Discussion
In this single-center retrospective cohort study of infants and young children with BPD and tracheostomies, identification of pathogenic respiratory bacteria including P. aeruginosa on respiratory culture was not associated with continued need for any respiratory support (e.g., oxygen, positive pressure) at 3 years post-tracheostomy placement. However, P. aeruginosa identification was associated with decreased probability of decannulation by 3 years. Furthermore, the small subpopulation of children with chronic P. aeruginosa had a distinctly lower survival probability as compared with children with no bacterial isolation or only sporadic P. aeruginosa isolation, an association that was not explained by differences in medical complexity. Our findings suggest that respiratory tract P. aeruginosa , when identified sporadically, may not influence long-term respiratory dysfunction, but does delay decannulation. Findings also raise the question of whether chronic P. aeruginosa is inherently harmful or if it is representative of other important sequelae driving mortality.
The lack of association between presence of respiratory bacteria, including P. aeruginosa , and continued use of respiratory support at 36 months post-tracheostomy placement suggests that identification of pathogenic bacteria, whether during ARI or during surveillance testing, may not directly cause or propagate respiratory dysfunction. This is in contrast to what is known among other populations (i.e., cystic fibrosis, COPD), in which such pathogenic respiratory bacteria has been demonstrated to decrease lung function over time, as directly measured by pulmonary function testing and indirectly measured by disease exacerbation risk.14-18,25-30 This lack of association with ongoing respiratory support among children with tracheostomies is particularly important because it was identified in spite of the fact that children with pathogen identification had far more cultures obtained than their peers without pathogen identification. In additional analysis of what factors do drive untimely respiratory support weaning, not surprisingly, a child’s number of complex chronic conditions was associated with continued need for respiratory support in this cohort. While this finding has been described elsewhere,31 the interaction between complexity and pathogenic organism identification warrants further study, as does the role of bacterial quantity and timing in relation to outcomes.
In contrast, children with any identification of P. aeruginosahad only half the probability of achieving decannulation by 3 years post-tracheostomy, suggesting delayed time to decannulation. This effect was additive, with each instance of P. aeruginosa identification decreasing the associated decannulation probability by 35%. This important association was not observed for the collective predictor of any respiratory pathogen identification, but instead was specific toP. aeruginosa .
In the setting of P. aeruginosa isolation specifically, we hypothesize that children with P. aeruginosa identification may be more prone to chronic respiratory symptoms, and therefore be poor candidates for decannulation. This group may also have more frequent culture testing obtained, which, if cultures are positive and are being treated with antimicrobials, could lead to delays. It is also possible that children with other respiratory causes for delayed time to decannulation, such as comorbid airway malacia, obstructive sleep apnea, subglottic stenosis, or other anatomical considerations are more likely to have P. aeruginosa identified on respiratory cultures. There is some limited evidence of an association between malacia and stenosis with non-pseudomonal respiratory bacteria in other pediatric populations, but it is not clear if P. aeruginosa exerts a direct or indirect influence on airway anatomy, or if this effect would be enough to delay decannulation or lead to a requirement for surgical airway reconstruction.32-34
Furthermore, clinicians may perceive an elevated risk of future respiratory illness due to P. aeruginosa and thus hesitate to swiftly decannulate following liberation from respiratory support. Our prior analysis from this cohort identified that P. aeruginosaisolation is not associated with episodes of clinician-diagnosed ARI when controlling for repeated testing and colonization;21 thus the decreased probability of achieving decannulation with P. aeruginosa is not likely explained by direct delays from culture-positive pseudomonal ARI diagnoses or treatments. However, the risk of future ARIs after priorP. aeruginosa is unknown. Similarly, clinicians might perceive a risk of respiratory dysfunction related to this organism (as is well-documented in cystic fibrosis, but not supported by our data here) and therefore proceed with caution towards decannulation.
In addition to potential respiratory-related reasons for delayed decannulation, active non-respiratory comorbidities could increase a child’s risk for P. aeruginosa , as has been demonstrated in adults with chronic disease,35-37 and may simultaneously de-prioritize or delay decannulation proceedings. Although we controlled for comorbid conditions broadly in the form of number of CCC categories in analysis, specific relevant comorbidities may be unaccounted for. There may also be important social, family, or healthcare factors influencing time to decannulation that do not affect time to wean respiratory support. At our institution, steps to wean respiratory support can be advanced in the outpatient or telemedicine settings. However, some steps for decannulation readiness evaluations necessitate hospital-based care (e.g., sleep studies, airway evaluations), which is more difficult and time-intensive to coordinate and requires children be illness-free for longer periods.
Although the prevalence of chronic P. aeruginosa identification in our cohort was very low – lower than reported elsewhere19,20 – the 50% mortality rate identified in this group over the 3 years post-tracheostomy placement warrants attention. Whether this high mortality is a direct effect of P. aeruginosa itself or an indirect effect is unclear from our data, which lacks causes of death. Respiratory infections and antibiotic use are both associated with respiratory and gastrointestinal dysbiosis, which in turn each cause diminished immune system functioning and increased risk for further acute infection of various types, including ARI, among both murine models and humans.38-41 It is furthermore possible that this group of children died of pseudomonal ARIs occurring after pseudomonal colonization; increased frequency of purulent tracheobronchitis and pneumonia have been documented among adults with tracheostomies who have tracheobronchial Gram-negative organism colonization.42 On the other hand, children who are at risk for chronic P. aeruginosa due to immunocompromised status, comorbidities, or high hospital utilization are also likely at higher risk for mortality related to these non-pseudomonal factors, as has been reported in other populations.37,43-47
This study demonstrated a similar overall mortality rate to that reported in other studies of infants and young children with severe BPD and tracheostomies.9 In survival analysis, we identified that most deaths occurred in the first 1 year following tracheostomy placement. In our adjusted analyses, children of non-White, non-Black race had a nearly threefold higher risk of 3-year mortality across predictor groups as compared with white peers; notably, the other covariates of sex, insurance type, and CCCs included in this model did not reach statistical significance. This racial disparity in such an important outcome raises concern for inequitable access to care, barriers to care utilization, inadequate cultural sensitivity or accommodations, or other socioracial factors that could underly this difference. This disparity follows some of the known racial differences in premature birth, a key risk factor for development of BPD.48,49 More distally, Lewis et al. recently identified a 2-fold increased risk of the shorter-term outcome of NICU mortality among non-White infants with severe BPD in a multicenter study;23 there was no racial difference in probability of tracheostomy placements in that study. Our findings provide some evidence that these racial mortality differences, likely the result of racist or biased institutional practices, persist beyond the NICU time course, but further study into causes and implications of longer-term outcome differences along racial lines is warranted.
This study has several limitations. Our study did not differentiate between bacteria identified during acute respiratory illness from bacteria identified in surveillance culture testing (i.e., during wellness). Although at our institution, children with tracheostomies are unlikely to seek medical care outside of CCHMC, it is possible that our study excluded respiratory cultures obtained from external sites, leading to potential rare misclassification of predictor status. The mortality rate of our population was higher than expected; our primary outcome was defined only for alive children, leading to possible selection bias for this analysis. The retrospective design of this study also creates potential for residual confounding, in which other clinical or demographic factors influencing respiratory pathogen detection and outcomes are not captured by our dataset. Furthermore, our center’s results may not be generalizable to other institutions; our institution’s positive culture prevalence is notably lower than that observed at other institutions,20,50 but consistent with our prior internal studies.21,44 This lower prevalence is hypothesized to be related to differences in our population and/or local factors (e.g., infection control policies, lab reporting procedures). Similarly, as noted above, the number of children meeting chronic P. aeruginosa identification criteria was very small which limits the conclusions from that subgroup’s analyses.