DISCUSSION
In this retrospective cohort study of all respiratory cultures from children with tracheostomies, cultures obtained in children with a diagnosis of ARI had a 29% higher odds of overall organism isolation compared to children without ARI. Although many organism species were isolated in both groups, ARI diagnosis was only associated with isolation of 4 specific organisms (H. influenzae , M. catarrhalis , S. pyogenes , and S. pneumoniae) , all of which are expected in usual bacterial respiratory infections. After controlling for patient-level factors and serial culture sampling, isolation of P. aeruginosa was not associated with ARI diagnosis, suggesting this organism may not be considered causative of ARI and may not require acute treatment. Furthermore, respiratory cultures performed poorly as a screening test for bARI, with low sensitivity and moderate specificity. Taken together, our data suggest that the utility of respiratory culture testing to diagnose, direct treatment for, or even screen for ARI and bARI among children with tracheostomies is limited.
The clinical interpretation of respiratory cultures in children with tracheostomies is highly complex, both during states with ARI and without ARI, and is becoming more nuanced as epidemiology evolves.7 The respiratory tract is not a sterile site and many factors influence the dynamic composition of oropharyngeal flora in children with and without artificial airways.8,17,18 Chronic bacterial colonization of the respiratory tract is a presumed entity, but is difficult to define and identify in practice.19-21 Emerging studies are illuminating the complex interaction of the respiratory tract flora with viruses (i.e., Haemophilus and Moraxella “blooms”), colonizing bacteria, inflammatory biomarkers, and the microbiome-host interplay.10,22-26 Thus the traditional, reductionist notion of attributing an ARI to a single bacteria, virus, or even single group of pathogens is increasingly recognized as inadequate.9,27
In our study, respiratory cultures obtained during ARI had higher adjusted odds of identifying a bacterial organism, a finding which seems to support some role of respiratory culture testing in diagnosing ARI. Presumably, the identified organism is a pathogenic cause of ARI in many of these circumstances, though the nuanced reasons stated above and retrospective studies in related populations would argue the isolation of some organisms may still be circumstantial.11,19,28Despite this seemingly straightforward association, this study highlights other perplexing and contradictory epidemiologic culture findings. One the one hand, the majority of respiratory cultures in children with ARI (76.9%) in our study were negative; such a finding could be the result of multiple factors including an underlying viral etiology of ARI in many of these children (who would not be expected to have positive bacterial cultures), symptomatic microbiome shifts27,29 or bacterial “blooms”,10 inadequate culture sampling, or a generally low yield of the respiratory culture test. In contrast, a number of positive respiratory cultures were identified among children without ARI; in the absence of a clinician diagnosis of ARI, positive cultures may indicate clinician interpretation of chronic bacterial colonization of the respiratory tract.19,20,30,31These contradictory culture findings suggest that respiratory culture positivity alone has unclear diagnostic yield in differentiating acute bacterial infection, viral infection, and chronic colonization.
During ARI in children with tracheostomies, clinicians may use respiratory culture results to inform antibiotic prescribing decisions including continuation, modification, or discontinuation of therapy. Increased respiratory culture acquisition has been associated with increased antibiotic use among children’s hospitals.32,33 In our study only 4 species remained associated with ARI on adjusted, multinomial analysis. These species,H. influenzae , M. catarrhalis , S. pyogenes , andS. pneumoniae , are all expected organisms implicated in usual bacterial respiratory infections among other populations.34 Evidence-based treatment guidelines typically recommend empiric antibiotic therapy directed at these pathogens in uncomplicated cases, without need for organism-identification testing. The association of ARI with this group of organisms challenges the utility of respiratory cultures in directing antibiotic treatment among children with tracheostomies.
Adjusted analysis demonstrated that ARI diagnosis was not associated with isolation of P. aeruginosa and S. aureus . Isolation of these two species is thus more likely related to patient factors (e.g., ventilator dependence, time with tracheostomy tube), and recurrent sampling, as opposed to true ARI. With an equal likelihood of identification both with and without ARI, our findings imply that these organisms may not be causative of ARI but instead be consistent with chronic colonization. Given the weak association of P. aeruginosaidentification with bARI diagnosis, there may be some clinician interpretation of this organism as additionally disease-causing in certain circumstances. Both P. aeruginosa and S. aureusare known to cause biofilm formation of airway devices, a fact which may or may not be the same as airway colonization.30,31,35,36 This study questions the necessity for reflexive anti-pseudomonal and anti-staphylococcal antibiotic treatment of positive cultures in some clinical situations, such as in the absence of infectious symptoms or when viral mono-infection is suspected. How these potentially colonizing airway bacteria may contribute to ARI susceptibility and frequency is not known.27
As a screening test for bARI, the respiratory culture overall demonstrated unfavorable test characteristics.37Respiratory cultures correctly identified only 27.2% of children diagnosed by clinicians with bARI (sensitivity), and had only a 32.9% probability of identifying children with bARI (PPV) with a high false positive rate. The culture had a somewhat better probability of identifying children without bARI (85.4% specificity, 81.7% NPV).37 In this case in which both false positive and false negative test results are common, and both are associated with measurable harm including antibiotic overuse, these test statistics are unsatisfactory. For the clinician at bedside, the positive and negative likelihood ratios for respiratory cultures here are modest at best, and suggest respiratory cultures are not particularly clinically useful as bARI screening tests. This is corroborated by recent evidence of poor concordance between tracheal aspirate and BAL cultures.38
Further evaluation of treatment approaches and clinical outcomes for both positive and negative cultures in relation to ARI diagnosis are needed. In the absence of clinical guidelines to direct clinician ordering or interpretation of respiratory cultures, clinicians order and interpret respiratory cultures in different ways.5,11Clinicians may interpret respiratory culture results in the context of the individual patient, the clinician’s experience, institutional norms, and knowledge of local microbiology lab practices. However, studies have demonstrated wide inter-institutional variability in culture ordering practices, microbiology lab processing, culture results (both positivity rate and organism type), and clinician response to results.5,7,39 Variability in sample quality and lab processing may also contribute, as has been documented in endotracheal tube cultures.39 The consequence of this variability is clinical inconsistency in diagnosing ARI,5 use of and types of antibiotic treatment,32 and probably also patient outcomes including severity, length of illness, and respiratory support needs, all of which limit research and improvement efforts.
This study has several limitations. The use of diagnostic codes to define ARI and bARI predictor status could lead to misclassification of predictor for children with and without these conditions. Although we restricted codes to those most consistent with true infection, it is possible that cultures were incorrectly classified. Furthermore, the association of positive bacterial cultures with ARI cannot imply bacterial causation of these infections; our retrospective study was not designed to explore causation of respiratory bacteria in ARI. The retrospective design of this study also creates the potential for residual confounding; there may be other clinical or demographic factors influencing respiratory culture acquisition and interpretation that we are unable to capture with our discrete dataset. Furthermore, our center’s results may not be generalizable to children with tracheostomies at other institutions. Our institution’s positive culture prevalence is lower than that observed at other institutions;15,40 this is consistent with prior internal studies, and is hypothesized to be related to differences in our population and/or local factors (e.g. infection control policies, lab reporting procedures).