Check out this in-depth interview with the lead author on the recent New England Journal paper on the use of probiotics in gastroenteritis. David Schnadower was kind enough to sit down with me and James Gray, a Pediatric Emergency Medicine Fellow from Cincinnati Children’s to talk about the study and its implications for the care of children with infectious gastroenteritis. You will find a full transcript of the podcast following the References.
David Schnadower, M.D., M.P.H., Phillip I. Tarr, M.D., T. Charles Casper, Ph.D., Marc H. Gorelick, M.D., M.S.C.E., J. Michael Dean, M.D., Karen J. O’Connell, M.D., Prashant Mahajan, M.D., M.P.H., Adam C. Levine, M.D., M.P.H., Seema R. Bhatt, M.D., Cindy G. Roskind, M.D., Elizabeth C. Powell, M.D., Alexander J. Rogers, M.D., Cheryl Vance, M.D., Robert E. Sapien, M.D., Cody S. Olsen, M.S., Melissa Metheney, B.S., R.N., Viani P. Dickey, A.B., Carla Hall-Moore, B.S., and Stephen B. Freedman, M.D.C.M. NEJM 2018; 379:2002-2014. DOI: 10.1056/NEJMoa1802598.
Tell us a little bit about yourself
Hi, my name is David Schnadower. The first question everyone asks me is about my accent. I was born in the UK, my mother tongue is French, and I grew up in Mexico, hence the weird accent, there you go. I’m an emergency department physician and the academic director for the division of emergency medicine at Cincinnati children’s hospital. My first love is taking care of patients; however, a large part of my work is dedicated to education and research. My main research interests are in improving the diagnosis and management of young children presenting with infectious diseases to the emergency department, particularly UTIs, viral gastroenteritis, bloody diarrhea caused by STEC and lately I’ve become interested in understanding the role of gut microbiome in young infants with serious bacterial infections.
Why are probiotics such an attractive therapy for children with gastroenteritis?
There is not much we can do for kids with diarrhea. We can try to prevent and treat dehydration and prevent transmission among family members and daycare attendees, that’s it! Antidiarrheals are dangerous and contraindicated in children. For many centuries, millennia? People have used fermented products for nutrition, and during illness, including yoghurt. It is also known that the gut flora is disrupted during episodes of gastroenteritis. Probiotics are bacteria, grown in a lab, that are supposed to be good for you. Wouldn’t it be great if we had a product that could help regenerate the gut environment after a period of illness? Or after a course of antibiotics? Or in any disease process where the microbiome is disrupted…?
Probiotics have previously been shown to reduce the duration of illness in gastroenteritis and were incorporated into evidence-based care pathways at many institutions. Why was this study necessary and what did it show?
Prior research in probiotics for kids with gastroenteritis was seriously flawed. Limitations included small studies, unclear outcomes, different product formulations, lack of blinding, allocation concealment etc. Also, many of the studies were performed in inpatients in other countries, and many of them were sponsored by the industry. Meta-analyses of these flawed studies showed a benefit, and in the absence of other options or better studies, parents and doctors started using them more and more, despite these limitations. Finally, because probiotics are marketed as dietary supplements, not drugs, manufacturers have few limits in claiming unproven benefits, and the probiotic industry is worth over 30 billion dollars worldwide and growing at a rampant pace.
It was therefore important to design a definitive high quality double blind randomized controlled trial to assess their effectiveness. We used one of the leading probiotic products in the US, LGG or Culturelle, which is also the product for which there was the most evidence supporting its use, and we set out to put it to the test.
In a few words, after studying close to 1000 patients with acute gastroenteritis in 10 US hospitals, we found that probiotics did not improve patient outcomes when compared to placebo. We looked at every outcome we could think of (combined gastroenteritis severity score, duration and severity of diarrhea and vomiting, duration of fever, unplanned health care visits, household transmission rates, daycare and work absenteeism) as well as in every subgroup (young vs older, on or off antibiotics, viral or bacterial GE, exclusively breast fed vs not) and the answer was always the same: there were absolutely no differences between the probiotic and the placebo.
How important was it that a large research network like PECARN support this study?
PECARN was essential in helping us plan, launch and conduct the study at 10 different sites in the US. Having the backing of such as robust network also helped us secure funding from the NIH.
There is another study that was performed in Canada – can you comment on what it showed and why a parallel study is valuable?
You are correct, Stephen Freedman from Calgary conducted a similar study in Canada, using a different probiotic, and the results are pretty much identical. That article is published in the same issue of the NEJM. The results of these two large and definitive studies do not imply that every probiotic is ineffective in every disease, but they give us pause in addressing an important issue: we should not be prescribing and spending billions of dollars in therapies that are not backed up by solid, high quality evidence. Metanalyses of limited and flawed studies provide limited and flawed recommendations, and about a third of them are debunked once a sufficiently powered RCT is conducted. And there are many such examples in the probiotic literature.
In summary, what do you now recommend regarding the use of probiotics in children with acute gastroenteritis?
Bottom line: Based on these studies we cannot recommend LGG (Culturelle) or Lacidofil for the treatment of acute gastroenteritis in children. I would not recommend parents spending money on these or other probiotics, for this or other conditions, until there are strong data supporting their use. Parents should spend their money in providing the best nutrition that they can afford to their children, including fruits and vegetables.
And for the scientific community: manipulating the microbiome to improve health outcomes is an emerging and exciting science which will require a sophisticated understanding of pathophysiology and high-quality studies. I would hope funding towards those studies outpace the rampant growth of the probiotic industry, but that is my moonshine dream.