Research out of IWK Health is investigating the impact cancer treatment has on the microbiome of pediatric oncology patients. The study draws on an array of medical expertise and statistics to examine the effect antibiotics and antifungals have on this vulnerable population.
Antibiotics and antifungals are regularly used in pediatric hematologic-cancer patients to prevent severe infections and febrile neutropenia, high fever combined with low white blood cell count, the most common serious complication of cancer therapy. Both cancer and the treatment children receive to combat it impact the microbiome, the community of microbes that live naturally in the human gut.
“The routine use of anti-infectives in pediatric oncology patients may contribute to a decline in the integrity of the gut and its microbiome, which impacts its ability to defend itself from germs,” says Dr. Katherine Dunn, research associate at the IWK. “It could also simultaneously create a more welcoming environment for opportunistic pathogens.”
The general effect of antibiotics on the human gut microbiome is profound, but its specific effect on children being treated for cancer has not been well-studied. The effect of antifungal use is even less understood.
“Looking more closely at the microbiome allows us to detect changes related to the clinical effects before they happen and possibly identify markers of disease and/or toxicity,” says IWK Clinical Pharmacy Specialist Dr. Tamara MacDonald.
The pediatric population is particularly challenging because the composition of the microbiome is age dependent, with some of the most pronounced changes occurring in the first three years of life.
“While all of us are humans, data is clear that we are enormously different in terms of our genetics, susceptibilities, the risk for adverse events, drug tolerance, and toxicities,” says IWK hematologist, oncologist and principal investigator Dr. Ketan Kulkarni. “We have demonstrated very significant associations of the microbiome in relation to treatment toxicity and outcome. Our work is paving the way for using microbiome and genomics as biomarkers in our steps towards individualizing therapies and innovation.”
“In general, large and complex microbial datasets are very challenging to analyze because there are many more parameters than samples,” says Joseph Bielawski, statistician and computational biologist at Dalhousie University. ”For this reason, we devoted considerable attention to setting up and interpreting our statistical analyses.”
The study pioneers Canadian research in microbiome in oncology as well as multi-omics (discovery across multiple levels of biology) research in oncology. The research program has flourished because of inhouse expertise in clinical oncology, microbiome, genomics, pharmacology, pathology, bioinformatics, and computational biology.
“Bringing science to practice requires a strong collaboration between the scientists and clinicians,” says Macdonald. “It is imperative that expertise in cancer treatments and disease behavior along with scientific experts in the microbiome and big data analysis work closely together to explain the complicated microbiome and its possible impact on drug delivery and disease outcomes.”
“Having a multidisciplinary team is essential when conducting research like this,” says Masters student Zara Forbrigger. “Clinical expertise can help ensure the results are translatable, bioinformatics ensures the analysis and validity of large data sets, and pharmacists can advise on the possible drug effects.”
“A lot of previous research wasn’t translational,” says Kulkarni. “It looked at one aspect of the microbiome and didn’t include clinical outcomes. Our spectrum of microbiome work encompasses purely basic science work, translation work and clinical studies and guidelines. We are very focussed yet broad to ensure clinical relevance and impact.”
Collectively, these findings have important implications for the treatment of leukemia and lymphoma patients.
The study Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense was published in Frontiers in Cellular and Infection Microbiology.
This research was funded by a Nova Scotia Health Research Foundation (now Research Nova Scotia) establishment grant, Beatrice Hunter Health Research Institute New Investigator grant, and JD Irving Foundation grant to Ketan Kulkarni. In addition, Katherine Dunn was funded by a IWK Research Associateship and The Weston Foundation.
The authors would like to thank participating children and their families, and the nurses at the IWK Health Centre for assistance with sample collection. This work has benefited from the generous support of IWK Foundation.