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

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 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 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study Maya Wietske Keuning, Nikki N. Klarenbeek, Hidde J. Bout, Amber Broer, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3843029/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Apr, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Evaluation of guidelines in actual practice is a crucial step in guideline improvement. Retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice. Methods Prospective observational multicenter study, including children three days to sixteen years old presented for FWS at one of seven Emergency Departments in participating secondary and tertiary care hospitals in the Netherlands. Adherence to the Dutch FWS guideline, adapted from the National Institute for Health and Care Excellence (NICE) guideline, was evaluated and patterns in non-adherence and the impact of non-adherence on clinical outcomes and resource use were explored. Results Adherence to the guideline was 192/370 (52%). Adherence was lowest in patients categorized as high risk for severe infection (72/187, 39%), compared to the low risk group (64/73, 88%). Differences in adherence were significant between risk categories (P < 0.001) but not between age categories. In case of non-adherence, less urinalysis, less bacterial cultures (blood, urine and cerebral spinal fluid) and less empirical antibiotic treatment were performed (P < 0.050). Clinical outcomes were not significantly different between the non-adherence and the adherence group, particularly regarding missed severe infections. Conclusions We found a high non-adherence rate of 48%, which did not lead to unfavorable clinical outcomes. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing and antibiotic treatment. fever without a source children clinical practice guidelines guideline adherence Figures Figure 1 Figure 2 Figure 3 Figure 4 What is Known – What is New What is Known: Despite the development of national guidelines, variation in practice is still substantial in the assessment of febrile children to distinguish severe infection from mild self-limiting disease. Previous retrospective research suggests low adherence to national guidelines for febrile children in practice. What is New: In case of non-adherence to the Dutch national guideline, similar to the National Institute for Health and Care Excellence (NICE) guideline from the United Kingdom, physicians have used less resources than the guideline recommended without increasing missed severe infections. Introduction 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 a high use of ED resources increasing the burden for children presenting with FWS. Likewise health care costs increase, with an almost five-fold higher use of ED resources among infants younger than three months compared to children older than six 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 improving 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 improvement of clinical outcomes. 7 Thus, the presence of a guideline does not guarantee 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 implementation of the Dutch guideline we retrospectively evaluated guideline adherence, measuring low to moderate adherence in children younger than three months without 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. Materials and methods Study design and participants : This prospective observational multicenter study included children presenting with FWS at the ED in one of seven participating secondary and tertiary care hospitals, organized in the Pediatric Research and Evaluation Network Amsterdam, in the North-West region of the Netherlands during December 2020 to May 2022. Inclusion criteria, directly adopted from the national guideline, were (I) children aged 3 days to 16 years; (II) presenting with FWS, defined as a temperature of ≥ 38.0°C at home or during ED visit and (IIA) no evident focus of infection after history and physical examination or (IIB) a clinical presentation not fitting the potential focus according to the treating physician. 4 Exclusion criteria were: children with hospital-acquired or post-operative fever and children initially presenting with a typical febrile seizure in case of a clear focus for the fever. FWS guideline definitions : Severe infection was defined according to the guidelines: a confirmed Herpes Simplex virus (HSV) encephalitis, sepsis, bacterial meningitis, urinary tract infection (UTI), septic arthritis, osteomyelitis, pneumonia or Kawasaki disease. 4 The guideline recommends separate diagnostic and treatment pathways based on age category of the patient and the risk of severe infection category (Fig. 1 ). Age categories are defined as children younger than one month, one to three months, and older than three months and risk of severe infection is categorized as low (green), intermediate (amber) and high risk (red) (Fig. 1 ). The risk of severe infection is categorized based on a combination of age, red or amber flags of the NICE traffic light system (supplementary table 1 ), Rochester criteria for children younger than two months (supplementary table 2) and the results of initial diagnostic testing. Initial diagnostic testing include dipstick urinalysis, C-reactive protein (CRP) and, in children younger than three months, white blood cell and differential count (WBC) (Fig. 1 ). Subsequently, patients younger than one month can be categorized as having an intermediate or high risk of severe infection while patients aged one to three months or older than three months can be categorized as having a low, intermediate or high risk of severe infection (Fig. 1 ). Age younger than 13 days was considered a red flag and therefore always categorized as high risk. Per the age and risk of infection category, the guideline provides recommendations for additional diagnostic testing (bacterial cultures, viral Polymerase Chain Reaction (PCR) testing, cerebral spinal fluid (CSF) analysis and chest X-rays), hospital admission and empirical antimicrobial treatment similar to the NICE guideline (Fig. 1 ). Treatment recommendations include empirical intravenous (IV) antibiotics, oral antibiotics and IV acyclovir. When rapid viral testing was positive for influenza or respiratory syncytial virus (RSV) in its endemic season, the guideline states to only perform a diagnostic work-up for a potential severe infection in case of an ill-appearing patient. In case of a positive rapid viral test and a well-appearing patient, bacterial cultures and empirical antibiotic treatment were not indicated. Since rapid diagnostic testing of severe acute respiratory syndrome coronavirus (SARS-CoV-) 2 was implemented in the course of the study and recommendations for this novel virus were not yet described in the FWS guideline, we calculated adherence for SARS-CoV-2 positive and negative patients separately. Adherence in patients with a positive rapid test for SARS-CoV-2, the coronavirus disease 2019 (COVID-19) cohort, was evaluated similar to influenza and RSV infection recommendations. For further analyses of patterns and impact of adherence, patients with a positive SARS-CoV-2 rapid test were excluded. Data collection Eligible patients were managed in the ED according to the judgement of the treating physician. After informed consent was obtained, data regarding the ED visit evaluation and management was collected prospectively by the treating physician. These data included patient characteristics, history and physical examination during ED visit, diagnostic testing and treatment, testing results and clinical outcomes collected seven days after the initial ED visit. Subsequently, adherence of each case to the Dutch FWS guideline was assessed. Data analysis and outcomes The primary study outcome was the proportion of cases with full adherence to all the recommendations of the guideline. Non-adherence was subdivided in non-adherence to diagnostic and/or treatment recommendations. Cases with an unclear adherence or diagnosis were discussed in the study team blinded for the hospital and treating physician. Antibiotic treatment performed while this was not recommended was also considered non-adherence. In case CRP or urinalysis was missing and risk category could not be determined, the risk category was considered as missing data and considered as non-adherence. For the secondary study outcomes, the adherence group and the non-adherence group were compared in terms of: patient characteristics, clinical outcomes and the use of diagnostic and therapeutic resources. For patterns in non-adherence, the patient characteristics were compared between adherence groups. For the clinical outcomes we assessed potentially missed severe infections in the adherence and non-adherence group based on reported delayed antibiotic treatment (> 12 hours) in confirmed bacterial infections, ED revisits and (re)admissions within 7 days after initial visit. Further clinical outcomes included: final discharge diagnosis as reported in medical charts, need for IV fluids, O2 support or intensive care unit (ICU) transfer, mortality, length of admission and delayed antibiotic treatment (> 12 hours) overall. The use of resources was measured as the number of performed testing and treatment per age and risk category in the adherence and the non-adherence group. Statistical methods : SPSS Statistics version 26.0 (IBM Corp, New York, USA) was used for all analyses. For continuous variables means with standard deviations or medians with interquartile ranges were calculated. Differences between groups in not-normally distributed variables were analyzed with a Mann-Whitney U test. Categorical variables were depicted in proportions and differences between proportions were analyzed using Pearson’s Fisher’s exact test. The following potential predictors of non-adherence were identified: age category, risk of severe infection category and comorbidity. As the guideline did not provide a definition of comorbidity, in this analysis we defined comorbidity as a chronic underlying condition that is expected to last at least one year. 9 All variables with clinical importance and/or a P < 0.250 in univariable regression analysis were included in the multivariable regression model after checking for collinearity. For all comparisons an alpha value of < 0.050 was considered statistically significant. The Bonferroni correction method was used to adjust p-values for multiple comparisons. Study approval The study protocol was approved by the Medical Ethics Committee of the Amsterdam University Medical Centers (W20_309 # 20.344) and a waiver for the Medical Research Involving Human Subjects Act was provided. Written informed consent was obtained from parents/guardians and/or from children above the legal age of consent. Results Patient selection : A total of 370 patients were included in the cohort and further analysis of adherence was performed on n = 333 after exclusion of SARS-CoV-2 positive patients identified with rapid viral testing upon arrival at the primary ED visit (figure 2). Patient characteristics (n=370) : Characteristics, number of performed diagnostic testing and treatment, final diagnoses and clinical outcomes are shown in table 1. Of the total cohort, 110/370 (30%) patients were younger than one month, 165/370 (45%) were one to three months old and 95/370 (26%) were older than three months. The risk of severe infection was categorized as low in 90/370 (24%), intermediate in 62/370 (17%) and high in 201/370 (54%) of the patients. The overall hospital admission rate was 269/370 (73%) with higher proportions in the high risk group (169/187, 90%) and medium risk group (45/57, 80%) compared to low risk (28/73, 38%). Overall antibiotic treatment rate was 141/370 (38%),which was given IV in 121/370 (33%). In the high risk group 115/187 (62%) received antibiotics, in the medium risk group 16/57 (28%) and 6/73 (8%) in the low risk group. Of the patients categorized as high risk of severe infection, a lumbar puncture was performed in 88/201 (44%), of which 80/201 (39%) were tested for HSV and 61/201 (30%) patients were empirically treated with IV acyclovir. There were no ICU transfers or deaths in the cohort. Severe infections : A final diagnosis of bacterial infection was confirmed in 56/370 (15%), a clinical diagnosis of pneumonia in 7/370 (2%) and HSV encephalitis in 2/370 (0.5%) (Table 1). Viral infections were identified in 153/370 (41%). Rapid viral testing identified a viral infection upon presentation in 53/370 (14%). A viral and bacterial coinfection was confirmed in 9/370 (2%). The bacterial infection rate correlated with risk of severe infection according to the guideline categorization: 2/90 (2%) in the low risk group compared to 6/62 (10%) in the intermediate and 48/209 (24%) in the high risk group. Similarly, the bacterial infection rate was higher in patients younger than one month compared to the older age categories (table 1). Adherence (n=370) : Full adherence to all recommendations was reported in 192/370 (52%) and after exclusion of patients with positive SARS-CoV-2 rapid testing 167/333 (50%) (figure 2). Non-adherence to one recommendation was 67/370 (18%), non-adherence to two recommendations was 47/370 (13%), to three separate recommendations was 27/370 (7%) and to four or more recommendations was 39/370 (11%). Patterns of non-adherence (n=333) : For our secondary aim we evaluated patterns in non-adherence by describing patient characteristics per adherence group, excluding patients with a positive SARS-CoV-2 rapid test. In case of non-adherence mostly blood or urine cultures and lumbar punctures were not performed (figure 3). Antibiotics were not started in 72/187 (39%) of patients in whom empirical treatment was recommended (figure 3). Figure 4 shows adherence per age and risk category. Adherence was lowest in patients younger than one month categorized as intermediate risk of severe infection 5/19 (26%) and highest in patients one to three months categorized as low risk 37/39 (95%). Differences in adherence were significant between risk categories (P < 0.001) but not between age categories (P= 0.095). In multivariable logistic regression (including age category, risk of severe infection and comorbidity) only the risk category was an independent predictor for non-adherence: the high risk category showed an adjusted odds ratio of 11.67 (95% confidence interval 5.18 – 26.25, P < 0.001) compared to the low risk category. There were no significant differences between the adherence and the non-adherence group in the number of severe infections or time of ED visit (table 2). Impact of non-adherence (n=333) : To evaluate the impact of non-adherence, we compared the clinical outcomes (table 2) and the number of performed diagnostic testing and treatment in the adherence group versus the non-adherence group (table 3 and 4). The median admission rate was one day shorter in the non-adherence group (P= 0.010). There were no significant differences in mortality, ICU admission, readmission rates, or missed severe infections between the adherence and non-adherence group (table 2). If treated according to the guideline, 187 patients would have received antibiotic treatment of which 53 patients were diagnosed with a bacterial infection. Regarding missed severe infections, the FWS guideline did not recommend antibiotic treatment in three patients in the adherence group (2%), which were later diagnosed with a UTI or bacterial meningitis. In the non-adherence group five patients did not receive antibiotic treatment while this was recommended (3%). These patients received delayed antibiotic treatment and were later diagnosed with a UTI, UTI with bacteremia or a bacterial and viral meningitis. In the high risk category, there were significantly lower rates of blood/urine cultures, lumbar punctures and antimicrobial treatment in the non-adherence group (table 3). In the low risk category, significantly less cultures were performed in patients younger than one month and urinalysis and admission in patients older than three months (table 4). Adherence in COVID-19 cohort (n=37) : In 26/37 (70%) of the COVID-19 cohort there was no ill appearance reported and the other 11/37 (30%) presented with an ill appearance, meaning the presence of a red flag. Adherence was 23/37 (62%) in the COVID-19 cohort. Non-adherence in this cohort consisted of bacterial cultures or empirical antibiotic treatment while there was no ill appearance or incomplete bacterial cultures or antibiotic treatment in case of an ill appearance. Hospital admission rate was 24/37 (65%) and IV antibiotic treatment was 4/37 (11%). One patient was diagnosed with Multisystem Inflammatory Syndrome in Children, one co-infection with influenza was reported, and one bacterial coinfection with a UTI. Discussion 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 less urinalysis, bacterial cultures, lumbar punctures and antimicrobial treatment were performed compared to the adherence group with no differences in missed severe infections. We were able to corroborate the findings from our retrospective study in infants younger than three months in this multicenter prospective 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. 10 Regarding measurement of NICE-recommended vital signs a 52% non-adherence was reported. 11 Non-adherence can be explained by several factors concerning the physician’s knowledge, attitudes and behavior as well as complicated or variating guidelines. 12 A comparison of ten high-income countries showed wide variation between guidelines in definitions of high risk for severe infection. 13 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 as to not affect behavior of physicians during our evaluation. Particularly in the 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. 14 As UTIs are the most frequent cause of FWS yet their clinical presentation remarkably nonspecific, this requires specific attention. 15 Our findings raise the question 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 one to three months categorized as high risk, indicating that physicians applied a higher threshold to antibiotic treatment than the guideline. 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. 16 Furthermore, a large meta-analysis calculated roughly half the rate of severe infection in this age group compared to younger infants. 17 The new United States guideline published in 2022 similarly suggested a less defensive approach of well-appearing febrile infants while the 2021 update of the NICE guideline remained to recommend their traffic light system and concurrent recommendations. 18 , 19 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 of 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. 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, others studies showed a significantly lower risk for severe infection in febrile infants positive for viral infections compared with virus-negative infants. 20 , 21 As viral PCR testing for enterovirus, although not available as rapid test, has also shown potential to shorten admission duration and use of antibiotic treatment, evidence-based guidance on the use of viral testing (both rapid and non-rapid methods) should be implemented in the revised FWS guideline. 22 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 that were not recruited by the physician or refused participation. Selection bias could therefore have overestimated the number of high-risk patients, as the physician may have not considered using the guideline in very well-appearing FWS patients. Second, adherence could be overestimated if participation to 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 selection 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 health care seeking behavior. 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 less 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. Abbreviations COVID-19 coronavirus disease 2019 CRP C-reactive protein CSF cerebral spinal fluid ED Emergency department IV intravenous HSV Herpes Simplex virus FWS Fever without an apparent source NICE National Institute for Health and Care Excellence PCR polymerase chain reaction RSV respiratory syncytial virus SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 ICU intensive care unit UTI urinary tract infection WBC white blood cell count Declarations Confict of interest and funding : No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Author contributions: All authors contributed to the study conception and design, patient inclusion and data collection. Data analysis were performed by Maya W. Keuning. The first draft of the manuscript was written by Maya W. Keuning and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethical approval : The study was approved by the Medical Ethics Committee of the Amsterdam University Medical Centers (W20_309 # 20.344) and a waiver for the Medical Research Involving Human Subjects Act was provided. The study was performed in accordance with the Declaration of Helsinki and written informed consent was obtained from parents/guardians and/or from children above the legal age of consent. Data availability statements: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgements : This study would not have been possible without the financial support of the Tergooi Scientific committee. We are thankful for the hard work and enthusiasm of the physicians and medical students supporting patient inclusion and data collection. Finally, we are most grateful to all the parents and children participating in this study. References Alpern ER, Stanley RM, Gorelick MH, Donaldson A, Knight S, Teach SJ, et al. Epidemiology of a pediatric emergency medicine research network: the PECARN Core Data Project. Pediatric emergency care. 2006;22(10):689–99. Nijman RG, Vergouwe Y, Thompson M, van Veen M, van Meurs AH, van der Lei J, et al. Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study. Bmj. 2013;346:f1706. Leigh S, Grant A, Murray N, Faragher B, Desai H, Dolan S, et al. The cost of diagnostic uncertainty: a prospective economic analysis of febrile children attending an NHS emergency department. BMC medicine. 2019;17(1):48. Oostenbrink RN, RG; Tuut, MK; Venmans, L. 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Table 3 Differences in testing and treatment for high risk of severe infection Risk category High risk for severe infection Age category 3 months Characteristics Adherence N = 38 Non-adherence N = 44 p value Adherence N = 27 Non-adherence N = 62 p value Adherence N = 7 Non-adherence N = 9 p value Diagnostics, N (%) Blood count 38 (100%) 43 (98%) 1.000 27 (100%) 61 (98%) 1.000 7 (100%) 7 (78%) 0.475 CRP 38 (100%) 43 (98%) 1.000 27 (100%) 62 (100%) 1.000 7 (100%) 7 (78%) 0.475 Urinalysis 38 (100%) 37 (84%) 0.765 27 (100%) 56 (90%) 0.172 7 (100%) 8 (89%) 1.000 Blood culture 38 (100%) 27 (61%) 0.001 27 (100%) 20 (32%) 0.001 7 (100%) 4 (44%) 0.034 Urine culture 38 (100%) 28 (64%) 0.001 27 (100%) 27 (44%) 0.001 6 (86%) 3 (33%) 0.060 CSF culture 38 (100%) 16 (36%) 0.001 16 (60%) 2 (3%) 0.001 7 (100%) 5 (56%) 0.088 CSF PCR entero/parechovirus 38 (100%) 11 (25%) 0.001 16 (59%) 2 (3%) 0.001 6 (86%) 2 (22%) 0.041 Treatment , N (%) Admission 38 (100%) 42 (96%) 0.497 27 (100%) 50 (81%) 0.099 7 (100%) 6 (67%) 0.212 Antibiotics 38 (100%) 28 (64%) 0.001 27 (100%) 10 (16%) 0.001 7 (100%) 5 (56%) 0.088 Acyclovir 29 (76%) 11 (25%) 0.001 12 (44%) 2 (3%) 0.001 4 (43%) 1 (11%) 0.106 For all children categorized as high risk of infection the performed diagnostic testing and treatment are depicted per age group and compared between the adherence and non-adherence group (sample n= 187). Proportions were compared between the adherence and non-adherence group with chi-square or Fisher’s exact testing and corrected for multiple testing. An alpha value of < 0.050 was considered statistically significant and depicted in bold. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis. Abbreviations: CRP, C-reactive protein; N, number; PCR, polymerase chain reaction. Table 4 Differences in testing and treatment for low/intermediate risk of severe infection Risk category Low/intermediate risk for severe infection Age category 3 months Characteristics Adherence N = 5 Non-adherence N = 14 p value Adherence N = 44 Non-adherence N = 5 p value Adherence N = 46 Non-adherence N = 16 p value Diagnostics, N (%) Blood count 5 (100%) 14 (100%) 1.000 41 (93%) 5 (100%) 1.000 41 (89%) 13 (81%) 0.668 CRP 5 (100%) 14 (100%) 1.000 43 (98%) 5 (100%) 1.000 46 (100%) 14 (88%) 0.063 Urinalysis 5 (100%) 12 (86%) 0.591 39 (89%) 5 (100%) 0.644 44 (96%) 11 (69%) 0.010 Blood culture 5 (100%) 3 (21%) 0.005 6 (14%) 1 (20%) 1.000 12 (26%) 2 (13%) 0.322 Urine culture 5 (100%) 5 (36%) 0.033 16 (36%) 3 (60%) 0.363 16 (35%) 1 (6%) 0.048 CSF culture 0 (0%) 0 (0%) 1.000 1 (2%) 0 (0%) 1.000 0 (0%) 0 (0%) 1.000 CSF PCR entero/parechovirus 0 (0%) 0 (0%) 1.000 1 (2%) 0 (0%) 1.000 0 (0%) 0 (0%) 1.000 Treatment , N (%) Admission 5 (100%) 14 (100%) 1.000 26 (60%) 2 (40%) 0.639 24 (52%) 2 (13%) 0.007 Antibiotics 2 (40%) 0 (0%) 0.058 1 (2%) 0 (0%) 1.000 12 (26%) 7 (44%) 0.218 Acyclovir 0 (0%) 0 (0%) 1.000 0 (0%) 0 (0%) 1.000 0 (0%) 0 (0%) 1.000 For all children categorized as low or intermediate risk of infection the performed diagnostic testing and treatment are depicted per age group and compared between the adherence and non-adherence group (sample n = 130). Proportions were compared between the adherence and non-adherence group with chi-square or Fisher’s exact testing and corrected for multiple testing. An alpha value of < 0.050 was considered statistically significant and depicted in bold. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis. Abbreviations: CRP, C-reactive protein; N, number; PCR, polymerase chain reaction. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx FINCHmanuscriptsupplementarytablesWJOP30.11.23.docx Cite Share Download PDF Status: Published Journal Publication published 15 Apr, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 08 Mar, 2024 Reviews received at journal 02 Feb, 2024 Reviewers agreed at journal 19 Jan, 2024 Reviewers invited by journal 10 Jan, 2024 Editor assigned by journal 09 Jan, 2024 Submission checks completed at journal 09 Jan, 2024 First submitted to journal 07 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3843029","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266310255,"identity":"142ce23c-14ab-40f3-a9d0-f773418bc306","order_by":0,"name":"Maya Wietske Keuning","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYJACxgYgwQakH0AFDKA0cwMhLcwgpRJIWhjxawHpkiBKi24DjwHjjIrDeXzS7dcqfubU1fFLH9746WbbNnkG6UasWswOALVsOHO4mE3mTNnN3m2HJST70oqlc9tuGzbIHMShhXcD48O2w4ltEjlpN3i3HZAwOMNjANKSwCCRiEfLP4iWwr/b6iTsz/AY/yaoZWMDSEv6MWbebcwSBjw8ZvhtOcz/4eCMY+kgW5ilZbcdlpxxhq3MOufcbcM2XFqOtyU+7KmxTpw/I/3hx7fb6vj5e5g3384puy3PL5F8AJsWBmYGBqgEjwGqDBtW9SiA/QFhNaNgFIyCUTAiAQBbHWRj7cyCfgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Amsterdam, Emma Children's Hospital, Amsterdam Reproduction and Development Research Institute","correspondingAuthor":true,"prefix":"","firstName":"Maya","middleName":"Wietske","lastName":"Keuning","suffix":""},{"id":266310256,"identity":"a7530dd7-f2e2-4032-85f9-a8cb1c5771e5","order_by":1,"name":"Nikki N. 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Bout","email":"","orcid":"","institution":"University of Amsterdam, Emma Children's Hospital, Amsterdam Reproduction and Development Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Hidde","middleName":"J.","lastName":"Bout","suffix":""},{"id":266310258,"identity":"ce078354-5243-4bf4-a25d-4c92254bfae8","order_by":3,"name":"Amber Broer","email":"","orcid":"","institution":"Spaarne Ziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Amber","middleName":"","lastName":"Broer","suffix":""},{"id":266310259,"identity":"779a943b-991a-4243-ae66-8c4b98aa1c96","order_by":4,"name":"Melvin Draaijer","email":"","orcid":"","institution":"Spaarne Ziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Melvin","middleName":"","lastName":"Draaijer","suffix":""},{"id":266310260,"identity":"0b85114e-5ffd-4212-97a1-bb38e46de47b","order_by":5,"name":"Jeroen Hol","email":"","orcid":"","institution":"Noordwest Ziekenhuisgroep","correspondingAuthor":false,"prefix":"","firstName":"Jeroen","middleName":"","lastName":"Hol","suffix":""},{"id":266310261,"identity":"da280e71-912c-4cd6-a56f-0f04ff1ffb44","order_by":6,"name":"Nina Hollander","email":"","orcid":"","institution":"Flevoziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Nina","middleName":"","lastName":"Hollander","suffix":""},{"id":266310262,"identity":"fab2b75d-cf67-4fed-be7d-946d9d07170e","order_by":7,"name":"Marieke Merelle","email":"","orcid":"","institution":"Spaarne Ziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Marieke","middleName":"","lastName":"Merelle","suffix":""},{"id":266310263,"identity":"37d61df2-cf7a-4ab9-ab81-1dcc1f000831","order_by":8,"name":"Amara Nassar-Sheikh Rashid","email":"","orcid":"","institution":"Zaans Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Amara","middleName":"Nassar-Sheikh","lastName":"Rashid","suffix":""},{"id":266310264,"identity":"638f0923-d14b-456b-802f-35496dadaf4a","order_by":9,"name":"Charlotte Nusman","email":"","orcid":"","institution":"Noordwest Ziekenhuisgroep","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Nusman","suffix":""},{"id":266310265,"identity":"958f050c-13d6-4995-af13-d5238ecbfb64","order_by":10,"name":"Emma Oostenbroek","email":"","orcid":"","institution":"Spaarne Ziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Oostenbroek","suffix":""},{"id":266310266,"identity":"24aa9168-0720-4b62-86c1-ec8b0f4a6302","order_by":11,"name":"Milan L. Ridderikhof","email":"","orcid":"","institution":"Amsterdam University Medical Centers","correspondingAuthor":false,"prefix":"","firstName":"Milan","middleName":"L.","lastName":"Ridderikhof","suffix":""},{"id":266310267,"identity":"a21b8abf-0cf0-4bb7-8278-8e14d7ef6398","order_by":12,"name":"Manouck Roelofs","email":"","orcid":"","institution":"Zaans Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Manouck","middleName":"","lastName":"Roelofs","suffix":""},{"id":266310268,"identity":"d27d89dd-6b00-429b-ae20-9edb53fe25aa","order_by":13,"name":"Ellen van Rossem","email":"","orcid":"","institution":"Flevoziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Ellen","middleName":"van","lastName":"Rossem","suffix":""},{"id":266310269,"identity":"ed82160f-9dd4-4500-a7ca-197036687c61","order_by":14,"name":"Sophie R.D. van der Schoor","email":"","orcid":"","institution":"Onze Lieve Vrouwe Gasthuis","correspondingAuthor":false,"prefix":"","firstName":"Sophie","middleName":"R.D. van der","lastName":"Schoor","suffix":""},{"id":266310270,"identity":"7f826404-e93a-4839-8f16-966ca0700a84","order_by":15,"name":"Sarah M. Schouten","email":"","orcid":"","institution":"Noordwest Ziekenhuisgroep","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"M.","lastName":"Schouten","suffix":""},{"id":266310271,"identity":"3ecaac53-c944-433e-ad86-38437af88143","order_by":16,"name":"Pieter Taselaar","email":"","orcid":"","institution":"Onze Lieve Vrouwe Gasthuis","correspondingAuthor":false,"prefix":"","firstName":"Pieter","middleName":"","lastName":"Taselaar","suffix":""},{"id":266310272,"identity":"5ca00133-63bb-44fa-a8d2-44a95e43fc12","order_by":17,"name":"Koen Vasse","email":"","orcid":"","institution":"Onze Lieve Vrouwe Gasthuis","correspondingAuthor":false,"prefix":"","firstName":"Koen","middleName":"","lastName":"Vasse","suffix":""},{"id":266310273,"identity":"c4109d03-703a-4330-95db-8591908f64e9","order_by":18,"name":"Anne-Marie van Wermeskerken","email":"","orcid":"","institution":"Flevoziekenhuis","correspondingAuthor":false,"prefix":"","firstName":"Anne-Marie","middleName":"van","lastName":"Wermeskerken","suffix":""},{"id":266310274,"identity":"cad2ebc2-4b40-4ba7-8715-6ab2b4b2313f","order_by":19,"name":"Julia M.J. van der Zande","email":"","orcid":"","institution":"Onze Lieve Vrouwe Gasthuis","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"M.J. van der","lastName":"Zande","suffix":""},{"id":266310275,"identity":"ef306475-928f-452e-a9df-0700c46bb1cc","order_by":20,"name":"Roy P. Zuurbier","email":"","orcid":"","institution":"Tergooi MC","correspondingAuthor":false,"prefix":"","firstName":"Roy","middleName":"P.","lastName":"Zuurbier","suffix":""},{"id":266310276,"identity":"49140f6e-ec80-4af7-b54e-01cc1601cfdb","order_by":21,"name":"Merijn W. Bijlsma","email":"","orcid":"","institution":"University of Amsterdam, Emma Children's Hospital, Amsterdam Reproduction and Development Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Merijn","middleName":"W.","lastName":"Bijlsma","suffix":""},{"id":266310277,"identity":"d4591f8f-201e-4b7a-b7b9-df1e67ba47dd","order_by":22,"name":"Dasja Pajkrt","email":"","orcid":"","institution":"University of Amsterdam, Emma Children's Hospital, Amsterdam Reproduction and Development Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Dasja","middleName":"","lastName":"Pajkrt","suffix":""},{"id":266310278,"identity":"09d01fc5-cf45-4076-aba7-a01c688978a7","order_by":23,"name":"Frans B. Plötz","email":"","orcid":"","institution":"Tergooi MC","correspondingAuthor":false,"prefix":"","firstName":"Frans","middleName":"B.","lastName":"Plötz","suffix":""}],"badges":[],"createdAt":"2024-01-07 16:44:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3843029/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3843029/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05553-z","type":"published","date":"2024-04-15T06:05:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49486293,"identity":"21c0819e-35ca-48c8-a911-7dc432d88349","added_by":"auto","created_at":"2024-01-11 16:23:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":193268,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Dutch national fever without an apparent source guideline recommendations\u003c/strong\u003e \u003cbr\u003e\nPathway for diagnostic and treatment recommendations per age category as defined by the Dutch FWS guideline and derived from the NICE traffic light system. * Rochester criteria only applicable in children aged younger than two months. Abbreviations: CSF, cerebral spinal fluid; CRP, C-reactive protein; HSV, herpes simplex virus; IV, intravenous; PCR, polymerase chain reaction assay.\u003c/p\u003e","description":"","filename":"FINCHfigure1recommendationsflowchart7.6.22final.png","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/b38231badd941a4781b0e260.png"},{"id":49486289,"identity":"aeed49c2-bb9b-4fd6-9672-c5922efd01d0","added_by":"auto","created_at":"2024-01-11 16:23:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29151,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient inclusion and adherence\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e\u003cbr\u003e\n \u003c/strong\u003e\u003c/em\u003eAbbreviations: COVID-19, coronavirus disease 2019; FWS, fever without a source; n, number.\u003c/p\u003e","description":"","filename":"FINCHfigure3adherenceperrecommendation.png","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/6cb507aaa7548e498b1eaad7.png"},{"id":49486291,"identity":"91fed6d7-eaa8-4fc4-a1cd-5a6c4c0edd0a","added_by":"auto","created_at":"2024-01-11 16:23:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25887,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdherence per age and risk category\u003c/strong\u003e \u003cbr\u003e\nAdherence depicted in the bars is shown in proportions per risk category and per age category, as categorized according to the FWS guideline (sample n= 333). Number of patients per category were: \u0026lt; 1 month high risk n= 82, 1-3 months high risk n= 89, \u0026gt; 3 months high risk n= 16, \u0026lt; 1 month intermediate risk n= 19, 1-3 months intermediate risk n= 10, \u0026gt; 3 months intermediate risk n= 28, 1-3 months low risk n= 39 and \u0026gt; 3 months low risk n= 34. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis.\u003c/p\u003e","description":"","filename":"FINCHfigure4adherenceperageandriskcategory.png","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/70a6dfbf6792b9b04c31b93c.png"},{"id":49487023,"identity":"2c64629e-587e-42ac-b78e-dc74fd60af6d","added_by":"auto","created_at":"2024-01-11 16:31:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":45479,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdherence per recommendation\u003c/strong\u003e\u003cbr\u003e\nProportions of performed diagnostic and therapeutic recommendations (sample n= 333), with the total bar representing all patients for which CRP (n= 333), urinalysis (n= 333), blood culture (n= 206), urine culture (n= 190), cerebral spinal fluid (CSF) culture (n= 98), admission (n= 244) or antibiotic treatment (n= 187) was recommended according to the FWS guideline. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis.\u003c/p\u003e","description":"","filename":"FINCHfigure2FlowchartAdherence11.11.23.png","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/39534c3825a934b98e7e79ca.png"},{"id":55902872,"identity":"49b52caf-0e52-44f0-aaa7-04411df758e7","added_by":"auto","created_at":"2024-05-06 06:05:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1265069,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/cfa9cd8a-c658-4628-a3d7-3aaf1e22a35e.pdf"},{"id":49487022,"identity":"2b46f18f-3d94-4f8f-b28b-54de5c2c3d93","added_by":"auto","created_at":"2024-01-11 16:31:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24782,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/8b8bc557ccdc9d2eaa8ba3cb.docx"},{"id":49486290,"identity":"76cfdf7e-16fb-4262-a6b8-09ee809cd7e3","added_by":"auto","created_at":"2024-01-11 16:23:31","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15620,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/d9c6f5fd95e480384c95f57e.docx"},{"id":49486295,"identity":"df32afc6-573b-4040-ba36-258582aa0924","added_by":"auto","created_at":"2024-01-11 16:23:31","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14830,"visible":true,"origin":"","legend":"","description":"","filename":"FINCHmanuscriptsupplementarytablesWJOP30.11.23.docx","url":"https://assets-eu.researchsquare.com/files/rs-3843029/v1/a8385be86e6d031cdf9943bc.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"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","fulltext":[{"header":"What is Known – What is New","content":"\u003cp\u003e\u003cstrong\u003eWhat is Known:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDespite the development of national guidelines, variation in practice is still substantial in the assessment of febrile children to distinguish severe infection from mild self-limiting disease.\u003c/li\u003e\n \u003cli\u003ePrevious retrospective research suggests low adherence to national guidelines for febrile children in practice.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIn case of non-adherence to the Dutch national guideline, similar to the National Institute for Health and Care Excellence (NICE) guideline from the United Kingdom, physicians have used less resources than the guideline recommended without increasing missed severe infections.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eFever without an apparent source (FWS) is one of the most common reasons for children to visit the Emergency Department (ED\u003cem\u003e)\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Most cases of FWS are caused by a mild self-limiting infection, while approximately 6\u0026ndash;15% is caused by a severe infection requiring immediate treatment.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e 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 a high use of ED resources increasing the burden for children presenting with FWS. Likewise health care costs increase, with an almost five-fold higher use of ED resources among infants younger than three months compared to children older than six months.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The Dutch Association of Paediatrics published the national guideline \u0026ldquo;\u003cem\u003eFever in secondary care setting in children aged 0\u0026ndash;16 years\u003c/em\u003e\u0026rdquo; in 2013, aiming to improve early recognition of severe infections without increasing unnecessary diagnostic testing.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e 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.\u003c/p\u003e \u003cp\u003e In general, the purpose of guidelines is to support consistent and effective evidence-based health care and improving clinical outcomes. Practice variation in FWS management, however, remains substantial.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e 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 improvement of clinical outcomes.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Thus, the presence of a guideline does not guarantee 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 implementation of the Dutch guideline we retrospectively evaluated guideline adherence, measuring low to moderate adherence in children younger than three months without impact of non-adherence on clinical outcomes.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e 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.\u003c/p\u003e \u003cp\u003e Thus, this prospective multicenter study evaluated the adherence to diagnostic and treatment recommendations of the Dutch national guideline for children aged 0\u0026ndash;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.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cb\u003eStudy design and participants\u003c/b\u003e: This prospective observational multicenter study included children presenting with FWS at the ED in one of seven participating secondary and tertiary care hospitals, organized in the Pediatric Research and Evaluation Network Amsterdam, in the North-West region of the Netherlands during December 2020 to May 2022. Inclusion criteria, directly adopted from the national guideline, were (I) children aged 3 days to 16 years; (II) presenting with FWS, defined as a temperature of \u0026ge;\u0026thinsp;38.0\u0026deg;C at home or during ED visit and (IIA) no evident focus of infection after history and physical examination or (IIB) a clinical presentation not fitting the potential focus according to the treating physician.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Exclusion criteria were: children with hospital-acquired or post-operative fever and children initially presenting with a typical febrile seizure in case of a clear focus for the fever.\u003c/p\u003e \u003cp\u003e\u003cb\u003eFWS guideline definitions\u003c/b\u003e: Severe infection was defined according to the guidelines: a confirmed Herpes Simplex virus (HSV) encephalitis, sepsis, bacterial meningitis, urinary tract infection (UTI), septic arthritis, osteomyelitis, pneumonia or Kawasaki disease.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The guideline recommends separate diagnostic and treatment pathways based on age category of the patient and the risk of severe infection category (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Age categories are defined as children younger than one month, one to three months, and older than three months and risk of severe infection is categorized as low (green), intermediate (amber) and high risk (red) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The risk of severe infection is categorized based on a combination of age, red or amber flags of the NICE traffic light system (supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), Rochester criteria for children younger than two months (supplementary table 2) and the results of initial diagnostic testing.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInitial diagnostic testing include dipstick urinalysis, C-reactive protein (CRP) and, in children younger than three months, white blood cell and differential count (WBC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Subsequently, patients younger than one month can be categorized as having an intermediate or high risk of severe infection while patients aged one to three months or older than three months can be categorized as having a low, intermediate or high risk of severe infection (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Age younger than 13 days was considered a red flag and therefore always categorized as high risk. Per the age and risk of infection category, the guideline provides recommendations for additional diagnostic testing (bacterial cultures, viral Polymerase Chain Reaction (PCR) testing, cerebral spinal fluid (CSF) analysis and chest X-rays), hospital admission and empirical antimicrobial treatment similar to the NICE guideline (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Treatment recommendations include empirical intravenous (IV) antibiotics, oral antibiotics and IV acyclovir.\u003c/p\u003e \u003cp\u003e When rapid viral testing was positive for influenza or respiratory syncytial virus (RSV) in its endemic season, the guideline states to only perform a diagnostic work-up for a potential severe infection in case of an ill-appearing patient. In case of a positive rapid viral test and a well-appearing patient, bacterial cultures and empirical antibiotic treatment were not indicated. Since rapid diagnostic testing of severe acute respiratory syndrome coronavirus (SARS-CoV-) 2 was implemented in the course of the study and recommendations for this novel virus were not yet described in the FWS guideline, we calculated adherence for SARS-CoV-2 positive and negative patients separately. Adherence in patients with a positive rapid test for SARS-CoV-2, the coronavirus disease 2019 (COVID-19) cohort, was evaluated similar to influenza and RSV infection recommendations. For further analyses of patterns and impact of adherence, patients with a positive SARS-CoV-2 rapid test were excluded.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData collection\u003c/strong\u003e \u003cp\u003eEligible patients were managed in the ED according to the judgement of the treating physician. After informed consent was obtained, data regarding the ED visit evaluation and management was collected prospectively by the treating physician. These data included patient characteristics, history and physical examination during ED visit, diagnostic testing and treatment, testing results and clinical outcomes collected seven days after the initial ED visit. Subsequently, adherence of each case to the Dutch FWS guideline was assessed.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData analysis and outcomes\u003c/strong\u003e \u003cp\u003e The primary study outcome was the proportion of cases with full adherence to all the recommendations of the guideline. Non-adherence was subdivided in non-adherence to diagnostic and/or treatment recommendations. Cases with an unclear adherence or diagnosis were discussed in the study team blinded for the hospital and treating physician. Antibiotic treatment performed while this was not recommended was also considered non-adherence. In case CRP or urinalysis was missing and risk category could not be determined, the risk category was considered as missing data and considered as non-adherence.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eFor the secondary study outcomes, the adherence group and the non-adherence group were compared in terms of: patient characteristics, clinical outcomes and the use of diagnostic and therapeutic resources. For patterns in non-adherence, the patient characteristics were compared between adherence groups. For the clinical outcomes we assessed potentially missed severe infections in the adherence and non-adherence group based on reported delayed antibiotic treatment (\u0026gt;\u0026thinsp;12 hours) in confirmed bacterial infections, ED revisits and (re)admissions within 7 days after initial visit. Further clinical outcomes included: final discharge diagnosis as reported in medical charts, need for IV fluids, O2 support or intensive care unit (ICU) transfer, mortality, length of admission and delayed antibiotic treatment (\u0026gt;\u0026thinsp;12 hours) overall. The use of resources was measured as the number of performed testing and treatment per age and risk category in the adherence and the non-adherence group.\u003c/p\u003e \u003cp\u003e\u003cb\u003eStatistical methods\u003c/b\u003e: SPSS Statistics version 26.0 (IBM Corp, New York, USA) was used for all analyses. For continuous variables means with standard deviations or medians with interquartile ranges were calculated. Differences between groups in not-normally distributed variables were analyzed with a Mann-Whitney U test. Categorical variables were depicted in proportions and differences between proportions were analyzed using Pearson\u0026rsquo;s Fisher\u0026rsquo;s exact test. The following potential predictors of non-adherence were identified: age category, risk of severe infection category and comorbidity. As the guideline did not provide a definition of comorbidity, in this analysis we defined comorbidity as a chronic underlying condition that is expected to last at least one year.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e All variables with clinical importance and/or a P\u0026thinsp;\u0026lt;\u0026thinsp;0.250 in univariable regression analysis were included in the multivariable regression model after checking for collinearity. For all comparisons an alpha value of \u0026lt;\u0026thinsp;0.050 was considered statistically significant. The Bonferroni correction method was used to adjust p-values for multiple comparisons.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy approval\u003c/strong\u003e \u003cp\u003e The study protocol was approved by the Medical Ethics Committee of the Amsterdam University Medical Centers (W20_309 # 20.344) and a waiver for the Medical Research Involving Human Subjects Act was provided. Written informed consent was obtained from parents/guardians and/or from children above the legal age of consent.\u003c/p\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient selection\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e A total of 370 patients were included in the cohort and further analysis of adherence was performed on n = 333 after exclusion of SARS-CoV-2 positive patients identified with rapid viral testing upon arrival at the primary ED visit (figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient characteristics (n=370)\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e Characteristics, number of performed diagnostic testing and treatment, final diagnoses and clinical outcomes are shown in table 1. Of the total cohort, 110/370 (30%) patients were younger than one month, 165/370 (45%) were one to three months old and 95/370 (26%) were older than three months. The risk of severe infection was categorized as low in 90/370 (24%), intermediate in 62/370 (17%) and high in 201/370 (54%) of the patients. The overall hospital admission rate was 269/370 (73%) with higher proportions in the high risk group (169/187, 90%) and medium risk group (45/57, 80%) compared to low risk (28/73, 38%). Overall antibiotic treatment rate was 141/370 (38%),which was given IV in 121/370 (33%). In the high risk group 115/187 (62%) received antibiotics, in the medium risk group 16/57 (28%) and 6/73 (8%) in the low risk group. Of the patients categorized as high risk of severe infection, a lumbar puncture was performed in 88/201 (44%), of which 80/201 (39%) were tested for HSV and 61/201 (30%) patients were empirically treated with IV acyclovir. There were no ICU transfers or deaths in the cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSevere infections\u003c/em\u003e\u003c/strong\u003e: A final diagnosis of bacterial infection was confirmed in 56/370 (15%), a clinical diagnosis of pneumonia in 7/370 (2%) and HSV encephalitis in 2/370 (0.5%) (Table 1). Viral infections were identified in 153/370 (41%). Rapid viral testing identified a viral infection upon presentation in 53/370 (14%). A viral and bacterial coinfection was confirmed in 9/370 (2%). The bacterial infection rate correlated with risk of severe infection according to the guideline categorization: 2/90 (2%) in the low risk group compared to 6/62 (10%) in the intermediate and 48/209 (24%) in the high risk group. Similarly, the bacterial infection rate was higher in patients younger than one month compared to the older age categories (table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdherence (n=370)\u003c/em\u003e\u003c/strong\u003e: Full adherence to all recommendations was reported in 192/370 (52%) and after exclusion of patients with positive SARS-CoV-2 rapid testing 167/333 (50%) (figure 2). Non-adherence to one recommendation was 67/370 (18%), non-adherence to two recommendations was 47/370 (13%), to three separate recommendations was 27/370 (7%) and to four or more recommendations was 39/370 (11%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatterns of non-adherence (n=333)\u003c/em\u003e\u003c/strong\u003e: \u0026nbsp;For our secondary aim we evaluated patterns in non-adherence by describing patient characteristics per adherence group, excluding patients with a positive SARS-CoV-2 rapid test. In case of non-adherence mostly blood or urine cultures and lumbar punctures were not performed (figure 3). Antibiotics were not started in 72/187 (39%) of patients in whom empirical treatment was recommended (figure 3). Figure 4 shows adherence per age and risk category. Adherence was lowest in patients younger than one month categorized as intermediate risk of severe infection 5/19 (26%) and highest in patients one to three months categorized as low risk 37/39 (95%). Differences in adherence were significant between risk categories (P \u0026lt; 0.001) but not between age categories (P= 0.095). In multivariable logistic regression (including age category, risk of severe infection and comorbidity) only the risk category was an independent predictor for non-adherence: the high risk category showed an adjusted odds ratio of 11.67 (95% confidence interval 5.18 – 26.25, P \u0026lt; 0.001) compared to the low risk category. There were no significant differences between the adherence and the non-adherence group in the number of severe infections or time of ED visit (table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eImpact of non-adherence (n=333)\u003c/em\u003e\u003c/strong\u003e: To evaluate the impact of non-adherence, we compared the clinical outcomes (table 2) and the number of performed diagnostic testing and treatment in the adherence group versus the non-adherence group (table 3 and 4). The median admission rate was one day shorter in the non-adherence group (P= 0.010). There were no significant differences in mortality, ICU admission, readmission rates, or missed severe infections between the adherence and non-adherence group (table 2). If treated according to the guideline, 187 patients would have received antibiotic treatment of which 53 patients were diagnosed with a bacterial infection. Regarding missed severe infections, the FWS guideline did not recommend antibiotic treatment in three patients in the adherence group (2%), which were later diagnosed with a UTI or bacterial meningitis. In the non-adherence group five patients did not receive antibiotic treatment while this was recommended (3%). These patients received delayed antibiotic treatment and were later diagnosed with a UTI, UTI with bacteremia or a bacterial and viral meningitis. In the high risk category, there were significantly lower rates of blood/urine cultures, lumbar punctures and antimicrobial treatment in the non-adherence group (table 3). In the low risk category, significantly less cultures were performed in patients younger than one month and urinalysis and admission in patients older than three months (table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdherence in COVID-19 cohort (n=37)\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e In 26/37 (70%) of the COVID-19 cohort there was no ill appearance reported and the other 11/37 (30%) presented with an ill appearance, meaning the presence of a red flag. Adherence was 23/37 (62%) in the COVID-19 cohort. Non-adherence in this cohort consisted of bacterial cultures or empirical antibiotic treatment while there was no ill appearance or incomplete bacterial cultures or antibiotic treatment in case of an ill appearance. Hospital admission rate was 24/37 (65%) and IV antibiotic treatment was 4/37 (11%). One patient was diagnosed with Multisystem Inflammatory Syndrome in Children, one co-infection with influenza was reported, and one bacterial coinfection with a UTI.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e 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 less urinalysis, bacterial cultures, lumbar punctures and antimicrobial treatment were performed compared to the adherence group with no differences in missed severe infections.\u003c/p\u003e \u003cp\u003eWe were able to corroborate the findings from our retrospective study in infants younger than three months in this multicenter prospective study covering all age groups.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Regarding measurement of NICE-recommended vital signs a 52% non-adherence was reported.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Non-adherence can be explained by several factors concerning the physician\u0026rsquo;s knowledge, attitudes and behavior as well as complicated or variating guidelines.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e A comparison of ten high-income countries showed wide variation between guidelines in definitions of high risk for severe infection.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e 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 as to not affect behavior of physicians during our evaluation. Particularly in the missed severe infections it is of importance to understand the reasoning behind a physician\u0026rsquo;s non-adherence. Some patterns of non-adherence could indicate a lack of physician\u0026rsquo;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.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e As UTIs are the most frequent cause of FWS yet their clinical presentation remarkably nonspecific, this requires specific attention.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Our findings raise the question 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 one to three months categorized as high risk, indicating that physicians applied a higher threshold to antibiotic treatment than the guideline. 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.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Furthermore, a large meta-analysis calculated roughly half the rate of severe infection in this age group compared to younger infants.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The new United States guideline published in 2022 similarly suggested a less defensive approach of well-appearing febrile infants while the 2021 update of the NICE guideline remained to recommend their traffic light system and concurrent recommendations.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e 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 of 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.\u003c/p\u003e \u003cp\u003eMoreover, 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, others studies showed a significantly lower risk for severe infection in febrile infants positive for viral infections compared with virus-negative infants.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e As viral PCR testing for enterovirus, although not available as rapid test, has also shown potential to shorten admission duration and use of antibiotic treatment, evidence-based guidance on the use of viral testing (both rapid and non-rapid methods) should be implemented in the revised FWS guideline.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e 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.\u003c/p\u003e \u003cp\u003e This guideline evaluation study faced several limitations. First, we were not able to register patients presented at the ED that were not recruited by the physician or refused participation. Selection bias could therefore have overestimated the number of high-risk patients, as the physician may have not considered using the guideline in very well-appearing FWS patients. Second, adherence could be overestimated if participation to the study influenced the physician\u0026rsquo;s behavior. As our primary and secondary outcomes are very comparable to our previous adherence study, which is less vulnerable to selection 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 health care seeking behavior.\u003c/p\u003e \u003cp\u003e 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 less 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.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOVID-19\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;coronavirus disease 2019\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;C-reactive protein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCSF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;cerebral spinal fluid\u003c/p\u003e\n\u003cp\u003eED\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Emergency department\u003c/p\u003e\n\u003cp\u003eIV \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;intravenous\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHSV \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Herpes Simplex virus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFWS \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fever without an apparent source\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNICE \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;National Institute for Health and Care Excellence\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;polymerase chain reaction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRSV \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;respiratory syncytial virus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2\u0026nbsp; \u0026nbsp;severe acute respiratory syndrome coronavirus 2\u003c/p\u003e\n\u003cp\u003eICU \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;intensive care unit\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUTI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;urinary tract infection\u003c/p\u003e\n\u003cp\u003eWBC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;white blood cell count\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConfict of interest and funding\u003c/strong\u003e: No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design, patient inclusion and data collection. Data analysis were performed by Maya W. Keuning. The first draft of the manuscript was written by Maya W. Keuning and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e:\u0026nbsp;The study was approved by the Medical Ethics Committee of the Amsterdam University Medical Centers (W20_309 # 20.344) and a waiver for the Medical Research Involving Human Subjects Act was provided. The study was performed in accordance with the Declaration of Helsinki and written informed consent was obtained from parents/guardians and/or from children above the legal age of consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statements:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: This study would not have been possible without the financial support of the Tergooi Scientific committee. We are thankful for the hard work and enthusiasm of the physicians and medical students supporting patient inclusion and data collection. Finally, we are most grateful to all the parents and children participating in this study. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlpern ER, Stanley RM, Gorelick MH, Donaldson A, Knight S, Teach SJ, et al. Epidemiology of a pediatric emergency medicine research network: the PECARN Core Data Project. Pediatric emergency care. 2006;22(10):689\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNijman RG, Vergouwe Y, Thompson M, van Veen M, van Meurs AH, van der Lei J, et al. Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study. Bmj. 2013;346:f1706.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeigh S, Grant A, Murray N, Faragher B, Desai H, Dolan S, et al. The cost of diagnostic uncertainty: a prospective economic analysis of febrile children attending an NHS emergency department. BMC medicine. 2019;17(1):48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOostenbrink RN, RG; Tuut, MK; Venmans, L. Richtlijn: Koorts in de tweede lijn bij kinderen van 0\u0026ndash;16 jaar, Kindergeneeskunde NVK, (december 2013), 208. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nvk.nl/Portals/0/richtlijnen/koorts/koortsrichtlijn.pdf\u003c/span\u003e\u003cspan address=\"https://www.nvk.nl/Portals/0/richtlijnen/koorts/koortsrichtlijn.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRogers AJ, Kuppermann N, Anders J, Roosevelt G, Hoyle JD, Jr., Ruddy RM, et al. Practice Variation in the Evaluation and Disposition of Febrile Infants\u0026thinsp;\u0026le;\u0026thinsp;60 Days of Age. J Emerg Med. 2019;56(6):583\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHagedoorn NN, Borensztajn DM, Nijman R, Balode A, von Both U, Carrol ED, et al. Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study. PLOS Medicine. 2020;17(8):e1003208.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAronson PL, Thurm C, Williams DJ, Nigrovic LE, Alpern ER, Tieder JS, et al. Association of clinical practice guidelines with emergency department management of febrile infants\u0026thinsp;\u0026le;\u0026thinsp;56 days of age. J Hosp Med. 2015;10(6):358\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlarenbeek NN, Keuning M, Hol J, Pajkrt D, Pl\u0026ouml;tz FB. Fever Without an Apparent Source in Young Infants: A Multicenter Retrospective Evaluation of Adherence to the Dutch Guidelines. The Pediatric infectious disease journal. 2020;39(12):1075\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimon TD, Cawthon ML, Stanford S, Popalisky J, Lyons D, Woodcox P, et al. Pediatric Medical Complexity Algorithm: A New Method to Stratify Children by Medical Complexity. Pediatrics. 2014;133(6):e1647-e54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan CD, van der Walle EEPL, Vermont CL, von Both U, Carrol ED, Eleftheriou I, et al. Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study. European journal of pediatrics. 2022;181(12):4199\u0026ndash;209.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan de Maat J, Jonkman H, van de Voort E, Mintegi S, Gervaix A, Bressan S, et al. Measuring vital signs in children with fever at the emergency department: an observational study on adherence to the NICE recommendations in Europe. European journal of pediatrics. 2020;179(7):1097\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PA, Rubin HR. Why don't physicians follow clinical practice guidelines? A framework for improvement. Jama. 1999;282(15):1458\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraaf S, Keuning MW, Pajkrt D, Pl\u0026ouml;tz FB. Fever without a source in children: international comparison of guidelines. World J Pediatr. 2023;19(2):120\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsposito S, Rinaldi VE, Argentiero A, Farinelli E, Cofini M, D'Alonzo R, et al. Approach to Neonates and Young Infants with Fever without a Source Who Are at Risk for Severe Bacterial Infection. Mediators Inflamm. 2018;2018:4869329.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaufman J, Temple-Smith M, Sanci L. Urinary tract infections in children: an overview of diagnosis and management. BMJ Paediatr Open. 2019;3(1):e000487.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKerkhof E, Lakhanpaul M, Ray S, Verbakel JY, Van den Bruel A, Thompson M, et al. The Predictive Value of the NICE \u0026ldquo;Red Traffic Lights\u0026rdquo; in Acutely Ill Children. PLOS ONE. 2014;9(3):e90847.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiondi EA, Lee B, Ralston SL, Winikor JM, Lynn JF, Dixon A, McCulloh R. Prevalence of Bacteremia and Bacterial Meningitis in Febrile Neonates and Infants in the Second Month of Life: A Systematic Review and Meta-analysis. JAMA Network Open. 2019;2(3):e190874-e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePantell RH, Roberts KB, Adams WG, Dreyer BP, Kuppermann N, O\u0026rsquo;Leary ST, et al. Clinical Practice Guideline: Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old. Pediatrics. 2021;148(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Institute for Health and Care Excellence guideline. Fever in under 5s: assessment and initial management. Updated November 2021. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nice.org.uk/guidance/ng143\u003c/span\u003e\u003cspan address=\"https://www.nice.org.uk/guidance/ng143\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahajan P, Browne LR, Levine DA, Cohen DM, Gattu R, Linakis JG, et al. Risk of Bacterial Coinfections in Febrile Infants 60 Days Old and Younger with Documented Viral Infections. The Journal of Pediatrics. 2018;203:86\u0026ndash;91.e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreenfield BW, Lowery BM, Starke HE, Mayorquin L, Stanford C, Camp EA, Cruz AT. Frequency of serious bacterial infections in young infants with and without viral respiratory infections. The American Journal of Emergency Medicine. 2021;50:744\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLafolie J, Labb\u0026eacute; A, L'Honneur AS, Madhi F, Pereira B, Decobert M, et al. Assessment of blood enterovirus PCR testing in paediatric populations with fever without source, sepsis-like disease, or suspected meningitis: a prospective, multicentre, observational cohort study. Lancet Infect Dis. 2018;18(12):1385\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Differences in testing and treatment for\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;high risk of severe infection\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.39072847682119%\" valign=\"top\"\u003e\n \u003cp\u003eRisk category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"83.6092715231788%\" colspan=\"10\" valign=\"top\"\u003e\n \u003cp\u003eHigh risk for severe infection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.39072847682119%\" valign=\"top\"\u003e\n \u003cp\u003eAge category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.52980132450331%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.291390728476821%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"22.019867549668874%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1 to 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.291390728476821%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.549668874172184%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt; 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.927152317880795%\" colspan=\"2\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003c/p\u003e\n \u003cp\u003eN = 38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003c/p\u003e\n \u003cp\u003eN = 27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003cbr\u003eN = 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eDiagnostics,\u0026nbsp;\u003c/em\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eBlood count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e38 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e43 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e27 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e61 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e7 (78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e38 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e43 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e27 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e62 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e7 (78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eUrinalysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e38 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e37 (84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e27 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e56 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e8 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eBlood culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e38 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 (61%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e20 (32%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e7 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (44%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eUrine culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e38 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e28 (64%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 (44%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e6 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e3 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eCSF culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e38 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (36%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (60%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (3%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e5 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eCSF PCR entero/parechovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e38 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e11 (25%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (59%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (3%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 (86%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (22%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.041\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eTreatment\u003c/em\u003e\u003cem\u003e,\u0026nbsp;\u003c/em\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eAdmission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e38 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e42 (96%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e27 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e50 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e6 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eAntibiotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e38 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e28 (64%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e27 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 (16%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e7 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e5 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.417910447761194%\" valign=\"top\"\u003e\n \u003cp\u003eAcyclovir\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.447761194029852%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e29 (76%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.11608623548922%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e11 (25%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e12 (44%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.442786069651742%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (3%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.271973466003317%\" valign=\"top\"\u003e\n \u003cp\u003e4 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.78441127694859%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.301824212271973%\" valign=\"top\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFor all children categorized as high risk of infection the performed diagnostic testing and treatment are depicted per age group and compared between the adherence and non-adherence group (sample n= 187). Proportions were compared between the adherence and non-adherence group with chi-square or Fisher\u0026rsquo;s exact testing and corrected for multiple testing. An alpha value of \u0026lt; 0.050 was considered statistically significant and depicted in bold. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis.\u003cbr\u003eAbbreviations: CRP, C-reactive protein; N, number; PCR, polymerase chain reaction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4 Differences in testing and treatment for\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;low/intermediate risk of severe infection\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRisk category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"10\" valign=\"top\"\u003e\n \u003cp\u003eLow/intermediate risk for severe infection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1 to 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003c/p\u003e\n \u003cp\u003eN = 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003c/p\u003e\n \u003cp\u003eN = 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdherence\u003cbr\u003eN = 46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNon-adherence\u003cbr\u003eN = 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u0026nbsp;\u003cbr\u003e\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eDiagnostics,\u0026nbsp;\u003c/em\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e41 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e41 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e13 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.668\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e43 (98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e46 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e14 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUrinalysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e44 (96%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e11 (69%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (21%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e2 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUrine culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (100%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (36%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (35%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 (6%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.048\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCSF culture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCSF PCR entero/parechovirus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eTreatment ,\u0026nbsp;\u003c/em\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdmission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 (52%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (13%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAntibiotics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e7 (44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.218\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAcyclovir\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFor all children categorized as low or intermediate risk of infection the performed diagnostic testing and treatment are depicted per age group and compared between the adherence and non-adherence group (sample n = 130). Proportions were compared between the adherence and non-adherence group with chi-square or Fisher\u0026rsquo;s exact testing and corrected for multiple testing. An alpha value of \u0026lt; 0.050 was considered statistically significant and depicted in bold. Patients with a positive rapid test for SARS-CoV-2 were excluded from the analysis.\u003cbr\u003eAbbreviations: CRP, C-reactive protein; N, number; PCR, polymerase chain reaction.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"fever without a source, children, clinical practice guidelines, guideline adherence","lastPublishedDoi":"10.21203/rs.3.rs-3843029/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3843029/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003e Evaluation of guidelines in actual practice is a crucial step in guideline improvement. Retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e Prospective observational multicenter study, including children three days to sixteen years old presented for FWS at one of seven Emergency Departments in participating secondary and tertiary care hospitals in the Netherlands. Adherence to the Dutch FWS guideline, adapted from the National Institute for Health and Care Excellence (NICE) guideline, was evaluated and patterns in non-adherence and the impact of non-adherence on clinical outcomes and resource use were explored.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e Adherence to the guideline was 192/370 (52%). Adherence was lowest in patients categorized as high risk for severe infection (72/187, 39%), compared to the low risk group (64/73, 88%). Differences in adherence were significant between risk categories (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but not between age categories. In case of non-adherence, less urinalysis, less bacterial cultures (blood, urine and cerebral spinal fluid) and less empirical antibiotic treatment were performed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.050). Clinical outcomes were not significantly different between the non-adherence and the adherence group, particularly regarding missed severe infections.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe found a high non-adherence rate of 48%, which did not lead to unfavorable clinical outcomes. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing and antibiotic treatment.\u003c/p\u003e","manuscriptTitle":"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","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-11 16:23:26","doi":"10.21203/rs.3.rs-3843029/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-08T14:46:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-02T10:58:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3af3c26a-c0fe-4714-932e-39311effaa7c","date":"2024-01-19T13:23:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-10T16:03:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-10T03:23:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-10T03:23:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-01-07T16:38:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"219e77af-d4c7-4355-a678-8792774b57c8","owner":[],"postedDate":"January 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-06T06:05:31+00:00","versionOfRecord":{"articleIdentity":"rs-3843029","link":"https://doi.org/10.1007/s00431-024-05553-z","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2024-04-15 06:05:31","publishedOnDateReadable":"April 15th, 2024"},"versionCreatedAt":"2024-01-11 16:23:26","video":"","vorDoi":"10.1007/s00431-024-05553-z","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05553-z","workflowStages":[]},"version":"v1","identity":"rs-3843029","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3843029","identity":"rs-3843029","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}