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Archive for the ‘Principle into Practice’ Category

Sorry there’s been a delay in getting anything new out. I’ve had some exams, a quick trip to Colorado, and am now just finding my feet on my surgery clerkship. I have a bunch of things I intend to write about soon, but this paper popped up the other day and it ties in really nicely to some of the things I’ve already written about. I just had to write about it! I promise that in my upcoming posts I will get away from bowels and microbiota (though these subjects are incredibly important!).

You may remember Clostridium difficile from one of my previous posts on the appendix. C. diff is an anaerobic bacterium that frequently resides in the large intestine. After a course of antibiotics, when other gut-inhabitants have been killed, an overgrowth of C. diff can lead to a very nasty spectrum of symptoms ranging from mild diarrhea to death. Because of the frequent use of antibiotics and because of new hyper-virulent strains of C. diff, infection with this bacterium has reached epidemic levels. Alas, this is one of the most common infections found in hospitals, nursing homes, and other medical facilities.

The incidence of C. diff is on the rise, with both the number of cases and the mortality from infection recently doubling. There are approximately 3 million cases of C. diff infection in the US each year, and it’s estimated that care for these cases is in excess of $3.2 billion. C. diff infection leads to a number of discomforts, including abdominal pain, diarrhea, fatigue, and flu-like symptoms. Alas, treatment can be difficult, and symptoms can persist for months or even years.

As I mentioned in a previous post, the usual treatment for C. diff is further antibiotic treatment. C. diff infection usually occurs after all the normal gut flora has been eliminated and further antibiotics (sometimes given with probiotics to encourage the return of commensal bacteria) are targeted at eliminating C. diff (there’s even a new antibiotic (Dificid) specifically targeted at C. diff). The problem, of course, is that IF these antibiotics are effective, you now have a relatively unpopulated gut that is barren and ready for the taking by whatever stray bacteria have survived the courses of antibiotics or whatever quick growing bacteria happens to make their way to the intestines to claim the empty territory- unfortunately C. diff is frequently the victor in this foot race!

Recurrent rates of C. diff infection range from 15-30%, and once you’ve had one recurrence, you’re more likely to have another: a 40% chance of having a second, and a 65% chance of having a third. Obviously antibiotics are of limited efficacy here, so what is an appropriate course of action?

In my previous post, I discussed a paper that showed that having an appendix (and thus having a safe house for normal commensal bacteria that can repopulate your gut after infection or antibiotic treatment), is protective against a recurrence of C. diff [1]. But what if you don’t have that safe house, or if you get a recurrence despite having an appendix? Again, as mentioned in a previous post, a Fecal Microbiota Transplant (FMT) seems to do the trick.

A paper published at the end of March [2], combined data from 5 sites and showed that FMT can provide RESOUNDING cure rates in people suffering from recurrent C. diff infections. Here’s a quick review: 77 patients, with average symptom duration of 11 months (range 1-28) underwent FMT at 1 of 5 medical centers in an attempt to cure their chronic infection. On average, these patients had already undergone 5 treatment regimes to try and cure their infection. FMT (most donors were family members, spouses, partners, or friends) was infused by colonoscopy into the terminal ileum, cecum, and (depending on the site) parts of the colon. Resolution of a number of symptoms- abdominal pain, fatigue, and diarrhea, were recorded.

In 70% of patients, pain resolved with FMT, while it improved in an additional 23%. 42% of patients saw a resolution of fatigue, with an additional 51% reporting an improvement. An astounding 82% saw a resolution of diarrhea and 17% saw an improvement within 5 days of FMT. These are patients, remember, that have been suffering from symptoms for an average of 11 months.

Alas, 7 patients (just under 10%) experienced an early recurrence (less than 90 days after FMT), and required a secondary treatment (either antibiotics targeted at C. diff or another FMT), which successfully treated the recurrence. Thus, the “primary cure rate” (resolution of diarrhea within 90 days of FMT) was 91%, and the “secondary cure rate” (resolution of infection after a further course of antibiotics or a second FMT), brought the cure rate to 98%. (It is worth noting that the one not “cured” patient died in hospice and was not re-treated after failure of a primary cure).

Some patients did have late recurrent infections of C. diff. Not surprisingly, these cases all occurred in patients that took a course (or multiple courses) of antibiotics to treat an unrelated infection. Recurrence occurred in 8 of the 30 patients that took a course of antibiotics. Interestingly, recurrence may also be associated with the use of proton-pump inhibitors (perhaps not a surprise, as PPIs inadvertently affect our microbiota [3])

This paper is excellent evidence to support FMT becoming a first-line therapy for the treatment of C. diff infection (and I will add especially for those that lack an appendix). FMT restores a natural biodiversity to the intestine of someone who has had their own microbiota disturbed by disease and/or antibiotics. For many people (those that experienced a primary cure), the restoration of the biodiversity was enough to overcome C. diff infection. For others, the restored biodiversity gave them the edge to overcome infection with a further targeted antibiotic or a second transplant. Remember- these are patients that had failed MULTIPLE treatments for C. diff and had been experiencing symptoms for an average of 11 months.

While there are definitely risks to FMT (it is important that donors be screened to rule out dangerous transmissible infections such as HIV, hepatitis, and parasitic infections), there are arguably additional benefits. One patient in this study reported a significant decrease in allergic sinusitis and another reported an improvement in arthritis. Both associated the improvement of symptoms with FMT. Indeed, FMT has been reported as a successful treatment for a number of conditions including inflammatory bowel disease (such as ulcerative colitis), irritable bowel disease, idiopathic constipation and insulin resistance [2].

It is important to recognize that some of the patients in this trial did suffer from subsequent disorders that should be further explored. While the conditions were not apparently associated with FMT, 4 patients that received this therapy later developed conditions including peripheral neuropathy, Sjogren’s disease, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. Further studies need to determine if there is an association between FMT and autoimmune or rheumatologic disorders. If associations are found, I would expect that this would call into question the appropriate selection of donors for individual patients.

It is becoming increasingly obvious that an appropriate and diverse microbiome is important for health. When this microbiome is thrown out of whack, be it by an evolutionary-novel lifestyle, infection, or antibiotic treatment, the restoration of this environment should be the focus of medical treatment. Fecal Microbiota Transplant is a rational and effective method of restoring a healthy and diverse intestinal microbiome.

(It is worth mentioning that 97% of the patients in this study stated that they would undergo another FMT if they experienced a recurrence of C. diff, and 53% would choose FMT as their first treatment option before a trial of antibiotics. Yes, the idea of FMT may seem gross, but it is effective. For those that have suffered for upwards of a year, this treatment truly is a life-changing option.).

1.            Im, G.Y., R.J. Modayil, C.T. Lin, S.J. Geier, D.S. Katz, M. Feuerman, and J.H. Grendell, The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol Hepatol, 2011. 9(12): p. 1072-7.

2.            Brandt, L.J., O.C. Aroniadis, M. Mellow, A. Kanatzar, C. Kelly, T. Park, N. Stollman, F. Rohlke, and C. Surawicz, Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012.

3.            Vesper, B.J., A. Jawdi, K.W. Altman, G.K. Haines, 3rd, L. Tao, and J.A. Radosevich, The effect of proton pump inhibitors on the human microbiota. Curr Drug Metab, 2009. 10(1): p. 84-9.

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If you’re just reading my blog for the first time, I’d recommend you go back and read the last two posts where I talk about the fallacy of the appendix as a vestigial organ and how and why this organ sometimes goes off the tracks in our modern environment.

 

In this final installment on the appendix, I’d like to explore how we can take what we know about the appendix, consider it in an evolutionary light, and think about the practical implication of this knowledge. As discussed in my first post, it has been proposed that the appendix evolved as a safe house for the commensal microbiota that live in our gut. This safe house is useful in undeveloped communities where enteric pathogens are common, but is probably not so important (or may actually be problematic) in today’s hygienic world. A recent paper, however, challenges the idea that the appendix is no longer useful in our modern world.

 

Clostridium difficile (or as it’s referred to on the floor ‘C. diff.’) is an unpleasant little bacterium that causes a condition known as pseudomembranous colitis. Many people carry around some C. diff, but an overgrowth can occur after a course of antibiotics kills off other bacteria or after infection with a particularly nasty strain of C. diff. In these situations, serious colitis can occur. Infection with this bacterium can cause anything from mild diarrhea to fulminant colitis with shock and death. C. diff is the most common form of hospital-acquired diarrhea in acute care settings, and the prevalence is increasing due to the emergence of particularly virulent strains. Unfortunately, once you’ve acquired C. diff, you’re significantly more likely to contract it again- with 20% of people getting a recurrence. Do you see where this is going? As my previous post suggested, the appendix is probably helpful in developing countries with widespread food and water-borne GI infections, but not so useful in the developed world where these things are less common. But what about in the hospital, where rates of infection are unfortunately rather high?

 

In those that have been infected with C. diff, it appears that having an appendix is significantly protective against having a recurrence [1]. This protection could be conferred by two potential mechanisms (or a combination). The GALT tissue may provoke the appropriate immune response, and/or, the normal microbiota that were kept safe in the appendix can repopulate the gut, protecting it from a recurrence. I’m not quite sure how to apply option (a) to a practical approach right now, but I think option (b) offers some interesting ideas. Full warning- this is about to get a little gross…

 

The standard treatment for C. diff is a course of serious antibiotics (the fact that C. diff overgrowth is frequently caused by antibiotics sometimes seems to be lost in the mix). One of my fellow med students informed me recently that there’s a brand spanking new antibiotic on the market that is specifically geared towards preventing the recurrence of C. diff, (Fidamoxicin, trade name Dificid) but I’m not familiar with that treatment. What I am familiar with, however, are fecal transplants.

 

Fecal transplants (bacteriotherapy sounds so much less… gross), are exactly what they sound like. You take the feces from a healthy donor, test them for all types of nasty pathogens, and then implant them in your sick recipient. I had been informed by an infectious disease doc that the preferred route of entry was a nasogastric tube, but recent studies seem to imply that transplantations via colonoscopy are very effective [2] (and I don’t know about you, but for this particular procedure, going ‘up the out-hole’ seems a whole lot more appealing that going ‘down the in-hole’). In either case, the large intestines are first flushed with an isotonic solution and then the donor material is transplanted. This procedure seems to be very effective in treating and preventing a recurrence of C. diff, though it has yet to become a common or generally accepted practice (they don’t do it at my medical school for example). The obvious advantage of this procedure is that it inoculates the gut with a population of healthy/normal bacteria after an infection (and probably some antibiotics) that has knocked down (or out) the native flora. Additionally, in a world with progressively fewer and fewer effective antibiotics, it offers a therapeutic option that does not rely on pharmaceuticals. The obvious disadvantages are the gross factor and the pressing question of ‘who is the donor’ (for the record- they usually look to your spouse if you have one). Also, the procedure remains rather expensive because of the expense of testing samples and the nature of the procedure, however efforts to streamline the process appear effective [3]. Also- if you happen to be going in for a procedure that will see your native flora eradicated, you can actually save your own sample for an autologous transplantation at a later date.

 

Fecal transplants seems to be an interesting and appropriate treatment after C. diff overgrowth, and could also be beneficial in other GI conditions that are caused by dysbiosis. There’s definitely reason to think it might also be useful for treating a number of gut conditions such as Crohn’s disease, ulcerative colitis, irritable bowel, and maybe even systemic problems such as allergies and auto-immune conditions [4]. These are all things that warrant more research.

 

But how does this all tie back to the appendix?

 

Principle into practice. If we believe that the appendix acts as a safe house for commensal micro biota that are capable of repopulating the gut when needed, we should take special consideration for those that have had their appendix removed. While I tend to think that fecal transplants could be an appropriate therapy for most people as therapy for a C. diff overgrowth, it might be an exceptionally good choice for those without an appendix who do not have a reservoir of healthy bacteria to repopulate the gut after C. diff is eliminated. Furthermore, while I’m uncertain how effective supplemental and dietary probiotics are, it would seem reasonable to encourage those without an appendix (I think it is reasonable to encourage everyone to eat these things, but I think special recommendations should be given to those without an appendix) to eat fermented foods rich in microbiota after episodes of diarrhea. Additionally- the incorporation of dietary prebiotics to encourage the growth of commensal bacteria is probably also a reasonable recommendation. If nothing else, I would suggest that these considerations warrant further thought and potentially some research.

 

It’s also interesting to consider the potential role of the appendix in inflammatory conditions that appear to have an immune component such as ulcerative colitis. It seems that a misfunctioning appendix may play a role in the etiology of these disorders. While removal of the appendix might not be ideal, if it offers a mechanism by which to control these otherwise rather devastating conditions, it should not be overlooked. In these conditions, I would approach appendectomy as a procedure of last resort, but if normal gut function cannot be achieved by normalization of gut flora through other methods, it might appear to be a reasonable approach.

 

Finally- while the appendix appears to be a highly specialized organ, with important and interesting functions, acute appendicitis is a very serious and life-threatening condition. Appendectomy has been the gold-standard treatment for appendicitis for years, however recent research suggests that medical-management (antibiotics) may be effective for some patients [5]. Medical management of this condition represents a serious shift in the approach to treating appendicitis. It also offers an opportunity to save an organ whose importance and function we are only just starting to understand. Again- appendicitis is a life-threatening condition, and not treating it is not an option (if you suspect a problem- get to an emergency room ASAP), but the understanding that this organ plays a real and important role in human physiology suggests that if we can save the organ, perhaps we should (this is in contrast to current trend of ‘if in doubt, take it out’).

 

Understanding that the appendix is a specialized organ that has evolved to play a role in maintaining the gut micro flora is an important development in the study of normal and disturbed gut function. The realization that the appendix acts as a safe house for normal gut flora that can repopulate the gut after disease offers insight into how we might preferentially treat those who lack an appendix after episodes of gut dysbiosis. Furthermore, studying the role of the appendix in maintaining and regulating the actions of the immune system in the gut may offer important insights into understanding and then hopefully treating, immune-based gut conditions. How we might study this, however, is a story for another day. Until then- I hope you’ve enjoyed these musings on the appendix- thinking about the little organ in principle and in practice

 

 

1.         Im, G.Y., R.J. Modayil, C.T. Lin, S.J. Geier, D.S. Katz, M. Feuerman, and J.H. Grendell, The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol Hepatol, 2011. 9(12): p. 1072-7.

2.         Mattila, E., R. Uusitalo-Seppala, M. Wuorela, L. Lehtola, H. Nurmi, M. Ristikankare, V. Moilanen, K. Salminen, M. Seppala, P.S. Mattila, V.J. Anttila, and P. Arkkila, Fecal Transplantation, Through Colonoscopy, Is Effective Therapy for Recurrent Clostridium difficile Infection. Gastroenterology, 2012. 142(3): p. 490-6.

3.         Hamilton, M.J., A.R. Weingarden, M.J. Sadowsky, and A. Khoruts, Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012

4.         Borody, T.J. and A. Khoruts, Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol, 2011. 9(2): p. 88-96.

5.         Liu, K. and L. Fogg, Use of antibiotics alone for treatment of uncomplicated acute appendicitis: a systematic review and meta-analysis. Surgery, 2011. 150(4): p. 673-83.

 

 

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