Some implications of biologic plausibility

Ever since my... ahem... skirmish... with the folks over at the SBM, I have been contemplating the issue of biologic plausibility. They contend that our tax dollars are wasted by being allocated to the NCCAM to pursue research into CAM. Their reasoning is that there is no biological plausibility to any of it having any therapeutic effect. Now, this is a big bite to swallow. As I have said before there is CAM and then there is CAM. CAM seems to be a convenient wastebasket of modalities that we feel justified in bashing as "woo" since there is limited scientific evidence behind them. But really, I am more willing to give acupuncture and massage the benefit of the doubt than, say, healing crystals (even though I confess I really like rocks!).

So, what of this biologic plausibility, and who came up with it anyway? And is it truly fiscally irresponsible, and possibly even unethical, to test interventions that do not fit our biological plausibility criteria? As a corollary, is there a level of our understanding of biology that makes testing equally wasteful or even unethical? And finally, should plausibility of benefit and harm be required to reach the same evidentiary bar?

For the definition of biological plausibility we apparently thank the milestone 1964 Surgeon General's report linking smoking to cancer. This report was the first official US government document to state that there was enough evidence to implicate cigarette smoking in the rise in lung cancer and cancer deaths. Since the limitations of observational research were used by the critics for decades to derail this definitive statement, the report itself does a nice job laying out the methodologic considerations and the need to rely on the Bradford-Hill criteria. It was in the "coherence" criterion that biologic plausibility entered the picture.

A quick check of my favorite crowd-sourced information site, the Wikipedia, uncovers this treasure from Sir Bradford Hill himself:

It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day. To quote again from my Alfred Watson Memorial Lecture [1962], there was

"…no biological knowledge to support (or to refute) Pott’s observation in the 18th century of the excess of cancer in chimney sweeps. It was lack of biological knowledge in the 19th that led to a prize essayist writing on the value and the fallacy of statistics to conclude, amongst other “absurd” associations, that 'it could be no more ridiculous for the strange who passed the night in the steerage of an emigrant ship to ascribe the typhus, which he there contracted, to the vermin with which bodies of the sick might be infected.' And coming to nearer times, in the 20th century there was no biological knowledge to support the evidence against rubella."

In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr. Watson, "when you have eliminated the impossible, whatever remains, however improbable, must be the truth."^[1]

Aha, so biologic plausibility is a function of the state of our current knowledge, today. By this litmus test, Marshall and Warren should have been laughed out of all funding agencies. Instead, they rewrote our understanding of what can live in the stomach, and how a microorganism can cause peptic ulcer disease and stomach cancer. And got themselves a cool Nobel to boot. So much for the ethics and finances of biologic plausibility informing meaningful research.

Now, on to the question of whether there exist relationships with such high biologic plausibility that they do not require irrefutable proof. Well, how about tobacco and its health effects? How about radiation exposure? Now, how about what we know today about the evolution of microbial resistance to antibiotics? Is it enough that the biologic plausibility for ill-effects of antibiotics in our food chain is strong? Can we now stop the madness? If my colleagues over at SBM are given to the same logic, they would say yes to this. However, extrapolating from this post about organic food production, I somehow think that they would not. So, I am guessing that, although they believe that lack of biologic plausibility should preclude attempts at study, they will nevertheless be reluctant to set a threshold for biologic plausibility that might obviate the need for further research. I am just guessing, and would love to hear what they really think.

And finally, what of the plausibility of benefit vs. that of harm? Should our bar for biologic plausibility for harm be lower than that for benefit? Well, the question really boils down to this: How many bodies do we need to see lying in the streets before we concede that there is a problem? My point is that we Americans have a hard time subscribing to the precautionary principle, applied generously in other parts of the world. If we were a tad less reckless with our need for irrefutable evidence, how many decades of equivocation about tobacco and cancer would we have avoided? How many lives might have been saved? Biologic plausibility for the connection was known even in the 1930s, yet it took another three decades for us to act. What are we obfuscating today that will come back to bite us (and our children) tomorrow? Could it be the cynical injection of doubt that our food production system is causing irreversible damage to us and life around us?

So, what I am saying is that biologic plausibility has several facets. We have to admit humbly that its assumption relies on our necessarily incomplete knowledge, and denying this may prevent us from awe-inspiring discoveries that will advance science in leaps. However, if we feel strongly about the need for it in order to justify our research allocation, some careful soul searching is in order for those thresholds of probability, especially of harm, where we may admit that science makes us sure enough, and, instead of awaiting perfect evidence, we must act promptly.      

    

Microbiome: passenger or vehicle?

Remember how you learned in BIO 101 that many fluids in the human body are normally sterile? And you know how you laugh with condescension when someone dares to question this dogma? After all, we know that the gut and the skin are full of microorganisms, but the lung? The bladder? This is inconceivable, heretical!

Well, actually, this, like many other dogmas that seemed like God's word at the time, has been broken open by some very interesting research emerging from multiple laboratories around the world. I was first stopped in my tracks about a year ago, while listening to an NPR story in my car and learning that the number of bugs we carried on and in us was about 10-times greater than the number of our own cells. Then, in a farm house in Cornwall a couple of weeks ago, while on vacation, I read an article in an October 2009 issue of Eureka, The Times monthly science magazine, which once again made me ponder our sojourns in life, the bacteria that cohabitate with us. And finally, today I saw this story in yesterday's NYT, which galvanized me into writing action. This grabbed me in particular:

Scientists are even discovering ecosystems in our bodies where they weren’t supposed to exist. Lungs have traditionally been considered to be sterile because microbiologists have never been able to rear microbes from them. A team of scientists at Imperial College London recently went hunting for DNA instead. Analyzing lung samples from healthy volunteers, they discovered 128 species of bacteria. Every square centimeter of our lungs is home to 2,000 microbes.

It grabbed me for two reasons:
1). I am a lung doctor, and a lot of the research that I do centers around lung infections. One type of this infection, ventilator-associated pneumonia or VAP, is the subject of much scrutiny by policy makers and payers, and is emerging as a quality indicator. There are many challenging issue in VAP, not the least of which is its treatment: because it is likely to be caused by an antibiotic resistant organism, and because at least one-half of all cases of suspected VAP never grows out a specific microbe, the recommended empiric treatment is with broad-spectrum drugs. The clinician treads a fine line between undertreating the patient at the expense of increased mortality or overtreating and promoting antibiotic resistance.
2). I have already written here about my thoughts on evidence and how we tend to approach our knowledge with the arrogance that blinds us to the possibility of being either under-informed or plain wrong. Well, here is the case where we were so convinced of what we knew, yet it was plain wrong! With the scientific skepticism and appropriate tools we are learning something completely opposite to what we thought we knew.

Taking this line of thinking one step further, can we now conceive of the possibility that what we expose our bodies to actually plays a role in our long-term health? To be specific, I mean something as simple as food and the way our food is produced. Monoculture and food engineering have become staples of our food production. Animals are raised in CAFOs in conditions requiring them to be on antibiotics to ward off infections and to help with growth. Additionally, to leverage the subsidized and abundant corn supply, food animals are forced into diets completely unnatural to them. Cows, for example, evolved over millennia to be ruminants meant to eat grass and hay, are fed a corn-based grain diet, which, by altering their gut environment, makes them much more likely to carry toxigenic E. coli. Although there is much nay-saying about whether antibiotics (and hormones, by the way), are passed on to humans through meat or milk, I have never seen any convincing scientific evidence to the contrary. So, if we eat meat that is microbiologically altered, and may also be exposed to antimicrobial residues that may in turn change our own native microbiome, is it possible that at least some of the emerging health issues are due to the travesty of monoculture production?

I am not saying that I have all the answers -- clearly, this research has a long way to go to establish causal pathways and potential points of intervention. But let's exercise our common sense and at least ask the questions. Do it early and often. And let's please agree that there is a certain burden of proof here that resides with the food production oligopoly. Oh, yeah, and let's not forget to continue limiting the use of antibiotics in human health too. And have a little bit of dirt... for lunch... every day...  

Buddhism and antibiotic resistance

There is a concept called "samatha" in Buddhist meditation. It has to do with sitting quietly, doing nothing. The opposite of mindless action, samatha is the cornerstone of the mindfulness practice. But what does it have to do with antibiotic resistance?

Well, I came across this interesting slide presentation by Dick Zoutman from Canada. Starting at the top of page 5, the talk goes into several fascinating surveys about what influences antibiotic prescribing for upper respiratory tract infections (URTIs). The first survey was of 316 family MDs in Ontario, which, among other factors, determined "physician's desire to act" as a risk factor for prescribing an antibiotic. The next survey of 313 patients identified patient expectation to receive antibiotic as the most important driver of prescribing behavior. The latter can be interpreted as a). the patient's preference for some kind of an action or b). the patient's expectation of action on the part of the MD. Either way, "action" is the operative word.

So, what does this mean? Well, at the simplest, most immediate level, this finding confirms that education of both physicians and patients is a potentially fruitful target for antibiotic stewardship programs. But at a deeper level, perhaps something as fundamental as a re-evaluation of our approach to life is what is needed. Antibiotic overprescribing is a clear example where the philosophy that doing something is better than doing nothing is not just wrong, but threatens to send us back to the dark age of pre-antibiotic era.

Western medicine in general promotes rapid decision-making as its paradigm. In fact, when I was in practice, there used to be tremendous political capital in the bravado of rapid assessment and planning. But let's not kid ourselves: the majority of treatment decisions made in the outpatient setting do not necessarily need to be rushed in the way that our expectations have driven them to be rushed. So, let's take this sage advice and "don't just do something, sit there". It is time for some samatha in our decision-making as both physicians and patients, lest we continue knee-jerking our way into this escalating resistance catastrophe.    

 

Kids, schools and superbugs

What do the three have in common, you might wonder? Well, more than we used to think.

This story in today's UK's Telegraph reports on a school child who developed diarrhea and tested positive for C difficile. The alarming thing is that there did not seem to be any explicit risk factors for this. The appalling thing is the mis-information by the story that

Children rarely become ill with C-diff, which normally strikes elderly people in hospital. 

This is how things used to be, before the BI/NAP1/027 bug evolved in the early first decade of the millenium. We and others have shown that kids are not immune from it, and neither are other people previously thought not to possess any risk factors for it. In fact, we have a paper coming out shortly in the CDC's journal Emerging Infectious Diseases showing that in the US the rate of pediatric hospitalizations with C diff rose from 7.2 cases per 10,000 hospitalizations in 1997 to 12.8 cases/10,000 in 2006.

So why is this happening? Well, there are a couple of ways to answer this question. The proximal answer is that the new bug is better equipped to propagate. Its spore possesses greater stickiness than the old pathogenic version which we all knew and loved in the '90s, and thus is more difficult to eradicate from fomites and anatomic surfaces. It also produces on the order of 20-times more of the toxins responsible for wreaking havoc in the colon. So, clearly, this is a bug for the new millenium.

But here is the real reason for this, albeit a little more removed: antibiotic overuse. All physicians are aware of this, and we all get the connection. The way this works is that C diff is impervious to many of the antibiotics employed to treat other infections, while its neighbors in the gut are decimated. Thus, C diff proliferates to fill the void and takes a firm hold under the right circumstances. The new superbug is, of course, very likely the result of the all-too-familiar saga of resistance evolution.

Here is the frightening part: we are still overusing antibiotics! I frequently hear from my friends that their MDs offered antibiotics for something that to me is clearly a non-bacterial issue. The most frustrating situation is when I am convinced that the friend has a post-viral reactive airways cough and needs an inhaler, but instead comes home with a handful of antibacterial pills. And no one wants to take the chance. We are so risk averse that even when we are well educated about the perils of antibiotic overuse, we are still likely to take them if our doctor prescribes them. And for a doctor, with the shrinking appointment times, what is the most expedient course, particularly with a patient with an entitled attitude? You guessed it, antibiotics!

So, what do we do? My feeling is that the action has to be multi-pronged. Yes, physicians need to be held accountable for their treatment choices, but so do patients. We need to do a much better job educating the public about the dark underbelly of antibiotics, so that they can be partners in these decision. In my opinion, this may be the most critical healthcare issue of our time, given the concerns raised by both the WHO and the FDA that, if resistance emergence continues at this pace, we will be back to the dark ages of pre-antibiotic era.

To this end, The Surgeon General should pick up the banner of antibiotic education. In fact, I recently sent her a letter outlining why she might want to make this a part of her Public Health agenda. If anyone is interested in making it a more public effort, I am happy to share it and resend with more signatures than just my own. She after all puts the "Public" into Public Health.

We have got to start talking to the people about this. The resistance train needs to reverse direction. And now!        

  

Medical tourism and superbugs

Here is another reason to reform healthcare: proliferation of superbugs. How are they related, you might ask. Well, a couple of days ago the British paper Telegraph reported that 22 cases of an antibiotic resistant bacterium imported from India have been discovered in 17 hospitals in the UK. These bacteria are in the family that commonly cause urinary tract infections, which themselves are exceedingly common among hospitalized patients.

What is medical tourism? It is a growing industry where patients from developed nations travel to the developing world for procedures that are elective, inaccessible or overpriced at home. I first read about it about 4 years ago in a magazine in a story that featured an American without health insurance traveling to India for a joint replacement surgery. While the surgery was performed by a team of US-trained specialists, the price of it was an order of magnitude lower than in the US. This disparity in cost, and therefore access, is driving the expansion of the industry, which is predicted by Deloitte to grow by a factor of ten over the ensuing decade. In fact, the numbers from the US alone are predicted to double from 750,000 in 2008 to 1.5 million in 2009. But these costs certainly do not incorporate the public health risks presented by the worldwide spread of antimicrobial resistance.

To be sure, we have not done so well in this country at curtailing the spread of superbugs. Why, hospitalizations with infectious diarrhea due to a bug called Clostridium difficile alone have increased at an annual rate of 23% in the US, not to mention the over 1 million hospitalizations every year involving resistant bacteria. So, while it is hard to blame the woes of resistance on medical tourism alone, what is of concern is how rapidly these organisms can infiltrate even those geographic areas that practice good antibiotic stewardship and other preventive measures.

I see this as yet another wake up call for the US. We can limit the growth of medical tourism by improving access to healthcare in the US. We can do this by reducing the egregious waste that is so rampant in the current system. And most importantly, we need to change our trajectory of over-medicalization that is not only driving the waste here in the US, but is now also sending our citizens abroad on ill-advised hunts for cheap snake oils laced with hidden peril.

Telegraph story via @EvidenceMatters