We performed a cost-effectiveness analysis to compare commonly cited strategies for risk-stratification in the evaluation of febrile infants, finding that Boston and PECARN strategies provided economically reasonable risk stratification strategies compared to other published clinical prediction rules. Models for each type of SBI varied with respect to treatment costs and health risks after misdiagnosis; the PECARN strategy was favored in the UTI model while the Boston strategy was increasingly cost-effective with higher risk infection types.
We found that the Boston strategy was the most cost-effective strategy in both the bacteremia and bacterial meningitis models. Despite lower sensitivity compared to other strategies, the protective effect offered by empiric ceftriaxone and the cost-savings introduced by a higher specificity outweighed the disutility and costs associated with universal lumbar puncture and CSF testing. Alternatively, the PECARN strategy, which does not require CSF testing or empiric antibiotic administration, was an economical option in both models and may provide benefits not measured in this study, depending on individual risk tolerance or preferences.
We found that in the UTI model, most strategies had a sensitivity ≥ 90% and the risks associated with delayed antibiotics were less substantial than in the other models. Because of this, the benefits of empiric ceftriaxone had a smaller impact, and the model became more sensitive to the costs and disutility associated with admitting patients who were ultimately not diagnosed with UTI.
We found that there were no scenarios in which application of clinical suspicion alone was economically reasonable. In this strategy, infants with fever were assumed to undergo no diagnostic testing if the treating physician assessed their risk to be < 1%. Prior studies investigating variation in infant fever management have noted that a proportion of young febrile infants are discharged from pediatric EDs without additional testing.(4) Our model suggests that the benefits of decreased upfront resource utilization are outweighed by the increased risk and associated costs for the few missed infants with SBI.
To our knowledge, this is the first cost-effectiveness analysis of risk-stratification of febrile infants to evaluate the most recently reported clinical prediction rules for febrile infants. Lieu, et al, demonstrated the benefits of outpatient management of low-risk infants with ceftriaxone using Boston and Philadelphia criteria.(22) In their study, sensitivity analyses indicated that treatment of low-risk infants with ceftriaxone would not be the preferred strategy if an alternative diagnostic strategy had ≥ 97% sensitivity. In our sensitivity analysis, the PECARN strategy would be preferred over the Boston strategy if its sensitivity were ≥ 98%. Our study builds on prior work by considering the impact of modern disease prevalence and epidemiology, as well as prediction rules with improved diagnostic accuracy.
One of the strengths of this study is the separate consideration of the three most common serious bacterial infections in infants. While their presentations can be similar and prior studies have analyzed them as a group, the prognosis and the consequences of misdiagnosis for each are substantially different, particularly for bacteremia and bacterial meningitis.(8, 23–27) Recent investigators have also attempted to separate UTI from bacteremia and bacterial meningitis, using the term invasive bacterial infection for the latter.(4, 11–14) In this study, developing disease specific models allowed for a better understanding of how each rule performed across the spectrum of disease, from the low risk and low costs of UTI to the high risk and high costs of bacterial meningitis.
Our findings are subject to limitations. Older prediction rules, such as the Philadelphia, Rochester and Boston criteria, were developed and validated during a period when invasive bacterial infection had a higher incidence.(39) In contrast, some recent rules, such as the Modified Philadelphia, Aronson, and Step-by-Step criteria, may be more reflective of present-day epidemiology but lack external validation. Local practices often do not strictly adhere to published protocols and our model was limited to strategies with published data.4 We attempted to account for these factors by examining sensitivity and specificity ranges across their calculated 95% confidence intervals in sensitivity analyses. We did not consider the impact of increased outpatient visits associated with a larger proportion of infants categorized as low-risk. Given that our sensitivity analysis did not demonstrate that the model was sensitive to either the large costs of hospitalization or the relatively low costs of CSF testing, it is unlikely that the additional cost of an outpatient visit would change model outcomes.
We adapted utility values from the literature. Infant health state utilities are poorly defined and understudied.(40) It is possible that an older individual’s experience with bacterial infection, lumbar puncture, or hospitalization is different from that of an infant. For this reason, selected utility values were varied over wide ranges. Varying these values did not change favored strategies.
We used a healthcare perspective and, as such, did not evaluate the perspective of families and caregivers, costs of missed or lost employment, or the disutility of caring for an ill child either in the hospital or at home. This, in turn, could bias results toward or against rules associated with higher hospitalization rates. We did not account for inherent risks of hospitalization and medical interventions, including iatrogenic complications and nosocomial infections, and subsequent associated costs. However, these would only increase the costs associated with strategies that require more frequent hospitalization and thereby not change the ultimate findings in our study. Despite these limitations, this study demonstrates the value associated with application of clincial prediction rules in the emergency setting, and how we can effectively and efficiently evaluate young febrile infants from the perspective of clinicians and health systems.