Prospective multicenter evaluation of adherence to the Dutch guideline for children aged 0–16 years with fever without a source—febrile illness in children (FINCH) study

Fever without an apparent source (FWS) is one of the most common reasons for children to visit the Emergency Department (ED) [1]. Most cases of FWS are caused by a mild self-limiting infection, while approximately 6–15% is caused by a severe infection requiring immediate treatment [2]. Clinical presentation is often nonspecific in young children, hampering prompt recognition and adequate management. This diagnostic uncertainty in differentiating severe from self-limiting infections, combined with a higher incidence of severe infection in young infants, leads to high use of ED resources increasing the burden for children presenting with FWS. Likewise, healthcare costs increase, with an almost fivefold higher use of ED resources among infants younger than 3 months compared to children older than 6 months [3]. The Dutch Association of Paediatrics published the national guideline “Fever in secondary care setting in children aged 0–16 years” in 2013, aiming to improve early recognition of severe infections without increasing unnecessary diagnostic testing [4]. The Dutch guideline, adapted from the National Institute for Health and Care Excellence (NICE) of the United Kingdom, provides a step-by-step pathway to assess the risk of infection and subsequently recommends diagnostic testing and treatment.

In general, the purpose of guidelines is to support consistent and effective evidence-based health care and improve clinical outcomes. Practice variation in FWS management, however, remains substantial [5]. A multicenter study reported wide variation in prescriptions of broad-spectrum antibiotics in febrile children between European EDs, of which at least half of the participating EDs had implemented the Dutch or NICE guideline [6]. In a study on the impact of FWS guidelines, the availability of a guideline was not associated with reduced direct costs, and some guidelines did not result in the improvement of clinical outcomes [7]. Thus, the presence of a guideline does not guarantee a positive impact on clinical outcomes. This substantiates the need for guideline evaluation to assess its adherence and applicability in current practice. In turn, this knowledge may reduce unwanted practice variation and ineffective use of guidelines or provide targets for guideline improvement. Evaluation of guideline adherence and outcomes in current practice is a crucial step in guideline development. After the implementation of the Dutch guideline, we retrospectively evaluated guideline adherence, measuring low to moderate adherence in children younger than 3 months without the impact of non-adherence on clinical outcomes [8]. This suggests possibilities for safely reducing diagnostics and treatment in children with FWS. Multicenter prospective evaluation of adherence to the national guideline, including all age groups, is needed to corroborate these findings.

Thus, this prospective multicenter study evaluated the adherence to diagnostic and treatment recommendations of the Dutch national guideline for children aged 0–16 years with FWS. As our secondary aims, we investigated patterns in non-adherence and the impact of non-adherence on clinical outcomes and on the use of diagnostic and therapeutic resources.

We found adherence to the Dutch national guideline in half of children presenting with FWS at the ED. Adherence to the guideline was lower in children categorized as high risk of severe infection. In the non-adherence group, significantly fewer urinalysis, bacterial cultures, lumbar punctures, and antimicrobial treatments were performed compared to the adherence group with no differences in missed severe infections.

In our previous retrospective study in infants younger than 3 months, adherence was 51% with fewer cultures and antibiotic treatment performed in case of non-adherence. We were able to corroborate these findings in the current more multicentered and prospectively performed study covering all age groups [8]. Adherence was particularly low in the high-risk groups, as well as the younger age groups, for which the guideline provides more numerous recommendations compared to the older or low-risk patients. While these are the first studies describing adherence to the Dutch guideline, the NICE guideline for FWS similarly showed low adherence across several European EDs in bacterial cultures and antibiotic treatment [13]. Regarding the measurement of NICE-recommended vital signs, a 52% non-adherence was reported [14]. Non-adherence can be explained by several factors concerning the physician’s knowledge, attitudes, and behavior as well as complicated or variating guidelines [15]. A comparison of ten high-income countries showed wide variation between guidelines in definitions of high risk for severe infection [16]. This variation in defining a patient as high risk, and thus indicating cultures and treatment, could play a role in the low adherence in patients categorized as high risk in this study. We deliberately did not include a survey of reasons for non-adherence so as to not affect the behavior of physicians during our evaluation. Particularly in missed severe infections, it is of importance to understand the reasoning behind a physician’s non-adherence. Some patterns of non-adherence could indicate a lack of physician’s awareness which should be targeted for education to improve adherence. For instance, less urinalysis and urine cultures were performed than recommended by the guidelines. Moreover, often urine cultures were not performed after a negative urinalysis while urinalysis of young infants does not have 100% rule-out value for a UTI [17]. As UTIs are the most frequent cause of FWS yet their clinical presentation is remarkably nonspecific, this requires specific attention [18].

Our findings raise the question of whether interventions need to be applied to increase adherence, or if these adherence rates are actually a symptom of decreased applicability of the current FWS guideline or its acceptability for physicians or patients. Physicians did not start antibiotic treatment in the majority of children aged 1 to 3 months categorized as high risk, indicating that physicians applied a higher threshold to antibiotic treatment than the guideline. The presence of one red flag already categorizes as high risk, while in a validation study of the traffic light system, most red flags showed little individual rule-in value for severe infection across multiple datasets [19]. Furthermore, a large meta-analysis calculated roughly half the rate of severe infection in this age group compared to younger infants [20]. The new United States guideline published in 2022 similarly suggested a less defensive approach to well-appearing febrile infants while the 2021 update of the NICE guideline remained to recommend their traffic light system and concurrent recommendations [21, 22]. If all patients were treated according to the guideline, 187 patients would have received antibiotic treatment of which less than a third was diagnosed with a bacterial infection. Importantly, there was no increase in missed severe infections or adverse clinical outcomes in our study due to non-adherence. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures and treatment. As we reported in our international comparison study, guidelines for febrile children are largely similar across countries and continents, and thus, our results and the need for critical evaluation of guidelines are generalizable to many high-income countries in addition to countries using the NICE guideline [16].

Moreover, rapid viral diagnostic testing, including SARS-CoV-2, RSV, and influenza, revealed a plausible source in 14% of all FWS cases. Although these tests may mostly be of value during their endemic seasons, this illustrates the potential to decrease further bacterial testing and treatment. In line with the low rate of bacterial coinfections in our cohort, other studies showed a significantly lower risk for severe infection in febrile infants positive for viral infections compared with virus-negative infants [23, 24]. As viral PCR testing for enterovirus, although not available as a rapid test, has also shown potential to shorten admission duration and use of antibiotic treatment, evidence-based guidance on viral testing (both rapid and non-rapid methods) should be implemented in the revised FWS guideline [25]. Considering we found a viral cause in our cohort in 41% with low rates of bacterial coinfection, future research efforts in rapid viral testing are needed to decrease ED resource use.

This guideline evaluation study faced several limitations. First, we were not able to register patients presented at the ED who were not recruited by the physician or refused participation. However, considering the distribution of high-risk patients was equal to our previous retrospective sample, the amount of selection bias may therefore be limited [8]. Second, adherence could be overestimated if participation in the study influenced the physician’s behavior. As our primary and secondary outcomes are very comparable to our previous adherence study, which is less vulnerable to participation bias due to its retrospective design, the impact on outcomes may be negligible. Third, our inclusion partly took place during the COVID-19 pandemic, which could have influenced the epidemiology of other pathogens and healthcare-seeking behavior. Fourth, we did not include a random effects model to analyze differences between sites in addition to the adherence per site and site-specific data. Fifth, although methodologically explainable considering participation bias, missing the rationale of physicians for non-adherence is an important limitation in the interpretation of our results.

In conclusion, in our multicenter prospective evaluation of the Dutch guideline for children presenting with FWS the high non-adherence rate did not lead to unfavorable clinical outcomes. In case of non-adherence, physicians have used fewer ED resources than the guideline recommended without increasing missed severe infections. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing, and antibiotic treatment.