Discussion

In this study, we examined direct and short-term indirect transmission of C. difficile originating from children <3 year old. The WGS interrogation of epidemiologically and MSLT-linked cases did not confirm any credible source of transmission from children <3 years old who tested positive for CDI. No clonal outbreaks originating from donor patients in our cohort were uncovered with the application of WGS. The contribution of common environmental reservoirs of C. difficile toward hospital-based transmission within the hospital environment deserves further exploration, especially among immunocompromised hosts. Previous assessments in pediatric healthcare settings including children of all ages have also found limited evidence of transmission from symptomatic children.^{Reference Kociolek, Gerding, Espinosa, Patel, Shulman and Ozer12,Reference Castagnola, Battaglia and Bandettini13} Most pediatric CDI cases are healthcare-associated and occur in older hospitalized children (>5 years old) with serious comorbid conditions, among which cancer is the most common.^{Reference Spigaglia, Barbanti, Castagnola, Diana, Pescetto and Bandettini14} In recent years CDI is increasingly been diagnosed among children <3 years old in oncology settings, largely due to the widespread use of highly sensitive molecular diagnostic methods.^{Reference Al Ghounaim, Longtin, Gonzales, Merckx, Winters and Quach6,Reference de Blank, Zaoutis, Fisher, Troxel, Kim and Aplenc15} Differentiating true disease from colonization can be especially challenging in younger children, particularly if adult criteria are used to define disease severity in pediatric cases.^{Reference Pai, Aliyu, Enoch and Karas16} The high frequency of symptomatic or asymptomatic C. difficile carriage in the very young posits a unique nosocomial threat to older susceptible children admitted to the same pediatric unit. Although cautious testing is advised for children <2 years old and treatment is often not indicated, control measures are almost universally instituted for C. difficile–positive cases. Our study sheds light on the possible transmission dynamics of C. difficile from patients <3 years old with likely route of cross infection to others through shared environment reservoir rather than direct patient to patient spread of a clonal strain.

Our data, although compelling for a lack of direct C. difficile transmission from the youngest oncology patients to other pediatric oncology patients, have some limitations. First, not all the pediatric patients identified as C. difficile–positive had stool retrievable for typing and subsequent sequencing, which could have led to an underestimation of overall transmission events. However, with >80% coverage of both community-acquired and healthcare-associated cases, the likelihood of missed transmission events is minimal. Our study was not designed to examine the indirect transmission potential arising from an environmental reservoir in the community or hospital setting. Finally, our WGS analysis was performed from a single colony, and a broader analysis would enable evaluation of mixed strain infections which are known to occur in up to 9%–15% of all CDI cases. Transmission from undetected coinfecting strains would be missed in our analysis, although such events may occur infrequently. Unfortunately, no benchmarks balancing cost and sensitivity exist for the number of colonies per isolate to sequence in WGS epidemiologic investigations evaluating transmission.^{Reference Eyre, Cule and Griffiths17,Reference van den Berg, Ameen, Furusawa, Claas, van der Vorm and Kuijper18}

In summary, the findings from our study do not indicate that CDI patients <3 years old pose a substantial immediate transmission risk to other hospitalized patients. Routine C. difficile testing, which often begets CDI treatment, should be balanced with downstream consequences, including potential for alterations of gut microbiome.^{Reference Isaac, Scher and Djukovic19} Transmission-based precautions are unlikely to further reduce CDI rates in this age group based on the dynamics revealed here, and larger epidemiologic studies are needed to identify appropriate scalable CDI prevention efforts.