Every day, over a thousand children die from diarrheal disease. With an estimated one billion cases affecting young children each year, diarrhea remains the second leading cause of death in children under the age of five after the neonatal period. In this month’s ID/IIDR Combined Rounds, infectious disease investigators Dr. Michael Surette and Dr. Jeffrey Pernica discussed the effects of childhood diarrheal disease on the human microbiome and presented their past and current studies regarding the use of probiotics as an effective treatment for this devastating disease.
Dr. Surette began the presentation with an introduction to the human microbiome, explaining how each individual’s unique microbial composition plays a critical role in health and disease. He discussed how the microbiome changes throughout the course of a lifetime and illustrated how the first two years are especially fragile. From birth, the microbiome expands and establishes an essential role in training and maintaining the body’s immune system. However, external factors such as antibiotic use, acute infection, and poor diet at an early age can greatly shift one’s bacterial composition, impacting development and correlating with an increased risk of developing a number of lifelong chronic diseases. In reference to early childhood diarrhea, Dr. Surette discussed it’s long-term consequences on the microbiome, and stressed the importance of effective treatment and prevention strategies.
Dr. Surette introduced the use of probiotics, which in general terms, are inexpensive, harmless interventions that have been found to correlate with significant health benefits. In regards to the reduction of diarrhea duration in children, several controlled experiments have found probiotic treatments to be effective. He also emphasized the role of the research lab in quality control and characterization of isolates from adverse events to determine if these were associated with the study product. Of the 160 ongoing clinical trials on probiotics, 9 of these are focused on pediatric patients and diarrhea. Dr. Surette identified Dr. Jeffrey Pernica’s involvement in over 20% of them, who followed with a thorough discussion on his most recent findings in the area of enteric infection diagnosis and management in children.
After further discussing the devastating impact of diarrheal disease on a global scale, Dr. Pernica identified the current flaws in diarrheal diagnosis and the limitations in management strategies. Because acute gastroenteritis in children is generally assumed to be viral, empiric antibiotic treatment is typically only administered to children who have blood in their stool. However, through the analysis of collected stool samples from children hospitalized for diarrhea in Botswana, Dr. Pernica and his colleagues were able to conclude that although viruses were the most common cause of disease, bacterial and protozoal enteropathogens were frequently isolated, especially in children who died. Indeed, infection with treatable enteropathogens was associated more strongly with mortality than bloody stools.
Dr. Pernica further presented the well-documented correlation between diarrhea and stunting – the pathologic loss of height, which in turn is closely linked with poor cognitive outcomes in later life. Identifying stunting as an objective outcome of clinical importance, Pernica and his team sought to determine if rapid testing and/or treatment with the probiotic Lactobacillus reuteri led to decreased height loss and diarrhea recurrence in children.
Dr. Pernica’s team conducted a pilot, randomized, controlled, factorial clinical trial where all children were randomized to either rapid testing (plus specific antimicrobial treatment for those found to have a treatable infection) or no testing (the standard of care), and all children were randomized to probiotic treatment or placebo treatment. In the group who received rapid testing and placebo, the odds of having a recurrent episode of diarrhoea within 60 days after enrollment was decreased by 55 percent compared to the control group. In comparison, the same odds for the group who received both rapid testing and the L. reuteri probiotic decreased by an astonishing 93 percent. When evaluating height changes, Dr. Pernica’s team found that the height of the children who received rapid testing and placebo was increased by 0.28 Z after 60 days compared to the control group. In the group of children receiving both the rapid testing and probiotic, their height at 60 days increased by 0.67 Z – findings that greatly support the administration of both rapid testing and probiotics to children hospitalized with severe enteric infection.
Dr. Surette and Dr. Pernica both hope to continue conducting controlled clinical trials with probiotics. In a future substudy, Dr. Surette aims to evaluate the impact of probiotics on the shift or stabilization of the microbiome. For Dr. Pernica, next steps include conducting larger studies that include more children with acute malnutrition – a severe consequence of enteric infection. Both researchers hope to further address the many challenges faced when administering studies with probiotics, such as choosing the right probiotic for the specific indication and individual, choosing the right course of duration for clinical trials, and understanding the mechanisms of probiotics with the aim of improving the next generation of probiotics. They also discussed the importance of identifying critical bacterial targets for diarrhoeal treatment, and the importance of evaluating socioeconomic considerations such as the cost-effectiveness of different types of diagnostic tests and probiotics for use in developing countries. These kinds of studies are imperative in expanding our knowledge of probiotics, and are vital in decreasing the global prevalence of diarrhea and it’s associated diseases.
IIDR Combined Joint Rounds are presented on the first Wednesday of every month at the McMaster University Medical Centre, and are open to all IIDR members and trainees.
Click on the link to view the ID IIDR Combined Rounds Schedule.