Febrile children with comorbidities at the emergency department — a multicentre observational study

We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3–1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2–3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1–2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1–2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8–7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7–2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2–6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5–24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1–6.9) or PICU admission (aOR 9.7, 6.1–15.5). Conclusions: Our data show how children with comorbidities are a population at risk, as they more often are diagnosed with bacterial infections and more often require PICU admission and life-saving interventions. What is Known: • While children with comorbidity constitute a large part of ED frequent flyers, they are often excluded from studies. What is New: • Children with comorbidities in general are more ill upon presentation than children without comorbidities. • Children with comorbidities form a heterogeneous group; specific subgroups have an increased risk for invasive bacterial infections, while others have an increased risk of invasive interventions such as PICU admission, regardless of the cause of the fever. Supplementary information The online version contains supplementary material available at 10.1007/s00431-022-04552-2.


Introduction
There is an important health paradox regarding children with comorbidities attending the emergency department (ED). On one hand, these children form an increasing group [1]; constitute a large part of the so-called "ED frequent flyers" [2,3]; have an increased risk for invasive bacterial infections (sepsis/meningitis) as well as serious bacterial infections, such as urinary tract infections, pneumonia, or bone and joint infections [4][5][6][7]; and use a larger amount of ED and hospital resources [8,9], yet on the other hand are very often excluded from studies [10][11][12][13]. When research does include children with comorbidities, it usually focuses on specific types of comorbidities, such as febrile neutropenia [14]. The most compelling evidence that shows how children with comorbidities form a very fragile population comes from a recent key paper, showing half of the infection-related deaths in the UK occur in children with comorbidities [15].
However, no details were provided regarding type of comorbidities or presenting problems. Our aim was to address this knowledge gap, by assessing presenting signs and symptoms, clinical management, and cause of infection of febrile children with comorbidities attending the ED in a large European cohort.

Study design
This study is part of the MOFICHE (Management and Outcome of Febrile children in Europe) study, which is embedded in the PERFORM (Personalized Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) study. The MOFICHE study is an observational multicentre study that evaluates the clinical management and outcome of febrile children in Europe using routinely collected data [16].

Ethics statement
The study was approved by the ethical committees of all the participating hospitals, and no informed consent was needed for this study: Austria (Ethikkommission Medizinische Universitat Graz, ID:28-518ex15/ 16 In all the participating UK settings, an additional opt-out mechanism was in place.

Study population and setting
Twelve EDs from eight different European countries (Austria, Germany, Greece, Latvia, the Netherlands (n = 3), Spain, Slovenia, and the UK (n = 3)) participated in the study. Participating hospitals were either tertiary university hospitals or large teaching hospitals (Appendix 1). Data were collected for at least 1 year, between January 2017 and April 2018. Inclusion criteria were children aged 0 months to 18 years presenting with fever to the ED (temperature ≥ 38.0 °C) or a history of fever in the previous 72 h.

Data collection
Data were obtained from patient records and entered into an electronic case report form. Data included general patient characteristics (age, sex, comorbidity, previous medical care, time of arrival, referral (self, primary care physician, Emergency Medical Services, or other), triage urgency, vital signs, and presence of "red traffic light" alarming signs for identifying risk of serious illness (National Institute for Health and Care Excellence (NICE) guideline on fever [17]. These alarming signs include level of consciousness, ill-appearance, increased work of breathing, age < 3 months, non-blanching rash, meningeal signs, status epilepticus, and focal neurological signs.
Data collection ranged from a 1 week per month sample to all visits, depending on the number of ED visits per hospital (Appendix 1).

Definitions
The presence of comorbidity and type of comorbidity (e.g., organ system involved) were taken directly from the patient's chart. Comorbidity was pre-defined as a chronic underlying condition that is expected to last at least one year. During data analysis, comorbidity was classified as either simple or complex. Complex comorbidity was defined as comorbidity that affects two or more body system, malignancy, or a progressive condition [18][19][20]. Children with malignancy and immunodeficiency were analysed together, as were children with neurologic disease and psychomotor delay.
Vital signs were classified as abnormal according to APLS reference ranges.
ED-Paediatric Early Warning Score (ED-PEWS) were calculated based on the PEWS specifically developed and validated for the ED by Zachariasse et al. (age, vital signs, capillary refill time, level of consciousness, and work of breathing combined into an ED-PEWS score) [21].
Triage categories were grouped together into low urgency (non-urgent, standard) and high urgency (urgent, very urgent, and immediate).
A previous ED visit was defined as a visit to either the same or a different ED in the previous 5 days. Duration of fever was defined as the duration of fever upon presentation at the ED.
The consortium developed a consensus-based flowchart [16,24] combining all available clinical data and test results. A more detailed description was published by Hagedoorn et al. [16] This flowchart was used to classify the presumed cause of infection for each patient visit (Appendix 3), depending on clinical signs, C-reactive protein (CRP), and microbiological tests (bacterial cultures, viral or bacterial PCR).
Serious bacterial infections were defined as "definite/ probable bacterial" with a focus of infection from the gastrointestinal tract, LRTI, urinary tract, bone and joints, central nervous system, or sepsis [22]. Invasive bacterial infection (sepsis/meningitis) was defined as a focus from the central nervous system or sepsis and "definite/probable bacterial" from the consensus-based flowchart [25].

Data quality and missing data
The use of a digital training module, which included the clarification of the National Institute for Health and Care Excellence alarming signs, allowed optimization and standardization of the clinical assessment and data collection processes. Universal guidance on entering the standardized data was issued prior to commencement of the study period. Furthermore, monthly teleconferences and biannual meetings were organized and quarterly reports of data quality were discussed with all partners.
Missing determinants were handled by using multiple imputation. Imputation was performed by using the MICE package in R, version 3.4. SPSS version 25 was used for the analysis of the data. This imputation process resulted in twenty databases on which statistical analysis was performed and pooled for a final result.

Data analysis
We performed descriptive analyses for general patient characteristics, vital signs, ED-PEWS and presence of National Institute for Health and Care Excellence alarming signs, clinical management (diagnostic tests, intravenous antibiotics, oxygen therapy, immediate life-saving interventions), disposition (discharge, hospital admission, Paediatric Intensive Care Unit (PICU) admission), and diagnosis (focus of infection, viral or bacterial disease). Characteristics of children with and without comorbidities were compared using chi-squared-tests and Mann-Whitney U tests. Results were deemed significant with a p-value < 0.05.
We analysed differences in management, disposition, and presumed cause of infection for children with and without comorbidities by multivariable logistic regression adjusted for ED of presentation and general patient characteristics (sex, duration of fever, previous medical care, time of arrival, and mode of referral).

Patient characteristics
Patients with comorbidities were older (median age 3.7 years versus 2.6 years, p < 0.001) and more often were male (59% versus 54%, p < 0.001) than children without comorbidities.
All differences were more pronounced in children with complex comorbidities (Table 2). Furthermore, they more often were described as ill appearing (range according to comorbidity: 18-25%), had increased work of breathing (range 6.2-31%), or presented with neurological signs or symptoms (range 3.8-18%, Table 2; Appendix 4).

Main findings
Children with comorbidities, with 16%, form a substantial part of the paediatric ED population. Our data show that children with comorbidities in general are more ill upon presentation than children without comorbidities, as they more often have abnormal vital signs, and a high ED-Paediatric Early Warning Score. In contrast with this, in our study, children with comorbidity presented with a shorter duration of fever, possibly due to awareness of a higher risk for serious illness. They more often present to the ED with common diseases such as lower respiratory tract infections as well as invasive bacterial infections such as sepsis/meningitis. While they are managed differently, with higher rates of resource use such as blood tests, admission, intravenous antibiotics, and rates of serious interventions (immediate life-saving interventions, PICU admission), this seems adequate as they are diagnosed with serious bacterial infections more often. Secondly, our data show that children with comorbidities form a heterogeneous group, with different types of comorbidities requiring a distinct pattern of management. As expected, children with malignancy/immunodeficiency more often had serious bacterial infections and were treated with intravenous antibiotics, and children with psychomotor delay/neurological disease most often required immediate life-saving interventions and PICU admission.

Findings in relation to previous literature
Studies on the prevalence of chronic comorbidities in the paediatric population are scarce and many articles base their numbers on US studies that took place more than a decade ago [26][27][28]. Using these numbers might underestimate the current prevalence and health care burden of children with comorbidities [1]. Furthermore, comparing studies is not straightforward due to the fact that studies differ in study methods (e.g. selfreported comorbidity versus hospital data versus national registries), definitions used and whether mental health is included in the definition [19,20,[28][29][30][31].
These differences might explain the large variation that is found in the prevalence of these children in Europe, which varies between 10 and 40% [29,31,32].
However, there is convincing data that regardless of the definition used, children with comorbidity have higher health care utilization and an increased risk of in-hospital mortality [20,28,[33][34][35].
For example, a recent European study showed that depending on the setting, between 10 and 38% of all ED visits were comprised by children with comorbidities [33]. Furthermore, several studies showed that between 40 and 75% of cases of childhood mortality were comprised by children with comorbidities [28,34,35].
Our study is in line with previous studies that found increased resource use in children with comorbidities and an increased risk of serious bacterial infections [4,9,14,36]. With our study, we aimed to provide a more detailed overview of these children and identify children at risk for serious illness.

Implications for clinical practice and research
Our data demonstrate how children with comorbidities form a fragile patient population. Clinicians should be aware of the increased risk for serious bacterial infections and PICU admission when evaluating febrile children with comorbidities at the ED.
Given their increasing numbers on one hand and increased risk for serious bacterial infections on the other hand, it is imperative that they are not being left out of studies or guidelines. Our study provides insight on which specific subgroups are specifically at risk for serious bacterial infections and interventions such as immediate life-saving interventions or PICU admission. Children most at risk for sepsis/meningitis were children with a history of malignancy/immunodeficiency, prematurity or neurologic disease/psychomotor delay. These data could be used to maintain a lower threshold for diagnostic tests, and start antibiotic therapy based on the combination of clinical assessment and diagnostic test results, children with a history of neurologic/psychomotor delay, pulmonary disease, cardiac disease, or prematurity most often required PICU admission or immediate life-saving interventions. Further research should identify which subgroups of children are most at risk for serious illness and provide detailed information on the disease course. This information should ideally be used to improve early recognition and interventions in order to improve the outcome of these children.
As most, though not all [37], studies predicting serious bacterial infections in febrile children have excluded children with comorbidities, future studies should focus on validating existing clinical prediction rules for this population, and if necessary, develop guidelines and prediction rules specifically targeted to this population. Our data show that, although overall, children with comorbidity have an increased risk for serious bacterial infections; this is not true for all subgroups of comorbidity. This data can be used to target antibiotic therapy.
Lastly, future research would benefit from the use of a uniform classification of children with comorbidities that can be used to provide an overview of the prevalence and resource use in these children at all levels of care. Furthermore, using a uniform classification can facilitate the comparison of different studies.

Strengths and limitations
To our knowledge, our study is the first to include a large multicenter cohort of febrile children with different types of comorbidities and includes detailed information on presenting signs and symptoms, management, diagnostic test results, and cause of infection.
Data were collected year-round and included different EDs with different rates of children with comorbidities, which largely increases the generalizability of the results [16,38].
Furthermore, we have included a large number of children with serious and invasive bacterial infections, which was determined by a uniformly applied and validated flowchart [16].
Using routinely collected data has its limitations. However, to ensure data quality and completeness, all study sites were extensively trained regarding the accurate documentation of patient characteristics and quality checks were performed regularly. Missing data were limited, and its effects were further reduced by using multiple imputation for missing values [39].
A second limitation is that in some settings, children that are likely to be admitted, for example due to a high risk for serious bacterial infections, such as children with febrile neutropenia, are sometimes seen at the ward directly and bypass the ED [40]. Furthermore, data were only collected at the ED and not at primary care facilities. Therefore, the patients included in our study might not represent the complete group of febrile children with comorbidity. Furthermore, although comorbidity was grouped by body system, these groups could still be heterogeneous. However, heterogeneity was reduced by further analysing children by level of complexity.
Lastly, although this study provided detailed information by children with comorbidity by body system, we did not study resource use and risk of serious illness for specific diagnoses.

Conclusion
Our data show that children with comorbidity form important part of the paediatric ED population. Febrile children with comorbidities in general are more ill with a shorter duration of symptoms, more frequently have abnormal test results, more often require admission and PICU admission and life-saving interventions, and more often are diagnosed with serious and invasive bacterial infections.
Authors' contributions All authors contributed to the design and data collection of the study. DB and NH verified and analysed the data. DB, NH, and HM interpreted the data. DB, NH, and HM drafted the manuscript. All authors critically evaluated and revised the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. This publication is the work of the authors who will serve as guarantors for the contents of this paper.
Funding This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 668303 and No. 848196. The research was supported by the National Institute for Health Research Biomedical Research Centre based at Imperial College (JH, ML) and at Newcastle Hospitals NHS Foundation Trust and Newcastle University (EL, ME), grant number not applicable.
Data sharing statement Individual participant data that underlie the results reported in this article, including a data dictionary, will be made available after de-identification to researchers who provide a methodologically sound proposal. Proposals should be directed to d.borensztajn@erasmusmc.nl. To gain access, data requestors will need to sign a data access agreement.

Declarations
Disclaimer The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Conflict of interest DB, UB, EC, ME, MF, NH, BK, FMT, HM, EL, ML, MP, IRC, MT, CV, DZ, and WZ report grants from the European Union Horizon 2020 research and innovation programme during the study conduct. MP reports a grant from Pfizer and financial support from Pfizer and Sanofi outside the submitted work. MF reports a grant from CSL Behring outside the submitted work. RN reports a grant from the National Institute for Health Research during the study conduct. ME reports financial support from the National Institute for Health Research Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University during the study conduct. MT is a member of the Advisory Board of MSD and Pfizer, a member of the National Committee on Immunization Practices, and a member of the national Scientific Advisory Group for the management of the pandemic. All other authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.