Discussion:
In a nationally representative sample of pediatric CF hospitalizations, we found that concomitant CDI is associated with higher mortality, length of stay, and hospital charges. Furthermore, we observed an increasing proportion of CF hospitalizations complicated by CDI over time between 1997 and 2016. Taken together, these data highlight the need for heightened awareness, early identification, and aggressive management of CF hospitalizations complicated by CDI.
Prior studies have reported the rare occurrence of CDI in CF, despite high colonization rates (47% to 50% of CF patients) with C. difficile . In contrast, our study adds support to the more recent case reports and small case series describing the severe, life threatening impact of C. difficile infection in CF patients, creating an urgent need for interventions to improve hospital outcomes among CF children with CDI.
Increasing CDI among children with CF could be due to several factors, including increased survival rates and thus more time at risk for acquiring nosocomial CDI, exposure to newer antimicrobial agents in the treatment of CF exacerbations, and the dissemination of a more-virulent epidemic strain of C difficile , such as North American pulsed-field gel electrophoresis type 1 (NAP1) . Alternative explanations include the possibility of more frequent testing and/or documentation and coding for CDI during inpatient admissions for CF. Our findings may also be partially explained by greater detection of asymptomatic carriage of C. difficile . Indeed, patients with CF and infants less than 1 year of age are the only populations reported in which C. difficile cytotoxin is frequently recovered from asymptomatic individuals. Early exposure to C. difficile with induction of an immunological response that offers protection against the effects of toxin(s) but not against colonization, epithelial cell associated factors that prevent the binding of cytotoxin, altered intestinal environment unfavorable for C difficile to exert its virulence have been proposed. As such, increasing awareness of C. difficile emergence overall and testing in hospitalized children may contribute to the rising trend, which may not necessarily reflect true infection with C. difficile in the CF population. In addition, in the late 2000s, the introduction of more sensitive C. difficile  assays, such as nucleic acid amplification tests (NAATs), could have probably led to potential overdiagnosis of CDI, since this test detects the gene encoding the toxin rather than the actual toxin. The relative contribution of each of these factors in the CF population has not been defined.
Nevertheless, the excess in-hospital mortality in C. difficile -CF was striking and persisted after multivariate analysis after adjusting for underlying patient and hospital characteristics. Clinicians caring for CF patients should be aware of this risk, particularly as CDI may have an atypical presentation with lack of diarrhea in CF patients. Given this excess mortality along with longer LOS and higher hospital charges, improved diagnosis and treatment will be needed to help mitigate the increased virulence of C. difficile that has been associated with greater morbidity and/or resistance to standard treatment in the general population..