitis, and acute cholecystitis to name a few.  Many exhibit non-specific behaviors like agitation, crying out, aggression, or unresponsiveness that can be due to either a psychiatric disorder or a medical problem.    

The second is a psychiatric presentation of a physical illness in a communicating patient. The classic presentations involve brain pathology that is infection, inflammatory, vascular, trauma, or neurodegenerative.  Systemic endocrinopathies and inflammatory disorders are a close second. 

Finally, there is the patient with a clear psychiatric disorder who has intercurrent illness that is or is not known.  Examples that I have seen many times include current or new onset diabetes mellitus, profound anemia usually secondary to an upper or lower GI bleed, dermatology conditions that have often been neglected, symptomatic nutritional deficiencies (B12, folate, D), sexually transmitted diseases, complications of substance use like cirrhosis, and various acute and chronic infectious diseases.

Given that large population with diverse medical and psychiatric problems as well as diverse presentations that can include denying any physical problems – I typically reviewed how the diagnoses occurred.  Pattern matching was the fastest.  The physician has seen a physical finding, lab, behavior, etc – many times before, knows what it is, diagnoses it and treats it.  A good example is a rash.  Dermatologists are rash experts and can correctly classify rashes and marginal cases much faster than primary care physicians (4).  The same is true for diabetic retinopathy and ophthalmologists (5).  Until you have seen a person with severe mania or catatonia, neuroleptic malignant syndrome, or serotonin syndrome it is less likely that you can diagnose the conditions by reading criteria in a book.  Patterns are important for all medical specialists.

On the other end of the spectrum is the contemplative side of diagnosis.  There are several possible diagnoses, and it takes additional data, thought, and reasoning to come to a final diagnosis. Every medical student does this in their initial internal medicine rotation.  There is encouragement to produce a list of many diagnoses that might account for the presentation – but even as the case is being recorded or presented that list rapidly narrows to the apparent diagnosis.

In psychiatry, it may take much more data and collateral information to make a specific diagnosis at the initial presentation.  First episode psychosis (FEP) is a case in point. It is very important to determine what the symptoms onset was like and whether there were any associated mood symptoms or substance use problems. The patient may not be able to describe the phenomenology and depending on the circumstances treatment may be initiated while the diagnostic process is ongoing.  Teaching about the diagnostic process, we would spend time discussing what that might look like combined with a recursive approach to the patient and an awareness of cognitive and emotional biases.  I provided several examples of non-psychiatric physicians making errors due to emotional biases.

Since my course, the literature on medical decision making has changed to some degree.  There is some literature that addresses expertise in general at both the level of cognitive psychology (1) and neurobiology (2).  The general approaches have been to analyze expertise and diagnostic reasoning from the perspective of typical domains (cognitive, perceptual, motor) or to look at a general model and how that has developed over the years.

A dual processing model (3) is generally considered the best current representation of clinical reasoning and decision making.  In this model, there is a fast automatic, heuristic, and unconscious system called Type 1 and a slower conscious, analytical, and effortful system called Type 2.  Additional properties are indicated in the following table.

Parameter	Type 1	Type 2
Speed	Fast, automatic, unconscious/preconscious, little effort	Slow, deliberate, analytical, varying degrees of effort
Control	Minimum control, similar to automatic associations in everyday life except more focused	Control over thought process and direction
Systems and Processing	Pattern recognition and completion, implicit learning, access to long term memory	Working memory and manipulation of data in working memory, planning and reasoning based on that data
Memory Systems	Long term memory	Short term and working memory
Localization	-Orbitofrontal cortex (OFC) -Basal ganglia (caudate, putamen) -Insula -Anterior cingulate cortex -Amygdala -Hippocampus	-Dorsolateral prefrontal cortex (DLPFC) -Left inferior frontal gyrus -Middle frontal gyrus -Inferior parietal lobule -Precuneus -Hippocampus

 A clinical example of Type 1 reasoning is when a trained clinician recognizes a classic presentation of a medical illness, diagnosis, or finding.  An example I frequently use is when one of my Infectious Disease attendings who was an expert in Streptococcal infections recognized characteristic rash from across the room on a patient we were consulted for a different problem.  He made the diagnosis within seconds and told us how it could be confirmed.  In studies of the process the orbitofrontal cortex and limbic connections are activated.  Training is a critical element, especially seeing a maximum number of patterns and their variations.  Although the characterization is that this is a fast and automatic process, there is some room for deliberation.  For example, recognizing or attempting to classify equivocal cases without classic presentations. 

Type 2 reasoning is considered more of the typical process of differential diagnosis.  The findings are compared, analyzed, and accepted or rejected based on additional data and clinical judgment. This process is thought to localize in dorsolateral prefrontal cortex (DLPFC) the home of the working memory where data can be maintained and analyzed.  The left inferior frontal gyrus contributes to rule-based reasoning and hypothesis testing.  A clinical example from my experience is the case of the agitated stuporous patient.  These cases require a great deal of caution because they are most likely to represent a serious or life-threatening illness.  It requires a clinician who knows how to examine patients with stupor or coma and rapidly makes sense of the history and findings. It is a problem that can rarely be solved by Type 1 reasoning alone due to a fairly non-specific presentation.  Some of the critical points for hypothesis testing will be signs of increased intracranial pressure, purposeful response to painful stimuli, eye movements, reflex and musculoskeletal exam abnormalities, signs of infection, and meningeal signs.

The interaction between Type 1 and Type 2 systems is not necessarily sequential but it can be with the Type 1 system matching patterns that lead to hypothesis generation.  There is some evidence that in most clinical situations most of the diagnoses occur with Type 1 reasoning.  Experts can operate at the level of Type 1 reasoning due to extensive experience.  There is not necessarily a hard separation based on the properties in the table. Some hypothesis testing can occur at both levels.  Both systems are commonly grounded in both the limbic system and the hippocampus.

The human brain is capable of parallel distributed processing of data or information.  This means that there are many processing areas in the brain that are interconnected and they can all be working at once.  The modern conceptualization is brain networks that are active processing areas connected by white matter tracts widely distributed through the brain.  

That brings me to my model of diagnostic reasoning (see lead graphic and click to enlarge).  It is based on the course I taught, neuroanatomy and neurology, and what I have observed clinically. When I was talking about pattern matching 20 years ago based on my observations and reading studies in dermatology, ophthalmology, radiology, and pathology – the term seemed to fade rapidly from the diagnostic reasoning literature.  It was revived somewhat by the more recent focus on AI and comparison of that modality to humans.

There was a lull in Bayesian analysis after the invention of computerized programs like Quick Medical Reference (QMR) and Iliad.  They were designed to facilitate medical diagnoses by providing an exhaustive list of findings and their probabilities. These were 20^th century personal computer programs and not AI.  A study of these and 2 additional programs suggests that the programs got 52-71% of 105 diagnostic cases correct with 19-37% being the mean portion of correct diagnoses (6). Despite those figures the programs provided an additional 2 diagnoses per case that experts considered as relevant.  The authors recommended that the programs be used only by physicians who could include the relevant and exclude the irrelevant information provided by the programs.  The programs were discontinued without further modification or updates.  

That is the 8-mile-high view.  I plan to do a deeper dive into the neuroanatomy and neurophysiology.  But the clear reality of the situation is the ability to make a psychiatric diagnosis resides in the brain of a psychiatrist and not a classification manual or a checklist.   Manuals and checklists are crude approximations of some of the cognitive features that psychiatric experts possess.  Like all experts – skill will vary based on practice, exposure, and interest because of the effects on these brain systems.  But we are well past the point of equating what a psychiatrist does to a crude manual.  A manual never saved or treated anyone.  Further – the diagnostic reasoning process emphasizes elements that are important for education and training. It seems that in the past decades there has been a preoccupation with evidence-based research rather than the evidence itself. It does not do the physician or patient any good to be in a situation where that physician is unable to communicate with a person who is in a critical state and has no idea how to assess that problem.  Rearranging diagnostic criteria in a manual for the ninth or tenth time does not get you there.   

 

George Dawson, MD, DFAPA

Supplementary 1:   Before anyone says the diagram is too complex - it is a general diagram for any human diagnostician.  The main modifications for physicians and psychiatrists are the interactive aspects that include empathic comments, formulations, and numerous verbal interventions that other diagnosticians may not need to use.  The specifics about how these memory systems interact are not known at this point - I will be researching that over the next several months.  I borrowed the superposition concept from quantum mechanics - even though there are no wave functions for memory.         

 References:

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1:  Bilalić M.  The Neuroscience of Expertise.  Cambridge University Press. Cambridge, United Kingdom. 2017.

2:  Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J,  Frackowiak RSJ, Frith CD. 2000. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci USA 97:4398–4403.

3:  Norman GR, Monteiro SD, Sherbino J, Ilgen JS, Schmidt HG, Mamede S. The Causes of Errors in Clinical Reasoning: Cognitive Biases, Knowledge Deficits, and Dual Process Thinking. Acad Med. 2017 Jan;92(1):23-30. doi: 10.1097/ACM.0000000000001421. PMID: 27782919.

4:  Federman DG, Concato J, Kirsner RS. Comparison of dermatologic diagnoses by primary care practitioners and dermatologists. A review of the literature. Arch Fam Med. 1999 Mar-Apr;8(2):170-2. doi: 10.1001/archfami.8.2.170. PMID: 10101989

5:  Sussman EJ, Tsiaras WG, Soper KA. Diagnosis of Diabetic Eye Disease. JAMA. 1982;247(23):3231–3234. doi:10.1001/jama.1982.03320480047025

6:  Berner ES, Webster GD, Shugerman AA, Jackson JR, Algina J, Baker AL, Ball EV, Cobbs CG, Dennis VW, Frenkel EP, et al. Performance of four computer-based diagnostic systems. N Engl J Med. 1994 Jun 23;330(25):1792-6. doi: 10.1056/NEJM199406233302506. PMID: 8190157.

The Reality of Mental Illness is Much More Than Stigma

 

The reality of mental illness is much more than stigma.

It was a simple enough exercise.  Take about 90 seconds and say how mental illness affected you or your family.  Do it in groups of six and when I say time is up - move on to the next person.  The exercise was suggested by a conference speaker who said a similar disclosure during an interview had given him cause for concern about stigma.  The setting was a psychiatry meeting focused on stigma and we had all spent the morning listening to presentations on the topic. 

I really don’t like any professional meeting that resembles an encounter group and think it should be actively discouraged.  I think most people are like me – they go to professional meetings to hear experts and passively absorb information.  Further - I had just commented on the psychodynamics of shame a few weeks ago in the seminar that I coteach and defined the emotion has origins in disclosing information that could be embarrassing or that others would potentially criticize you for.  Of the 5 other people at my table – I knew one professionally and had just met two.  I was the oldest person (by 30 years) and the only man.  When they asked for a volunteer to start – I volunteered.  I did not think there could be a more severe story, was thoroughly habituated to telling it over the past 50 years, and knew that 90 seconds was not nearly enough time to describe how bad it really was.  I was right on all three counts.

“When I was 16 – I woke up one morning, went downstairs, and found my father dead.  Sometime after that my mother began to have severe episodes of mania. During these periods she disrupted the lives of various people in town to the point that police were called repeatedly.  After several police calls, she was taken to a state hospital where she usually spent a few months until she was stabilized and came home.  The manic episodes usually happened around Christmas time.  I was the oldest of 5 children so I tried to keep things together.  One-time things got so bad my brother and I had to call the police ourselves and they came down and told us that we wanted her ‘locked up like a chicken in a chicken coop’. When I was a kid, I was not ashamed about the situation – I was pissed off.”

Time was up.  I was not excessively emotional about what I just said – but realized it was a very sanitized version.   I did not describe the symptoms – extreme paranoia, irritability, impaired judgment, and anger.  The disruption usually involved telephone calls to public officials or the local radio station when she would announce her name and begin swearing at whoever was on the other end of the phone. At times she would get very angry and carry a knife around suggesting that we should stab her with it.  She would throw us out in the middle of winter.  We would come home from school and find that she had thrown all of our clothing out of an upstairs window and we had to pick it up off the ground.  We would find strangers at dinner or once - sleeping in the bathtub.  At night when we tried to sleep, she would play the stereo loudly all night long – usually Danny Davis and the Nashville Brass Christmas album – punctuated by screaming up the stairway at us.  It was hard to get up and go to school the next day after one of those nights.

On a road trip – my wife and I stopped in to see her.  The floor in the house was covered in about 6 inches of debris (from emptied drawers and closets).  She would throw a dash of Galliano onto the piles. She was making bizarre statements while circling the mouth of a hot jar of peanut butter with a piece of celery and then throwing the molten peanut butter over her shoulder.  My wife was upset and had to leave.  She sobbed for the next half hour as we travelled down the road telling me she was sorry for what I had to endure as a teenager.   

Even if I had time to add this additional information, that only scratches the surface of my mother’s experience with severe mental illness and the impact on the family.  I could write a book about what happened.  I am including it here just to illustrate the severity of the problem. These symptoms typically lasted for many months and some eventually became chronic.  As a psychiatrist – I have no illusions that her symptoms were anything but the product of a severe mental illness that was not treated well.  Her primary care physicians at the time were using a combination of amitriptyline and chlordiazepoxide – medications that psychiatrists would not use – even back then.  She eventually had access to a psychiatrist and was given lithium but it was not very effective.   

Stigma was not the main problem.  The main problem is that when a person has a severe mental illness like my mother it disrupts the relationship you have with them, That disruption is more severe when you are a kid and can’t make sense of it. It can affect your development and self-image.  The broken relationship can be permanent.  It is more like grief and loss rather than stigma and shame.  After a while my mother was not the same person any more. I no longer recognized her.  I could not remember what she was like before the onset of severe bipolar disorder.  I don’t think anybody did.  It had a more severe impact on my mother than anybody – but the emotional and interpersonal impact on everybody else was undeniable. 

All of the discussions of psychiatric diagnosis and treatment do not touch on that.  The bizarre discussions of antipsychiatrists and philosophers don’t even come close.  If you are saying that my mother was not mentally ill or did not have a “natural kind” of illness – you do not know what you are talking about.   If you are suggesting that she needed “trauma informed care” – not much better.  The unexpected death of her 43-year-old husband was certainly stressful, but the expected reaction is not decades of severe bipolar disorder.  It is bereavement, a universal experience, and all that involves. The lack of psychiatric care early in the course of illness could certainly have been a factor.  Her care rarely involved any of the family.  I don’t think any of her physicians knew how severe that impact was.  Despite the fact that she lived in the state where Assertive Community Treatment (ACT) was invented in the 1970s – it was a rural county and active outreach by case managers was decades away. 

My mother’s siblings and parents were very supportive. It would have been very difficult to have made it through many of these episodes without them.  It took an emotional toll on all of them as they tried to reason with her and convince her to do the right thing – like curbing excessive spending and trying to get some sleep.  The female members of the family – my grandmother and aunt were much more effective than the men.  They were able to react at a level that was not strictly emotional.  My siblings who remained in town or returned also had a stabilizing effect.  She had two very supportive female neighbors who spent hours talking with her despite the obvious problems.  But even with all of those efforts - my mother was never restored to her baseline.  Recovery to baseline was a goal I eventually adopted with every person I saw as a psychiatrist.    

What seems like a good interactive exercise to make a point about stigma is a very blunt instrument.  There is no doubt that some of the local officials discriminated against her (and us) because of the stigma of severe mental illness.  That was not close to universal by any means.  At a recent reunion I greeted a retired police officer who was very helpful to our family with his advice and reassurance.  He did everything possible to avoid confrontations with my mother when she was confrontational.  I never got the chance to thank the women in our neighborhood who helped but did when I sought them out in a crisis.  

Stigma can be an important factor – but the take home message from this essay is that the overwhelming fact about severe mental illness is the illness itself.  It has a significant emotional impact on everyone.  It disrupts interpersonal relationships – some of them permanently.   Some of that can be grieving the loss of a person who is never coming back.  It produces progressive isolation and alienation of the person with the illness. It is used rhetorically at the political level - blaming people with mental illness for violence and other ills of society.  In the current context treatment resources are being removed at the same time and that is probably the biggest societal ill.

At the rhetorical level stigma is also confused or conflated with clinical psychiatry. The ultimate societal outcomes of stigma are labelling and stereotyping to define the socially undesirable group.  Much of the rhetoric aimed at psychiatry promotes this fallacy.  Psychiatry operates at the level of disease reality.  The same level that affected my mother and my family.         

The reality of mental illness is much more than stigma.

George Dawson, MD, DFAPA.  

Supplementary 1:   I posted this about 10 years ago on stigma.  If you use the search box on the front page of this blog there are 15 or additional posts where I mention the term in one context or another.  Since then, the jargon has advanced to define separate types of stigma.  Per this CDC web page they define three types with their suggestions for combating it.      

 

Mental health stigma can take many forms (CDC)

• Structural stigma, involving laws, regulations, and policies that can limit the rights of those with mental health conditions.3
• Public stigma, which include negative attitudes and beliefs from individuals or from larger groups towards people with mental health conditions, or their families or health care providers that care for them.3
• Self-stigma, which comes from within the person with a mental health condition.3 People living with a mental health condition may believe they are flawed or blame themselves for having the condition.4

These definitions leave out important dimensions.  For example – where are the insurance companies, managed care industry, pharmaceutical benefit managers, and governments that limit mental health coverage and treatment resources like psychiatric beds?  At the same conference I attended one of the advocates talking about the state government no longer funding an important clubhouse resource for people with mental illness. 

The public stigma is devoid of the politics that defines people with mental illnesses either as violent criminals or freeloaders getting benefits that they are not entitled to. If you really want to cancel that stigma why not clearly identify where it comes from?

Self-stigma seems to be describing self-image, self, and self-esteem concepts that most psychotherapy providers learn how to address in that process.  

For all of these reasons the stigma seems to be a rhetorical stretch to me.  If you want to address these issues point to the source of the discrimination and don’t make it into a general societal issue.  It is a societal issue only at the level that society never confronts the real source of discrimination. 

Supplementary 2:  Self disclosure is generally discouraged in psychiatry.  If you are practicing it may lead to speculation about your personality, biases, or style of practice.  In the case of this exercise it was encouraged even though there were no assurances of confidentiality and no therapeutic intent.  It was clearly an exercise to illustrate a point that could have as easily been made with a thought experiment.  In this case my mother has been deceased for 22 years. My limited discussion of her illness is done here to illustrate the reality of severe bipolar disorder and the associated effects compared with the issue of stigma.          

3 Million Reads

 

I crossed over 3 million reads on this blog sometime around 10 AM this morning.  I check the counter a couple of times per day and the number was 3,000,423 at a current rate of about 150K per month.  Earlier this month I confirmed with the host that this number represented actual pages downloaded and read and it does.  The Google Blogger site that I use seems to underrepresent individual page reads but the aggregate count is still good.  My speculation is that this has to do with a more widespread adoption of VPNs but have no confirmation of that.

In terms of an accomplishment – blogging is a mixed bag.  I always approached my work like I was a researcher in addition to being a physician.  That involved an enormous amount of additional reading and research. At the same time, it conflicted with my primary role as a clinician and it really conflicted with my role as an employee.  When I say conflicted, there were basically two spheres.  First, the time constraint.  Luckily, I had chronic insomnia so I could spend the time not sleeping by doing research and reading.  Second, the lack of time to do formal research and write papers.  The research I did was on a case-by-case basis and to teach courses to medical students, graduate students, and physicians.  I came very close to working with a world class research team prior to retirement – but was with them for only a couple of years.  It did give me a glimpse into what would have been possible.

From a historical perspective, it also speaks to how information is disseminated in the modern age.  Herman Melville lived from 1819-1891.  He wrote Moby Dick a book considered to be one of the greatest novels of all time and yet only 3,000 copies were published during his lifetime.  I know this blog is certainly not Moby Dick – but it speaks to what is currently possible and the range of quality writing and in many cases overt misinformation that is now published for free and open to all of the public.  

It took a while to figure out my approach.  In the Pages section of this blog (upper right corner of the main page) I briefly discuss the how and why I write this.  At this point it is basically a continuation of my work life into retirement. When you have done something almost all of your adult life it is both difficult and unnecessary to stop it.  It also provides a perspective to analyze other problems and areas of life like art and politics. By perspective I am talking about a way of thinking rather than diagnosing. The only people I diagnose are the ones sitting across from me in an office who come in to see me as a psychiatrist.     

I get emails from psychiatrists and other health care professionals from around the world.  Some of these folks are quite renowned.  Some are critical because they disagree with my viewpoints, but most of them are interesting and have similar observations.  Early on I made the mistake of publishing remarks that were not only highly critical but personal attacks.  Since adopting a no trolls policy things have been going a lot more smoothly.  It was interesting that in 30 years of Internet discussions I adopted that policy 20 years ago in discussions but it took me a lot longer on this blog.  I attribute that to an unconscious wish for acceptance.

At this point I have a lot of things in the pipeline including a discussion of Margaret Atwood’s work, discussion of a paper on involuntary treatment that involves pseudorandomization, involuntary treatment for substance use disorders, the ongoing psychiatric hospital bed shortage and a Scandinavian study that looked at correlates of suicide and beds, a book review of Psychiatric Neurology, and much more.  I find that I have to work on several things at once to avoid writer’s block.  I am also working on a chemistry and physics perspective that I think adds to the dimension of spirituality and just received a book about how elements that we are all composed of are formed in stars.

I recently celebrated the milestone of one year volunteering as a co-instructor in a weekly 2 hour seminar on psychodynamic psychotherapy for psychiatric residents.  That has led me to think about areas of life and psychiatry that I would not have without that participation.  I am grateful to my co-instructors and the residents in that seminar for stimulating discussions and emails.  I am quite willing to volunteer for other academic projects – either teaching or research.

That is where things stand today.  I am grateful for the reads and comments and plan to keep writing this blog into the future whether I get to the 4M mark or not.

 

George Dawson, MD, DLFAPA        

Two million reads was almost exactly 2 years ago:  https://real-psychiatry.blogspot.com/2024/03/a-million-reads-blogging-milestone-of.html

Kava and Kratom and Kava

 

Kava is described in the ethnopharmacology literature as “the most important psychoactive agent in Oceania” (1).  The plant Piper methysticum is cultivated on most of the islands of Polynesia.  It is used both culturally and for medicinal purposes.  It grows as a low evergreen shrub and is grown on plantations. Roots are harvested, peeled, and chopped and then extracted with alcohol or other solvents.  In the ethnopharmacology literature the active compounds are referred to as kavapyrones and in the chemistry literature kavalactones.  Structures of the main kavalactones are illustrated in the above graphic.

Kava has been cultivated and consumed in this area since prehistoric times when it was brought to the Hawaiian Islands. The effect of consumption described over time has been that of an intoxicant - euphorigenic and increased socialization. Consumption is decreased as varying widely (p 446 of Ref 1) – from 0.5-1 liter per day to 1-2 liters at ceremonies to 4 liters per day.  There are some very high consumptions of up to 13 liters per day.  High doses produce signs of toxicity including rash, hair loss, yellow coloration of the skin, reddened eyes and decreased appetite. Where it has been studied up to 4 liters per day does not product this toxicity. The standard prepared beverages contain about 70 mg of kavalactones per 100 ml, so 4 liters at this concentration is roughly 308 mg of kavalactones.  That is slightly above the upper limit that many countries who regulate kava suggest. 

From a psychiatric perspective, the pattern of use suggests that kava can be a problematic substance for many.  Although the specific epidemiology of consumption is not detailed if most people consume 1 liter a day, toxicity occurs at greater than 4 liters a day, signs of toxicity occur at higher doses, and some people are consuming up to 13 liters per day that suggests uncontrolled use and a potential substance use problem.  

From an ethnopharmacology standpoint there have also been descriptions of hallucinations occurring from kava ingestion.  The most famous one was a vision by a chief that led to the Polynesians colonizing the Easter Islands in the 3^rd or 4^th century.  More recent descriptions suggest that additional intoxicants are needed to produce these effects and kava by itself is not a psychedelic.   

 I remember the 2002 FDA warnings about kava toxicity (2,3).  The second reference is particularly useful because it reviews what I consider to be extensive evidence that kava extracts are toxic in many ways including as a direct hepatotoxin (hepatitis, cirrhosis, liver failure), a carcinogen, at the level of effects on the cytochrome system and drug-kava interactions, and as intoxicant.  The conclusion is that there was no rationale for using it as a food additive.   Several countries banned the sale of kava based on this toxicology information.  Despite these reports of multiple incidents of hepatotoxicity more recent comments suggest that these were isolated incidents and not a reason to avoid kava.  It is not clear to me what happened in the interim because although these studies were not controlled, they met Naranjo scale probability of being the causative factor in kava induced hepatotoxicity. 

Despite the above information, kava remains generally available as a food or nutritional substance in most states.  It can be easily ordered online where it is sold as a remedy for anxiety and insomnia.  That stands in contrast to kratom that is illegal in 6 states, regulated in 30, and unregulated in 20 states. In contrast to the reviews that show clear hepatotoxic and carcinogenic potential there are current papers that question that research and reference papers with those results.  They suggest that the incidence of kava induced hepatotoxicity is “rare”, but the true epidemiology is unknown specifically the total population exposed.

That brings me to the recent paper from the Mortality and Morbidity Weekly Report (MMWR) on the combination of kava and kratom.   The paper uses the same methodology of a recent post just about kratom.  It analyzes data from the National Poison Data System (NPDS) on exposures to kava alone (single substance exposure N= 1,754) or kava and other substances (multiple substance exposures N=1,347) and the outcomes over a 15-year period to 2025. 

The remarkable trend in multiple substance exposures was a shift from using alcohol and benzodiazepines with kava to kratom.  This coincides with an increase in kava use following an initial fall in use with the 2002 FDA warning on hepatotoxicity.  In addition, even though kava is not regulated in the US there are regulation limits in other countries (such as 250 mg of kavalactones per serving) that are not applicable in the US.  Some products have multiple 250 mg servings per container.  The lack of US specifications implies that the hepatotoxicity of kava is considered idiosyncratic rather than a population wide risk despite the lack of any organized pharmacovigilance and a recent decline in the quality of regulatory agencies. 

Since kava affects the GABA_A  receptor and kratom is a mu opioid receptor agonist there is also the pharmacodynamic risk of combining those substances. In my previous most about kratom’s mu opioid receptor affinity, it seemed that a lot of the risk from that compound was attenuated by using preparations with lower concentrations of the active drug (leaves rather than concentrated liquid).  In the case of kava, it is a GABA_A receptor allosteric modulator that binds to sites other than the benzodiazepine receptor (the effect is not reversed by flumazenil) (10).  Since kavalactones are active at multiple sites rather than a single receptor K_is are not available (see definitions in Supplementary below).  Comparing the EC50 of kavalactones (1.3-150 μM) to benzodiazepines (25-72 nM) shows a difference of 1,000 fold in potency.  The lower potency is reflected in the need for greater amounts of kavalactones to achieve similar effects of sleep and anxiety as well as lower abuse and overdose potential. 

Despite the decreased potency, the MMWR shows that there are more hospitalization and serious medical outcomes and they are more likely with the kava-kratom combination (click to enlarge). 

 

A comparison with acetaminophen is useful.  Acetaminophen is widely used and effective analgesic.  52 million people in the US take it on a weekly basis.  It has a unique pattern of hepatotoxicity that accounts for the warnings on the bottle about dose limitations and use with alcohol.  There are 500 deaths, 38,000 hospitalizations, and 100-150 liver transplantations per year from acetaminophen toxicity.  General risk benefit considerations include the need for a better pain medication, reducing the number of combination medications to reduce the exposure, and the current number of people who safely take the medication (11).  An analysis by MMWR of acetaminophen using the same technique they used for both kratom and kava would be useful.  The highest level of kava consumption I could find in US estimate was 21M kava drinkers.  It is likely they are not drinking it on a weekly basis but that is unknown.  It is also unregulated in the US so the dose of kavalactones and warnings about synergism with alcohol, benzodiazepines, opioids, and other sedative hypnotics is not available.  

The combination of kava and kratom is giving a clear early signal that it can potentially lead to serious medical outcomes.  Despite the reputation of being a benign herbal medication kava is associated with deaths and rare but very serious hepatic complications.  Like most of these situations unless there is a different regulatory environment or people decide to stop experimenting it is likely that these complications will increase.  There is no reason to use either kava or kratom.            

  

George Dawson, MD DFAPA

 

References:

1:  Food and Drug Administration. Consumer advisory: kava containing dietary supplements may be associated with severe liver injury. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2002. https://wayback.archive-it.org/7993/20170722144010/https:/www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm085482.htm.

2. Food and Drug Administration. Scientific memorandum: kava (review of the published literature pertaining to the safety of kava for use in conventional foods). Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2020. https://www.fda.gov/media/169556/download

3:  LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. [Updated 2019 May 4].

Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/

4:  Teschke R, Wolff A. Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate? Regul Toxicol Pharmacol. 2011 Feb;59(1):1-7. doi: 10.1016/j.yrtph.2010.09.006. Epub 2010 Sep 18. PMID: 20854865.

5:  Stickel F, Shouval D. Hepatotoxicity of herbal and dietary supplements: an update. Archives of toxicology. 2015 Jun;89(6):851-65.

Over 100 cases of liver damage attributed to kava – many resulting in death or liver transplantation as of 2015.  Mechanism unknown.  Durg induced liver disease typically reverses by stopping kava.

6:  Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013 May 21;19(19):2864-82. doi: 10.3748/wjg.v19.i19.2864. PMID: 23704820; PMCID: PMC3660812.

7:  Pantano F, Tittarelli R, Mannocchi G, Zaami S, Ricci S, Giorgetti R, Terranova D, Busardò FP, Marinelli E. Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat. Int J Mol Sci. 2016 Apr 16;17(4):580. doi: 10.3390/ijms17040580. PMID: 27092496; PMCID: PMC4849036.

“On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury.”

8: Bleifuss W, Boley S, Bardwell J, Goebel C, Wilkinson J. Severe kava withdrawal managed with phenobarbital. Am J Emerg Med. 2025 Oct;96:298.e5-298.e7. doi: 10.1016/j.ajem.2025.06.016. Epub 2025 Jun 16. PMID: 40541460.

9:  Towers EB, Williams IL, Holstege CP, Farah R. Increase in Poison Center Reports Linked to Kratom-Containing Kava Products - National Poison Data System, United States, 2000-2025. MMWR Morb Mortal Wkly Rep. 2026 Apr 2;75(12):157-163. doi: 10.15585/mmwr.mm7512a1. PMID: 41926333; PMCID: PMC13046178.

10:  Chua HC, Christensen ET, Hoestgaard-Jensen K, Hartiadi LY, Ramzan I, Jensen AA, Absalom NL, Chebib M. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700. doi: 10.1371/journal.pone.0157700. PMID: 27332705; PMCID: PMC4917254.

11: Lee WM. Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away? J Hepatol. 2017 Dec;67(6):1324-1331. doi: 10.1016/j.jhep.2017.07.005. Epub 2017 Jul 20. PMID: 28734939; PMCID: PMC5696016.

 

Supplementary 1: Some definitions of receptor kinetics:

Ki (inhibition constant) is the equilibrium dissociation constant for an inhibitor binding to its target, representing the concentration at which 50% of the target is bound by the inhibitor at equilibrium in the absence of competing substrate.  A fundamental constant independent of experimental conditions.

EC50 (half-maximal effective concentration) is the concentration of a compound that produces 50% of its maximal response in a functional assay.

IC50 (half-maximal inhibitory concentration) is the concentration that produces 50% inhibition of a measured activity.

Both EC50 and IC50 can vary with experimental conditions.

Graphic Credits:

The kavalactone graphic was done my me according to this method.

The MMWR graphic is directly from reference 9 and is in the public domain as a US government publication. 

Is The Next Zoonosis Lurking In Your Back Yard?

 

I just had a recent adventure with rabbits.  Like the experience of many suburbanites, rabbits like to eat all our ornamental vegetation. My wife oversees that department, and she does not like to see that vegetation depleted. She has tried all the repellants and the rabbits keep coming.  She has talked about shooting them like her father used to, but I convinced her that was not a good idea.  She settled on the idea of live trapping the animals and releasing them in an area far away from the house – like a park or wildlife reserve.

I researched the legality of it all.  I was surprised to find out that rabbits are considered a nuisance animal in the state of Minnesota.  As such you can kill them by various means other than poisoning without a license and at any time. There are obstacles to both relocating rabbits or how to dispose of them. I contacted both the county and city natural resource departments. They told me it was illegal to relocate rabbits onto city, county, or state lands including parks and wildlife areas.  The officials confirmed that I did not need a hunting license to kill them, but that if I did kill a rabbit, I needed to report it to the DNR.  I did not let anyone know I thought that killing a rabbit was bad karma and I had no intention of killing them.

I was advised that if I did kill a rabbit, I needed to handle it with nitrile gloves and double bag it in plastic.  Even then I must contact my garbage hauler to make sure that I could dispose of it in the trash. There were no further instructions from officials on the next step if the garbage hauler refuses to take it – but based on how the conversations were going I thought it was probably digging a deep hole in the yard.

Minnesota is populated by one true rabbit species – the Eastern Cottontail (Sylvilagus floridanus) and two hare species – the Snowshoe Hare (Lepus americanus) and the White-tailed Jack Rabbit (Lepus townsendii).  The hares are probably more common in the north.  The defining characteristics of rabbits versus hares include fewer chromosomes (44 versus 48), altricial birth state versus precocial, shorter gestation (30-31 days versus 42 days), smaller bodies and shorter ears, highly social versus solitary, and softer food preference (grass and leafy vegetables opposed to bark, twigs, and buds).  An altricial birth state means offspring are born in a state where they are unable to feed or regulate body temperature and as a result need a prolonged period of close parenting. In the past 10 years there have also been cladistic analyses based on nuclear and mitochondrial DNA.  Like all taxonomy there is some mismatch of classification.  Jackrabbits are hares and Rock hares are rabbits.     

Even before I heard those biosecurity measures from public officials, I researched the issue of rabbit to human disease transmission (1).  Domestic pet rabbits were noted to spread the expected pathogens like E. coli, Salmonella spp, Yersinia pseudotuberculosis, and Cryptosporidium.  They can also be a source of Hepatitis E.   Pasteurella multocida and Bordetella bronchiseptica can be spread as respiratory infections in humans.  Rabies was detected in one group of rabbits thought to have been infected by a wild animal.  Dermatophytes and rabbit fur mites can cause localized infections in humans.

Wild rabbits harbor Francisella tularensis the infectious bacteria causing tularemia. Tularemia is a systemic multisystem disease that can be difficult to diagnose and treat. In the worst case it can cause shock and death.  It has also been implicated as an agent that could be used for bioterrorism.   Rabbits can also have Babesia spp and Anaplasma phagocytophilum the infectious agents that cause babesiosis and human granulocytic anaplasmosis.  

Babesiosis is caused by the obligate intraerythrocytic protozoan parasite Babesia microti (2).  Severity of the illness is related to degree of parasitemia (concentration of parasites in the bloodstream) and host factors that lead to compromised immune response including age. In the extreme cases it can lead to life threatening complications that require acute care like acute renal failure, disseminated intravascular coagulation (DIC), congestive heart failure, acute respiratory distress syndrome (ARDS), and others.

Human granulocytic anaplasmosis is caused by intracellular bacteria from the Anaplasmataceae family – in this case Anaplasma phagocytophilum (3).  It is a tick-borne disease meaning that the major reservoir for the agent is small mammals who transmit it to humans via a tick vector.  Most people who are infected present with an acute flu-like illness that can progress to involved multiple systems (rash, pneumonitis, myocarditis, meningoencephalitis, secondary infections, coma).

Most of the infections identified from rabbits come from direct contact, contact with infected surfaces, and contact with blood, feces, or other bodily fluids. People raising rabbits as pets, as a food source, or hunters would appear to be at highest risk and the suggested biosecurity measures would be protective.  In talking with the local wildlife officials their concern was that rabbit relocation could be a significant source of disease spread – specifically Rabbit Hemorrhagic Fever – a viral illness that results in most rabbits dying of hepatic necrosis 48-72 hours post infection. 

Rabbit Hemorrhagic Disease Virus (RHDV) was first described in China in 1984 and has spread worldwide (4).  It is a small non-enveloped RNA virus about 40 nm in diameter.  The genome is about 8 kilodaltons is size. It is taxonomically classified in the Calciviridae family.  That family has 11 genera (Norovirus, Nebovirus, Sapovirus, Lagovirus, Vesivirus, Nacovirus, Bavovirus, Recovirus, Salovirus, Minovirus, and Valovirus) (5).  Of the major genera Norovirus and Sapovirus cause acute gastroenteritis in humans.  The etiological agent can only be distinguished by laboratory testing. The Lagovirus genus also includes European brown hare syndrome virus (EBHSV) (6).  While the original RHDV virus was species specific – there is a newer strain (RHDV2 (GI.2) that infects both rabbits and hares and is lethal to both.

All these details build a compelling story far beyond suburban landscapers wanting to protect their plants.  The recent pandemic and likely crossover of a bat coronavirus into the human population as well as past crossovers like human immunodeficiency virus and avian influenza highlight the dangers of proximity to animals with high levels of infection. There have been two recent worldwide epidemics of rabbit hemorrhagic disease virus (RHDV) initially from 1984 to the 1990s and more recently from 2010 to present.  At no point in my medical career was I made aware of this viral spread despite hearing about viral spread in other species like elk wasting disease. Evolutionary biologists have suggested the RHDV virus has been in existence for 150 years (7-10). 

The pathogenesis of the virus is known at this point. It causes apoptosis of hepatic cells and hepatic necrosis.  One of the main protective mechanisms’ antioxidant suppression of oxidative stress is overwhelmed.  Apoptosis of endothelial cells leads to procoagulant activity and disseminated intravascular coagulopathy (DIC) and resulting hemorrhage and shock. RHDV2 has enhanced virulence factors and previous infection with RHDV does not confer immunity.     

The risk of RHDV crossover to human is estimated to be low based on several factors.  First, in a large study of human exposure of 269 people exposed to infected rabbits there were no episodes of disease or antibody formation to the virus in any of those people.  Second, there is continued host specificity to lagomorphs with limited documented crossovers to other species (Alpine musk deer, Eurasian badgers).  Third, there is limited ability for viral replication in other mammalian models including mice with immune deficits (interferon 1 receptor deficits). Fourth, high specificity for histo-blood group antigens (HBGAs) (11-12) – that is the virus binds to rabbits specific HBGAs and cell receptor specificities.  Fifth, the molecular biology of the rabbit versus human HBGAs are such that there are no functional binding sites for RHDV virus.

In my efforts to understand why rabbits are considered a nuisance animal and a biohazard, I uncovered an interesting set of factors. Given the rabbit exclusive pandemics that have occurred I can understand why wildlife officials are concerned about the spread of disease from transported rabbits.  The concern about disease transfer to humans from feces, saliva, other bodily fluids, and rabbits carcasses also makes sense. One of my colleagues pointed out that there is a tularemia vaccination for dogs.  Other rabbit predators may be as susceptible as humans to many of these diseases and they are probably relatively protected from RHDV because of the aforementioned factors.  This post also highlights the need for veterinary virologists and epidemiologists to track the evolution and crossover potential of these viruses.   That used to happen in an organized way for Influenza viruses through the World Health Organization (WHO) but the current anti-science and anti-medicine administration has pulled the US out of that organization and had probably negatively impacted the viral surveillance necessary to prevent zoonoses.

At the practical level, if you are a suburbanite interested in protecting your hastes from rabbits, barriers like wire cages are recommended by the public officials I talked with.  Be sure to check with them about live trapping and relocation or other means of controlling rabbits. The literature I reviewed on live trapping recommended always using gloves when handling the trap to avoid contaminants and prevent the transfer of human scent to the trap.  Rabbit waste and carcasses should also be avoided by homeowners and pets.  Some of the pathogens in the table are transmitted by ticks – so the same precautions to prevent Lyme Disease apply.   In terms of surveillance, your state department of natural resources is probably the best resource.   They directed me to the problem of RHDV that is not listed in the human literature but is an ongoing global problem for rabbits at the epizootic level.

The lesson from rabbits so far is that non-humans also have epidemics or epizootics. The only epizootics that humans seem to pay attention to affect domesticated animals or potential high risk crossover situations like avian influenza. Those contacts of humans and animals in suburbia bear watching both for the immediate threats and implications for handling biological materials – but also the potential long term consequences. (13-16).    

 

George Dawson, MD, DFAPA

Supplementary 1:  I thought this was an excellent graphic but could not figure out where to put it in the above essay. It is an estimate of worldwide mortality due to infectious diseases. Zoonotic origins are on the left of the diagram and non-zoonotic on the right.  The authors point out that boundary is not as clear cut as it seems since common causes of crossover like bats, rats, and mice occupy the same biosphere.  In the case of rabbits I would say the backyard is the same biosphere.  

60% of human diseases have animal origins.  Based on the lab origins rhetoric of the past few years Mother Nature is by far the most significant bioterrorist.  It also speaks to why any reasonable approach to prevent these outbreaks requires infectious disease and epidemiology expertise in both human and veterinary medicine.

The graph also contains the implicit information on the non-zoonotic side.  The increasing candida auris infections are thought to be due to man-made climate change.  Warm blooded animals were thought to have natural resistance to fungal infections based on higher body temperature where fungi could not survive. That evolutionary advantage is vanishing due to increasing ambient temperatures and fungal adaptation.  There are also 5 vaccine preventable diseases. There is an active anti-vaccination campaign that has reduced access to some of these vaccinations.         

Graphic is reproduced here via Copyright: © 2022 Weiss RA et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, CC BY 4.0 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  Original work is cited as reference 14.

Supplementary 2:  Map of outbreak of RHDV2 a variant that was first detected in France in 2015.  Top map is from the USDA and the bottom map is from reference 17 per Creative Commons Attribution 4.0 (CC BY 4.0) International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format.

Photo Credit:  Photo of an Eastern Cottontail rabbit that I took in my back yard.  I was 5 feet away and the rabbit did not move it just continued to stare at me.  This is highly unusual behavior for wild rabbits who are generally programmed to run explosively in circles to avoid predators.  Similar behavioral changes are often signs of illness in wild animals but this rabbit eventually started moving and hopped away.  

References:

1:  Cotton CN.  Zoonoses: Animals other than dogs and cats.  UpToDate.  Accessed March 31, 2026.  https://www.uptodate.com/contents/zoonoses-animals-other-than-dogs-and-cats

2:  Krause PJ.  Babesiosis: Clinical manifestations and diagnosis.  UpToDate.  Accessed March 31, 2026.  https://www.uptodate.com/contents/babesiosis-clinical-manifestations-and-diagnosis

 3:  Dumler JS.  Biology of Anaplasmataceae.  UpToDate.  Accessed March 31, 2026.  https://www.uptodate.com/contents/biology-of-anaplasmataceae

4:  Abrantes J, van der Loo W, Le Pendu J, Esteves PJ. Rabbit haemorrhagic disease (RHD) and rabbit haemorrhagic disease virus (RHDV): a review. Vet Res. 2012 Feb 10;43(1):12. doi: 10.1186/1297-9716-43-12. PMID: 22325049; PMCID: PMC3331820.

5:  Smertina E, Hall RN, Urakova N, Strive T, Frese M. Calicivirus Non-structural Proteins: Potential Functions in Replication and Host Cell Manipulation. Front Microbiol. 2021 Jul 14;12:712710. doi: 10.3389/fmicb.2021.712710. PMID: 34335548; PMCID: PMC8318036.

6:  Fitzner A, Niedbalski W, Kęsy A, Rataj B, Flis M. European Brown Hare Syndrome in Poland: Current Epidemiological Situation. Viruses. 2022 Oct 31;14(11):2423. doi: 10.3390/v14112423. PMID: 36366520; PMCID: PMC9698305.

EBHSV can infect Sylvilagus spp but not European rabbits Oryctolagus cuniculus. 

7:  Fitzner A, Niedbalski W, Hukowska-Szematowicz B. Simultaneous Occurrence of Field Epidemics of Rabbit Hemorrhagic Disease (RHD) in Poland Due to the Co-8:  8: 

8:  Presence of Lagovirus europaeus GI.1 (RHDV)/GI.1a (RHDVa) and GI.2 (RHDV2) Genotypes. Viruses. 2025 Sep 26;17(10):1305. doi: 10.3390/v17101305. PMID: 41157577; PMCID: PMC12568209.

9:  Abrantes J, van der Loo W, Le Pendu J, Esteves PJ. Rabbit haemorrhagic disease (RHD) and rabbit haemorrhagic disease virus (RHDV): a review. Vet Res. 2012 Feb 10;43(1):12. doi: 10.1186/1297-9716-43-12. PMID: 22325049; PMCID: PMC3331820.

10:  Kerr PJ, Kitchen A, Holmes EC. Origin and phylodynamics of rabbit hemorrhagic disease virus. J Virol. 2009 Dec;83(23):12129-38. doi: 10.1128/JVI.01523-09. Epub 2009 Sep 16. PMID: 19759153; PMCID: PMC2786765.

11:  Stowell CP, Stowell SR. Biologic roles of the ABH and Lewis histo-blood group antigens Part I: infection and immunity. Vox Sang. 2019 Jul;114(5):426-442. doi: 10.1111/vox.12787. Epub 2019 May 9. PMID: 31070258.

12:  Stowell SR, Stowell CP. Biologic roles of the ABH and Lewis histo-blood group antigens part II: thrombosis, cardiovascular disease and metabolism. Vox Sang. 2019 Aug;114(6):535-552. doi: 10.1111/vox.12786. Epub 2019 May 14. PMID: 31090093.

13:  Carman JA, Garner MG, Catton MG, Thomas S, Westbury HA, Cannon RM, Collins BJ, Tribe IG. Viral haemorrhagic disease of rabbits and human health. Epidemiol Infect. 1998 Oct;121(2):409-18. doi: 10.1017/s0950268898001356. PMID: 9825794; PMCID: PMC2809540.

14:  Weiss RA, Sankaran N. Emergence of epidemic diseases: zoonoses and other origins. Fac Rev. 2022 Jan 18;11:2. doi: 10.12703/r/11-2. PMID: 35156099; PMCID: PMC8808746. (open access)

15:  Galindo-González J. Avoiding novel, unwanted interactions among species to decrease risk of zoonoses. Conserv Biol. 2024 Jun;38(3):e14232. doi: 10.1111/cobi.14232. Epub 2024 Jan 3. PMID: 38111356.

16:  Bengis RG, Leighton FA, Fischer JR, Artois M, Mörner T, Tate CM. The role of wildlife in emerging and re-emerging zoonoses. Rev Sci Tech. 2004 Aug;23(2):497-511. PMID: 15702716.

17:  Sun Z, An Q, Li Y, Gao X, Wang H. Epidemiological characterization and risk assessment of rabbit haemorrhagic disease virus 2 (RHDV2/b/GI.2) in the world. Vet Res. 2024 Mar 26;55(1):38. doi: 10.1186/s13567-024-01286-x. PMID: 38532494; PMCID: PMC10967181.

18:  Sharma R, Patil RD, Singh B, Chakraborty S, Chandran D, Dhama K, Gopinath D, Jairath G, Rialch A, Mal G, Singh P, Chaicumpa W, Saikumar G. Tularemia - a re-emerging disease with growing concern. Vet Q. 2023 Dec;43(1):1-16. doi: 10.1080/01652176.2023.2277753. Epub 2023 Nov 18. PMID: 37916743; PMCID: PMC10732219.