Bias in the NIH Grantome

I recently discovered a gem of an essay by John Alverdy and Monika Krezalek published in February 2017 in the Journal of Critical Care Medicine. Entitled “Collapse of the Microbiome, Emergence of the Pathobiome, and the Immunopathology of Sepsis” it manages to touch on all of my interests, evolutionary medicine, misguided approaches to sepsis, the importance of the microbiome, and the capacity for conflict and harm from an altered microbiome, what they term the “pathobiome.” The article is unfortunately behind a paywall but I excerpt a few key bits here, with my commentary.

Alverdy and Krezalek critique the widespread idea that patients with sepsis die because of the immune system not because of the pathogen. They describe the prevailing view as:

“a pervasive immunocentric view of sepsis research – an immune/inflammatory unit/pathway must be identified that is required for mortality in any model of sepsis, because – in terms of ultimate causality – mortality is due to the response and not to the inciting pathogen.”

They go on to write that this misguided view is evident in decades of NIH funding priorities:

“Evidence for this can be easily obtained by searching the National Institutes of Health website “Grantome” using sepsis as the search word. With no exception, every funded grant is based on the immunocentric theory of sepsis and almost every grant has a promissory note that blockade of a pathway or molecule will inform a strategy to improve the outcome of human sepsis. Implicit in each of these proposals is the practice of dismissing any ongoing involvement of the inciting pathogen or any role for the ecologic collapse of the normal microbiota (microbiome) in the sepsis process. Finally, in order for the immunocentric view to prevail, the cause of death from sepsis must be believed to be due to the response itself.”

Amen! I have been arguing along similar lines for as long as I have taught evolutionary medicine at the University of New Mexico. For example, I argued that blocking pro-inflammatory pathways in sepsis is a bad idea in Disabling the smoke detector in sepsis. I wrote that we have learned the wrong lessons from sepsis research in Sepsis what have we learned, and I have an entry questioning the Underlying assumptions of sepsis treatment.

Why is the prevailing view wrong?

Because it removes any culpability from pathogens and a microbiome gone bad. The article points out that the most common animal model of sepsis (cecal ligation and puncture) kills because “normal rodent flora” spills out of necrotic intestine. Removal of the necrotic tissue and anti-microbial treatment converts 100% mortality to 100% survival. The microbiome is central to death by sepsis. As the authors point out, we never exist in a germ free state, and are either hosts to a “normal” microbiome or a virulent “pathobiome.”

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Mouse sepsis due to cecal ligation and puncture (CLP) can be reversed with proper source
control. Mortality is 100% at day 2 following CLP. Source control and supportive therapy result in 0% mortality, and all mice recover completely by day 7 (p = 0.0023; n = 5 per group) From Alverdy and Krezalek 2017.

Unfortunately, we convert healthy microbiomes to pathobiomes with abandon. This  occurs when we destroy the commensal microbes using broad spectrum antibiotics, introduce hypervirulent hospital acquired pathogens, and perform procedures (intravenous lines, endotracheal tubes) that act as an on-ramp for pathogens that colonize vulnerable tissues. We physicians, surgeons, and nurses are indeed agents of selection. This selection can provoke the evolution of a harmful pathobiome.

Should we continue to ignore our role in shaping the pathobiome, and blindly pursue magic bullet therapies that block host immune defenses? No, but we undoubtedly will, believing that:

“pharmacologic interference will stop the insidious inflammatory disorder common to all sepsis. The many failures of clinical trials informed by this approach are testament to the failed thinking of this mechanistic framework. Perhaps some pathogens are simply short sighted and make the fundamental tradeoff to kill the very host upon whom their survival may depend. In some cases, this occurs rapidly, in others slowly. As one author declared “medicine needs evolution” and this is certainly the case with sepsis research.”

Here, Alverdy and Krezalek have clearly been influenced by evolutionary thinkers on health and disease, and they cite Nesse and Stearns.

It is great to read like-minded scientists on the front line of sepsis research.

Watch a video of John Alverdy lecturing on the same topic on YouTube:

 

Copyright © Joe Alcock MD

Killer antacids

Proton pump inhibitors (PPIs) are drugs commonly prescribed by your doctor for the treatment of heartburn. You can also skip the doctor visit and buy them over the counter at the supermarket or pharmacy. Since you can buy PPIs without a prescription then they must be safe, right?  Wrong. Recent work suggests that PPIs are harmful, even deadly.

Xie and colleagues recently published an article in BMC Open, Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. They report that PPIs increase the risk of death in long term users – by about 1.5x. In patients without gastrointestinal conditions, PPI use increased the risk of death even higher, almost 2 fold. These differences existed even when PPIs were compared to H2 blockers (think Zantac), antacids that employ a different mechanism and are not quite as potent as PPIs.

Screen Shot 2017-07-05 at 10.11.09 PMWhat about proton pump inhibitors causes harm? People take PPIs for heartburn, acid reflux, a painful condition in which stomach acid travels backwards into the esophagus, causing chest pain. By increasing the pH of the stomach contents, PPIs are effective in reducing pain from acid reflux. Remarkably, though, some 20-30% of PPIs are taken by people who have no gastrointestinal symptoms. The popularity of PPIs – they are the 9th most commonly prescribed medication in the US – is a clue that physicians and patients think these drugs are benign. More broadly, the story of PPIs betrays a mindset that the body is a simple machine, that symptoms indicate malfunction, and that blocking the mechanisms that cause symptoms is an unalloyed good. This is not so.

As I like to point out to my students: nothing is free in medicine.  You can’t block an evolved cellular function in a large percentage of the population and think that nothing will go wrong. Adaptive, fitness-enhancing processes are also blocked, along with symptoms. Unintended consequences are guaranteed. In this instance ignorance is not bliss. If you are blind to adaptation and evolution, it can literally kill you.

Let’s first examine what PPIs do and how they work. PPIs potently block the gastric proton pump in parietal cells of the stomach. Normally, this cellular pump moves H+ ions into the lumen (the inner part) of the stomach, thereby decreasing the pH of gastric juice. Proton pumps are responsible for acidic stomach contents, but also cause the relatively low pH in the small intestine. Why is low pH important? Many people think that stomach acid is important for digestion of food. Nope. The primary reason we have evolved strongly acidic gastric juice is to kill microbes entering the gut along with food. That’s right – stomach acid is a gatekeeper to the microbiome.

Low pH generally kills microbes by destabilizing the cell membranes of bacteria. Acid has synergistic effects along with high temperature in rupturing the cell membranes of pathogens. Parenthetically, that is why infected patients with sepsis often have a high temperature (fever) plus low pH in tissues and blood (lactic acidosis).

Acid killing of bacteria is the reason why some scientists refer to stomach juice as an acid barrier. It is also why the manufacturers of probiotics – living microbes with health benefits when consumed – must go to great lengths to protect their products from sterilization in the stomach. Thus, a consequence of normal activity of proton pump inhibitors is to prevent microbial growth in the stomach and protect us from food-borne infection.

Now we turn to the ways that PPI users die. Since the main function of the proton pump is to protect us from harmful microbes, we would predict that PPI users would have more gut infections. Do they? Indeed the answer is yes. Observational studies have shown that PPIs increase infection by the virulent gut pathogen Clostridium difficile in hospitalized patients. Interestingly C. diff spores are pretty acid resistant, which raises questions about the exact mechanims. However, it is postulated that the change in pH from PPIs changes the microbiome, reducing commensal bacteria that otherwise inhibit C. diff. This sets the stage for out of control growth of this deadly pathogen.

The acid barrier works both ways, since the gut can be a source of extra-intestinal infections. PPIs are also associated with pneumonia in hospitalized patients. Since PPIs eliminate the acid barrier, harmful pathogens that take up residence in the gut can more easily travel upwards to the pharynx, airway, and lung. Another potential explanation for increased pneumonia is that the same H+/K+ ATPase proton pump in the gut also exists in the airway. PPIs impair acidification of the respiratory tract, which is probably what allows pathogens to colonize the lung.

It gets worse. PPIs also inhibit the bactericidal function of immune cells like macrophages. How do they do that? Macrophages consume (phagocytose) errant microbes and destroy them in internal lysosomes. These lysosome compartments are loaded with antibacterial peptides, free radicals and… wait for it… acid. The acid pump is a little different. It is a H+ATPase, but it is also inhibited by proton pump inhibitor drugs. It makes sense, then, that PPIs are going to have widespread effects on your immune system’s ability to manage infectious threats.

What about the microbiome? I mentioned earlier that stomach acid barrier is the gateway to the microbome. It follows that PPIs would affect the body’s community of commensal microbes, known as the microbiome. Do they? Yes. After taking PPIs, the stomach, esophagus, and small intestine grow a thick carpet of unfriendly microbes – a condition known as small intestinal bacterial overgrowth. Let’s pause here for a moment and reflect on the fact that your microbiome is profoundly affected by PPIs. This is important. Here is why: The microbiome is plugged into virtually every part of your body’s functions. Microbiomes that are out of whack (aka dysbiosis) can cause chronic low grade inflammation. Chronic inflammation is important because it is a slow smoldering immune process that increases the risk for heart attacks, strokes, and some cancers.

So, it should not come as a surprise that PPIs drive a variety of chronic inflammatory diseases, like chronic kidney disease, also heart attacks, strokes and congestive heart failure. If that is no enough to convince you that PPIs are dangerous, note also that PPIs are associated with excessive weight gain and obesity (also a chronic inflammatory condition).

I will make a prediction here: we will soon see a variety of studies that will showing that the microbiome is central in the otherwise inexplicable links between PPIs and chronic inflammatory diseases.

I could go on and on, but you should wait for the podcast coming soon on PPIs for that. For now, I will leave you with these summary points:

  1. PPIs are dangerous drugs. They have some legit indications, but current widespread use is completely irrational, unsupported by evidence, and counter to public health.
  2. PPIs disable a a key adaptation (control of pH) that is central in infection-fighting and control of the microbiome.
  3. The cautionary tale of PPIs overuse is repeated in a variety of other medical domains and for many other drugs. Biomedicine has not yet learned its evolutionary lessons.
  4. Ignore adaptation at your peril – what you don’t know about evolution might kill you.

 

Too sweet or just right?

NEJM GlycemicA recent paper, published in the New England Journal of Medicine asked the question: does treating elevated blood sugar in children with critical illness help or hurt? We have asked the same question – regarding adult patients – previously on this blog.

To get you up to speed I will reprint part of that earlier entry:

“In 2001, a paper by van den Berghe and colleagues was published in the New England Journal of Medicine. It described a trial of intensive blood sugar control in critically ill patients and reported improved survival with intensive glucose treatment using insulin.

This study led to a substantial increase in aggressive hyperglycemia treatment known as “tight glycemic control” in the intensive care unit.

In 2009, another paper refuted the results of the first. The NICE SUGAR study enrolled 6000 critically ill patients, randomizing 3000 of them to tight glycemic control. The key result:

Mortality was higher (27.5% v. 24.9%) in the intensive insulin treatment arm.”

Now, in medicine, 2009 was something like a million years ago, and you might be forgiven for thinking that the NICE SUGAR study would be the final word on the subject. However, leaving high blood sugar alone – permissive hyperglycemia – is a heretical concept, and one that has not died easily.  So, in my hospital, blood sugars are normalized, though perhaps not as aggressively as in the pre- NICE SUGAR era.

To be sure, the NICE SUGAR study did not involve children. A subsequent study examined children after cardiac surgery – and did not show a benefit for normalization of blood sugar in that pediatric population. But non-surgical pediatric patients had not been studied. To the authors of the current study, that necessitated doing a randomized controlled trial of aggressive insulin treatment of hyperglycemia in sick kids.

Researchers enrolled 713 critically ill children and randomly assigned them to a lower target blood sugar group who received more insulin (doing more something) and higher target group who received less insulin (doing more nothing). The main outcome measure was ICU-free days – i.e. time not in the ICU up to day 28.  This outcome was similar in both groups.  Mortality was also similar.

But, this study was stopped early, because the interim analysis determined a low likelihood of benefit from giving more insulin and a high risk of harm. Indeed, in the enrolled group, children receiving more insulin had “higher rates of health care–associated infections” (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P= 0.04) in the group receiving less insulin. Not surprisingly, trying to aggressively normalize blood sugar resulted in higher rates of severe hypoglycemia (a blood glucose level below 40 mg/dl. (18 patients [5.2%] vs. 7 [2.0%], P = 0.03).

It is very unlikely that further pediatric trials on aggressive treatment of hyperglycemia will be performed. Why? Because we cannot make a case for equipoise, the state of scientific uncertainty between two possible treatments – that would make it ethical to undertake a similar trial. This is especially so for a study of kids: children are a vulnerable population unable to provide informed consent for themselves.

There are two points to made about these results, one clinical and one theoretical. Clinically, I will expect that ill children especially will not undergo aggressive insulin therapy for high blood sugars in the hospital. At least I hope so. There comes a time when antiquated ideas in medicine need to die. That time is now.

The second point is a reappraisal of the role of hyperglycemia in critical illness. It is my view that hyperglycemia is an adaptation that confers a survival benefit on average – making patients better able to meet the challenge of their critical illness. That view is supported by the recent NEJM study and the previous NICE SUGAR study.

Evolutionary medicine is useful as far as it leads to distinct and better outcomes than conventional, non-evolutionary, approaches in medicine. In the case of normalizing high blood sugars in critical illness, evolutionary medicine can help doctors identify adaptation where previously they saw only pathology. This evolutionary perspective will help save the lives of children by speeding the adoption of better, less aggressive treatments, now strongly supported by the best quality evidence.

 

 

Disabling the smoke detector in sepsis

smoke-detector

There are certain themes that I return to, and the smoke detector principle is one of them. I wrote an Op-Ed piece for the Evolution and Medicine Review last year. An excerpt:

“Randolph Nesse coined the term smoke detector principle to explain why some people display an exaggerated response to threats, perceived and real, resulting in anxiety disorders and panic. He writes “False alarms are to be expected” because of uncertainty about the nature of a threat. That alarming noise behind you that triggers an involuntary intake of breath and a racing heart might simply be a harmless falling branch, or a charging grizzly bear. The overreaction to the falling branch evolved because hair-trigger reactions protect us from the far greater cost of being eaten alive.”

I applied the smoke detector principle to the Toll-like Receptor TLR4 that alerts the body to the threat of invasive bacterial infection.

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Function (or dysfunction) of the Toll like receptor TLR4

Read the complete article at the Evolution and Medicine Review here

An epidemic of overtreatment

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Image from The Atlantic – click for content

I cannot recommend this recent Atlantic piece by David Epstein more strongly. It absolutely captures the problem of overtreatment and the pressures that fuel this source of medical waste and patient harm. Plus, it does a great job of explaining the number needed to treat and the number needed to harm. Read the original article here.

The audio version is here, for those who prefer to listen instead of read (I did both):

2017 Evolutionary Medicine meeting

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Mark your calendars. This August 18th-21st will be the third annual meeting of the International Society for Evolution Medicine and Public Health. The first two meetings were amazing and fun. This summer’s event promises to be that and more.

For more information click here

Important: November 15th is the deadline for abstract submissions. If you have not yet, please submit right away!

See you in Groningen, Netherlands, this summer!

 

Darwinian Medicine Interview

Screen Shot 2017-02-13 at 1.06.24 PM.pngI recently did a brief Q & A with Eirik Garnas who writes at the blog Darwinian-Medicine.com

Here is the interview:

  1. Who are you? What’s your profession and educational background?

I am an emergency physician and professor of emergency medicine at the University of New Mexico Health Sciences Center, and I am an adjunct professor in the UNM Biology Department, where I teach a course on evolutionary medicine. I have a background in evolutionary ecology, with a master’s degree in neurobiology and behavior from Cornell University. I received my MD from UCLA in 1997 and did my residency in emergency medicine at UNM.

  1. How did you get interested in Darwinian/evolutionary medicine and the human microbiome?

My original plan was to become an evolutionary biologist. I changed gears during graduate school after I heard a talk by Paul Ewald, the author of the book “The Evolution of Infectious Disease.” He explained why microbes like Vibrio cholerae (the one that causes cholera) have evolved to be deadly pathogens, untamed despite a long coevolutionary history with humans. I found his argument very convincing and I was excited to study evolutionary questions that apply to human health and disease. Soon after, I decided to go to medical school hoping to contribute to the emerging scientific field known as evolutionary medicine, or Darwinian medicine.

  1. What’s the main focus of your research?

My research uses evolutionary principles to understand cooperation and conflict in the human gut microbiome, specifically in relation to diet, stress and sleep. One of the things I am interested in is the effect of workplace stress on gut bacteria, and how that affects on-the-job eating, especially during night shifts.  It is known that overnight shift work causes weight gain, obesity, and mood disturbances. My current research is exploring whether there is a link between those outcomes and the microbiota. 

  1. 2014, you published an excellent review paper entitled Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms in the journal Can you briefly summarize what that article is about?

We proposed in that paper that unhealthy food preferences, cravings and aversions may serve the evolutionary interests of our gut microbes. One possibility is that microbes hijack our nervous systems with neurotransmitters and appetite peptides that mimic our own. If so, our food choices may be less an issue of willpower, and more the result of our gut bacteria. Many examples exist of microbes manipulating the behavior of host organisms, and we hypothesized that microbes influence eating behavior, in part by rewarding us for eating the foods upon which they depend, and by making us feel bad if we do not provide a constant supply of growth-limiting nutrients. In other words, the problems of overeating, obesity and diabetes may lie less in our genes or our brains, and more in the composition of our guts.

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