Background
Delayed treatment in patients presenting to the emergency department (ED) with a suspected infection may result in a prolonged hospitalisation, an increased morbidity, and a greater rate of infection-related mortality [
1‐
3]. An accurate assessment of the severity of the host response and the potential for further disease progression and organ dysfunction is therefore crucial in order to administer a rapid and targeted therapeutic response.
The lack of validated tools to help guide therapeutic decision-making in patients presenting with low severity National Early Warning Score (NEWS) or quick Sequential Organ Failure Assessment (qSOFA) values, but with a high subsequent likelihood of further disease progression, is therefore of significant concern [
4,
5]. Antibiotics are often administered before any final clinical diagnosis can be made [
6], resulting in an increased likelihood of inappropriate therapy, growing levels of antibiotic resistance, and detrimental effects on the microbiota. Conversely, delayed treatment in high severity patients may lead to increased morbidity and mortality rates [
7]. In addition, an early and inappropriate discharge from the ED may also result in higher mortality rates in patients later rehospitalised and directly admitted onto an intensive care unit (ICU), with similar findings also reported after an inappropriate initial admission onto a medical ward [
8]. Thus, difficulties in identifying infection-related disease severity and the early pathophysiological changes involved in a deteriorating host response may contribute to poor overall decision-making and higher subsequent rates of hospital readmission [
8‐
10].
Despite the presence of a number of independent risk factors [
11‐
13], few studies have identified patient subgroups at risk of delayed antibiotic therapy or ICU triage, and the subsequent likelihood of further disease progression. It is therefore unsurprising that no validated test has been incorporated into routine clinical use. A recent investigation, however, found that the blood biomarker, mid-regional proadrenomedullin (MR-proADM), could accurately identify patients with non-severe clinical signs of infection but a high likelihood of further disease progression [
4]. Indeed, recent studies have shown MR-proADM to improve National Early Warning Score (NEWS) performance in an undifferentiated ED population with mild clinical symptoms [
14], identify disease progression in sepsis patients with decreasing procalcitonin (PCT) concentrations [
15], and accurately identify non-surviving patients with low levels of organ dysfunction who later developed multiple organ failure [
16].
This study therefore aimed to assess the potential use of MR-proADM in identifying high severity patient subgroups at risk of a delayed or insufficient initial treatment, identified by a decision to (i) withhold or delay antibiotic administration, or (ii) delay ICU admission. Biomarker kinetics between ED presentation and 72 h within patient subgroups were further investigated to identify subsequent cases of disease progression and mortality.
Methods
Study design and ethical approval
This prospective study consecutively enrolled patients presenting with a suspected infection to the EDs of three large tertiary level university hospitals (> 800 beds), comprising of the Hospital Clínico Universitario San Carlos (Madrid), the Hospital Universitari de Bellvitge (Barcelona), and the Hospital General Universitario de Alicante (Alicante). All patients were enrolled in accordance with the Helsinki Declaration, and ethical approval granted from the relevant governance bodies. The study was registered on
ClinicalTrials.gov with the identifier NCT03992794.
Inclusion and exclusion criteria
Inclusion criteria comprised of patients ≥ 18 years of age presenting with a clinical suspicion of infection as judged by the treating physician based on usual clinical practice, and could be made according to vital signs, main presenting symptoms, the request for a blood culture, or overall laboratory findings during standard ED assessment. Local study coordinators were responsible for collecting and recording all clinical data on a standardised case report form for each patient throughout the investigation. Exclusion criteria comprised of patients < 18 years of age, pregnancy, a refusal to participate, and no obvious clinical signs or symptoms of infection.
Data collection and biomarker measurements
Patient demographics, comorbidities, initial diagnoses, and results from routine laboratory and microbiology tests were either recorded upon study enrolment or retrospectively added. CRP and lactate measurements were measured as part of the standard routine assessment, with a second blood draw taken from each patient during the initial clinical assessment to measure PCT and MR-proADM concentrations using a non-commercially available point-of-care duplex biomarker device (Samsung LABGEO IB10, Nexus, USA). The location of each patient after 72 h was further identified, with both clinical data and an additional blood sample for PCT and MR-proADM measurement taken in patients still hospitalised at this time point. Samples were measured within 15 min of being drawn by the study coordinator at each site; thus, neither PCT nor MR-proADM results were made available to the treating physician throughout patient enrolment or hospitalisation. Survival and ICU admission time was censored at 28 days following ED presentation, and patients discharged prior to this time point were subsequently contacted by phone to ascertain survival status.
Study endpoints
Study endpoints were defined as follows:
antibiotic administration — administration of intravenous, oral, or intramuscular antibiotics during ED treatment;
length of time to antibiotic administration — length of time from arrival in the ED to the first administration of antibiotics;
delayed antibiotic administration — initiation of antibiotic therapy ≥ 180 min following arrival in the ED [
17,
18];
hospitalisation — hospital admission with a subsequent stay of > 24 h;
intensive care unit (ICU) admission — all-cause ICU admission within 28 days of study enrolment which could be further categorised into three categories: immediate (0 days - same day as ED presentation), delayed (between 1 and 7 days following ED presentation), and late (> 7 days following presentation);
hospital readmission — readmission due to an infection-related symptom or cause within 28 days following ED or hospital discharge;
28-day mortality — mortality within 28 days due to an infection-related cause; and
disease progression — composite endpoint consisting of infection-related 28-day mortality, ICU admission, and a ≥ 2 point increase in NEWS or SOFA score between presentation and 72 h.
Primary and secondary outcomes
Primary study outcomes comprised of 28-day mortality prediction and the identification of patient populations enriched for a delayed (i) antibiotic administration, or (ii) ICU admission. Secondary outcomes comprised of patient populations enriched according to (iii) subsequent disease progression.
Statistical analysis
Symmetrically distributed data were reported using mean and standard deviation values, whilst skewed data reported using median, first quarter, and third quarter values. Demographic and clinical data were assessed using the chi-square (
χ2) for categorical variables, and either Student’s
t test or the Mann-Whitney
U test for symmetrical or skewed continuous variables, respectively. Receiver operating characteristic (ROC) and areas under the curve (AUC) determined the predictive value of each parameter for 28-day mortality, antibiotic administration, hospitalisation, and ICU admission decisions, with 95% confidence intervals (95% CI) used to determine significance. Optimised cut-off values for sensitivity and specificity were determined using Youden’s criterion, and patient subgroups subsequently identified according to optimised cut-off values for the prediction of 28-day mortality, similar to methods outlined by Saeed et al. [
4]. Kaplan-Meier curves categorised patients on ED presentation according to either optimised or pre-established 28-day mortality cut-offs for all biomarkers and scores, with the most accurate parameter used to further stratify subgroups. Treatment and outcome characteristics of each resulting subgroup, comprising of antibiotic, hospitalisation, disease progression, intensive care, and mortality-related variables, were compared using the log-rank test for mortality; the chi-square (
χ2) test for disease progression, hospitalisation, ICU admission, and antibiotic administration; and the Mann-Whitney U test for the overall length of hospitalisation. Univariate and multivariate Cox regression analyses assessed the association of each parameter with time to mortality, whilst corresponding logistic regression assessed the association with antibiotic administration, hospitalisation, and ICU admission decisions. Potential confounding variables were selected based on a univariate survival analysis for infection-related 28-day mortality and subsequently included in all further multivariate analyses as adjusting variables. Results were presented as either the hazard (HR) or the odds (OR) ratio per 1 interquartile-range increase for Cox and logistic regression analyses, respectively. A
p value < 0.05 was considered statistically significant, and all data analysed using the statistics software R (version 3.1.2). Due to the exploratory nature of the primary and secondary endpoints, no a priori sample size calculation could be performed.
Discussion
The results of this prospective multicentre study confirm those from previous investigations [
4,
19], highlighting the ability of MR-proADM to identify patients with a high potential for subsequent disease progression [
15,
16,
20]. Results also indicate that patients with low presenting symptoms and high MR-proADM concentrations had an increased risk of a less intensive treatment despite high subsequent mortality rates, characterised by a withheld or delayed antibiotic therapeutic response, a delayed admission onto the ICU, and a high readmission rate due to the reoccurrence of an infection-related complication.
Treatment during ED assessment is often initiated before any definitive diagnosis can be made in order to limit the potential for subsequent clinical deterioration [
6]. This, however, may be complicated by the heterogeneous and multifaceted host response to infection [
21], as well as difficulties in assessing the severity and potential for further disease progression. There is therefore a high likelihood of either an over- or an under-treatment of patients, both of which are associated with undesirable outcomes. Hence, the use of an easily measurable parameter to accurately assess infection severity and short-term disease progression is highly desirable in order to help guide optimal treatment decision-making. Based on recent evidence, the blood biomarker mid-regional proadrenomedullin (MR-proADM) may potentially fulfil this unmet clinical need, with elevated concentrations found due to increased capillary leak and deteriorating microcirculatory integrity [
22‐
24]. Such pathophysiological changes, however, are not unique to patients with infection. Indeed, elevated MR-proADM concentrations have been observed across of range of non-infection-related conditions, such as acute and chronic heart failure [
25,
26], non-specific complaints [
27], and in the build-up to acute episodes of systemic capillary leak syndrome (Clarkson’s disease) [
28]. Thus, any increase in MR-proADM concentration in patients with suspected infection cannot be specifically attributed to the presence of an infectious source, although it may provide an early and accurate prediction of developing organ dysfunction and subsequent mortality [
29‐
34]. Thus, the fundamental challenge in incorporating such a parameter into routine clinical practice therefore relates to the extent to which real life decision-making can either be altered or optimised.
Three potential areas of further observational and interventional research using MR-proADM can therefore be proposed based on the results of this study, as well as current clinical requirements, namely as a potential aid to (i) guide appropriate and timely antibiotic administration, (ii) minimise the risk of inappropriate triage before admission onto an intensive care unit, and (iii) identify treatment failure and disease progression in patients with low severity clinical symptoms.
Firstly, the early administration of oral or intravenous antibiotics in patients presenting with a suspected infection plays a central role in most emergency medicine treatment strategies. However, challenges concerning their unnecessary administration are well documented, primarily due to increasing antibiotic resistance and rising healthcare costs. Conversely, the importance of ensuring therapy is rapidly administered to both high severity patients and those with a high potential for further disease progression cannot be overstated [
6,
35‐
38]. As such, no standardised strategy exists to guide antibiotic administration in the ED. Interestingly, our results highlight a greater association with the requirement for antibiotic administration using NEWS and MR-proADM, as opposed to more commonly used parameters such as CRP and PCT, which confirm the results of a recent subset analysis [
39] from a previous study. This may be in part explained by the rapid kinetical profile of MR-proADM, which is increased significantly earlier than PCT [
40,
41] and many other cytokines [
42] in response to microbial infection. Nevertheless, elevated MR-proADM concentrations can also be observed in many non-infectious conditions, albeit to a lesser extent than during a severe infectious episode, making its sole use in guiding antibiotic administration problematic. The combination of PCT and MR-proADM, therefore, may provide an attractive alternative [
43‐
45].
Secondly, the rapid triage of high severity patients onto the ICU is mandatory in order to prevent further disease progression and maximise the chances of a successful treatment. Nevertheless, many patients are inappropriately triaged following ED presentation back into the community or onto a medical ward before any subsequent ICU admission, thus increasing the likelihood of a prolonged hospitalisation or ultimate mortality [
8,
46,
47]. Our results suggest that the presence of low severity vital and physiological signs of infection may create a false impression concerning the requirement for immediate ICU admission, whilst elevated MR-proADM concentrations — indicative of the early stages of developing organ dysfunction — may provide significant additional information in order to optimise decision-making. Similar findings have also previously been reported to predict renal replacement therapy (RRT) requirement in patients where no RRT was previously initiated [
20] and in patients who progressed towards multiple organ failure [
15,
16].
Finally, the results of this study suggest that MR-proADM can accurately identify specific patient subgroups based on the likelihood of further clinical deterioration, thus helping to optimise subsequent treatment and triage decision-making. Results confirm those of a previous investigation [
4], whilst further patient evaluation at 72 h found that MR-proADM was the only parameter to significantly decrease in surviving patients with low clinical scores, whilst tending to increase in non-survivors. Similar results have been found in previous investigations where continuously high or increasing MR-proADM concentrations in the ED [
48] or ICU [
15] were indicative of a subsequent detrimental outcome, or the requirement for an urgent clinical intervention.
We note several limitations and strengths of this study that deserve greater discussion. Firstly, a significant number of non-surviving patients showed no clinical deterioration at 72 h according to the calculation of clinical score values. Consecutive measurements should therefore be made across further time points to fully capture any subsequent deterioration. Nevertheless, such a finding is likely to be of relative clinical interest, since continuously elevated or increasing MR-proADM concentrations between both time points may potentially provide an earlier warning of treatment failure than conventional clinical scores. Secondly, numerous factors such as ED waiting times and physician availability may influence the timing of initial antibiotic administration [
17], thus contributing to the differential analysis between clinical score and biomarker subgroups within this study. Future studies should therefore account for these variables in order to provide a more detailed calculation of time to administration. Thirdly, based on previous publications investigating the clinical utility of MR-proADM, additional secondary outcomes such as respiratory failure [
49], acute kidney injury progression [
50], and coronary ischaemia [
25,
51] should be collected in order to further enhance our understanding of this novel biomarker due to its likely physiological action in endothelial injury and capillary leak. Finally, the relatively small number of patients in each subgroup, as well as low corresponding mortality and delayed ICU admission rates, allows for only initial hypotheses to be made and makes more detailed conclusions problematic. In addition, the presence of an independent validatory cohort, similar to that of Saeed et al. [
4], utilising pre-specified and optimised cut-off values, would confer a greater degree of certainty to the obtained results.
Acknowledgements
The authors are grateful to the staff at all participating hospitals for their continued vigilance in identifying patients presenting with infections and for enrolling patients into this study. DCW would like to acknowledge the contributions made by Monika Wittmann concerning graphical presentation.
Addendum collaborators
Members of the Infectious Disease Group of the Spanish Emergency Medicine Society (INFURG-SEMES) participating in this study: Joan Ramon Pérez-Mas, Elena Fuentes-González, and Concepción Martínez-Muñoz (Emergency Department, Hospital Universitari de Bellvitge, Barcelona, Spain); Elena Martínez-Beloqui (Emergency Department, Short Stay Unit and Home Hospitalization Unit, Hospital General de Alicante, Alicante, Spain); and Francisco Javier Martín-Sánchez, Paula Mostaza Gallar, Luis Picazo García, and Alejandro Malo de Molina Herrera (Emergency Department, Hospital Clínico San Carlos, Madrid, Spain).
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.