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How Clostridium difficile Affects the Gastrointestinal System

DEC 05, 2017 | PANELISTS: PETER L. SALGO, MD; YOAV GOLAN, MD, MS; ERIK DUBBERKE, MD; LAWRENCE J. BRANDT, MD; DALE N. GERDING, MD; AND DANIEL E. FREEDBERG, MD, MS
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Peter L. Salgo, MD: So, here’s Clostridium difficile. For whatever reason, it’s now allowed to proliferate, whereas prior, it’s either been held in check or was at a rational level. What does the bug do? How does it cause disease?

Erik Dubberke, MD: Once you’re in that Clostridium difficile-promoting state after antibiotics, it grows. Then, as part of the natural growth cycle of Clostridium difficile, it starts to produce toxins. The 2 main toxins that lead to symptomatic Clostridium difficile infection, the diarrheal disease that we’re all familiar with, is toxin A and toxin B. And again, historically, what we have been taught is that toxin A was probably the primary mediator. But what we’ve learned since then is that toxin B is probably more important than toxin A.

Peter L. Salgo, MD: Just when you thought it was safe to remember your medicine, they switch it up on you. What do these toxins do? What are they?

Erik Dubberke, MD: So, regarding the toxins, we don’t know the exact mechanism of what’s going on. But essentially, what happens is that they bind to receptors on the colonocytes. Exactly what those receptors are, we don’t know yet. Then, they’re internalized. They get released within the colonocyte, and then they start to cleave the cytoskeleton; you get colonocyte death. Then, once the toxins hit the submucosa, they’re very pro-inflammatory. You get very intense inflammation—characteristic pseudomembranous colitis. You get death of a colonocyte and then some toxin onto that submucosa. Then you get an explosion—a volcano is how it’s described in the pathology of inflammation.

Peter L. Salgo, MD: You mentioned the pseudomembranous colitis. I can remember when that phrase first popped up in my hospital. It was associated with 1 or 2 really specific antibiotics, and we were taught that those antibiotics cause a membrane. It’s the Clostridium difficile, right?

Erik Dubberke, MD: Yes, yes.

Peter L. Salgo, MD: OK.

Lawrence J. Brandt, MD: There are 2 very important things to know about pseudomembranes. One is that it’s not specific to Clostridium difficile. You can get pseudomembranes with bacterial infections, viral infections, and also with parasitic infections. The second thing is that if you see patients with recurrent Clostridium difficile, and I’m sure we’ll talk about this later, they very unusually have pseudomembranes in their colon. Despite the fact that they have Clostridium difficile and despite the fact that they have diarrhea, they do not have pseudomembranes. Maybe that’s because they were treated with antibiotics so much along the way?

Peter L. Salgo, MD: But then, I think it’s fair to get rid of this whole phrase “pseudomembranous colitis” as a synonym for Clostridium difficile. The 2 are distinct. You can have membranes without Clostridium difficile and can have Clostridium difficile without membranes.

Dale N. Gerding, MD: You can, but about half of all people who are diagnosed with Clostridium difficile, if they’re scoped, have pseudomembranes. Only half though—not 100%.

Daniel E. Freedberg, MD, MS: And that kind of patient is usually the kind of patient we’re more accustomed to seeing in the hospital—that patient with a massive systemic inflammatory response and a very high white count that can be 100,000 or in the tens of thousands (not at all unusual). In the outpatient ambulatory setting, the patient phenotype is a little bit different. It’s someone with much milder disease who maybe doesn’t have a white count through the roof or these other signs of systemic inflammatory response.

Peter L. Salgo, MD: In my hospital, if somebody is in my ICU and their white count is 50,000 and they’re having diarrhea, it is not so hard to at least consider Clostridium difficile. But I want to go back and examine that later because the physician in the community may have a tougher time. Now, you talked about toxin A and toxin B. You talked about that, a cardiotoxic toxin. Is that 1 of those 2? Or is that a third toxin?

Dale N. Gerding, MD: It’s one of those 2 that gets into the circulation. Once it gets out of the colon, at least in animal models, it causes a lot of devastation.

Lawrence J. Brandt, MD: Does it do the same thing? How does it do its devastation?

Dale N. Gerding, MD: Well, it seems to be able to affect some of the cells in the heart itself.

Lawrence J. Brandt, MD: The same way it does the colon?

Dale N. Gerding, MD: Yes, it causes destruction of the cells. We’ll find cardiac hemorrhage or lung hemorrhage. And I think it’s probably doing the same thing, but we’ve had a very difficult time proving that in humans—simply because it’s so hard to detect.

Lawrence J. Brandt, MD: Are there toxin receptors in the heart and in the lung?

Dale N. Gerding, MD: That’s a good question. I don’t know the answer to that.
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