Background
All infections have the potential to manifest into life-threatening conditions, depending on the virulence of the infecting organism and the subsequent pathophysiological host response [
1]. An early diagnosis and assessment of infection severity is therefore crucial in order to initiate appropriate therapeutic strategies.
Recent changes to the definition and diagnostic criteria used to identify sepsis have resulted in an emphasis on the identification of a dysregulated host response and the presence of life-threatening organ dysfunction [
2,
3]. The use of the Sequential Organ Failure Assessment (SOFA) score as part of the clinical criteria to identify and characterise sepsis [
2], rather than an emphasis on the non-specific systemic inflammatory response syndrome (SIRS) [
4], has proven controversial due to the complex nature of the score. The alternative quick SOFA (qSOFA) score to screen infected patients likely to have a poor outcome has also been reported to have significant sensitivity and kinetical limitations [
1,
5‐
8]. In both cases, a focus on the identification of high severity patients may lead to either a delayed therapeutic response or inappropriate discharge decisions in those with initially low severities but a high potential for disease progression [
9,
10]. Such patients at risk of this transitional status have previously been described as “pre-septic” [
10]. Conversely, the unnecessary hospitalisation of patients with uncomplicated infections who are at no further risk of disease progression can lead to an additional increase in clinical workload and financial burden. Thus, a more accurate assessment of the pathophysiological host response to infection, and the potential for further disease development, is essential [
11,
12].
The use of biological markers which have a high sensitivity for assessing disease severity and are significantly increased during the initial stages of sepsis development may therefore be of significant clinical interest in facilitating early therapeutic decisions [
13]. Biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) are already well established in the field of infectiology [
14,
15], whilst elevated lactate levels can reflect significant infection-related cellular dysfunction despite being increased due to other pathophysiological abnormalities [
2]. Conversely, the clinical utility of novel biomarkers such as mid-regional proadrenomedullin (MR-proADM) remains less clear. Recent studies have shown MR-proADM concentrations to be rapidly induced in response to LPS stimulation [
16] and invasive fungal infections [
17], as well as in the initial stages of sepsis development [
18] and progression towards sepsis-related multiple organ failure [
19,
20]. Thus, MR-proADM may be of significant clinical relevance in settings such as the ED where an early assessment of the potential for further disease progression is vital.
This study therefore aimed to investigate the performance of each biomarker (MR-proADM, PCT, lactate and CRP) and clinical score (SIRS, SOFA, qSOFA, NEWS and CRB-65) in patients presenting to the emergency department with a suspected infection in order to identify (i) those with an increased risk of further disease progression and mortality, and (ii) patients with uncomplicated infections where out-patient treatment may be most appropriate.
Discussion
In this derivation and validation analysis of 2071 suspected infection patients presenting to 9 emergency departments across Europe and the USA, MR-proADM measurement at presentation could accurately assess disease severity and identify specific patient populations based on the likelihood of subsequent disease progression. This is of particular importance in patients with few pathophysiological signs and symptoms, as indicated by low SOFA, qSOFA or NEWS scores, where initial treatment may either be withheld, delayed or insufficient. Our study therefore, for the first time, highlights the use of MR-proADM in potentially identifying this patient population in order to initiate appropriate treatment strategies at the earliest opportunity.
An early and accurate identification of this key patient demographic, however, may be complicated by the lack of pathognomonic symptoms and the highly complex, heterogeneous and multifaceted host response to infection [
27]. An early diagnosis of developing sepsis therefore invariably requires a complex clinical investigation incorporating numerous factors such as presenting symptoms, physician judgement, and standard laboratory and biomarker tests. Accordingly, earlier indicators of deteriorating host response are essential in order to provide relevant information at the earliest opportunity possible [
19]. In this respect, MR-proADM is an interesting biomarker candidate, with previous studies showing increased concentrations in response to deteriorating microcirculatory integrity and resulting capillary leak, thus reflecting the early stages of developing organ dysfunction [
28‐
31]. An early assessment of microcirculatory function may therefore contribute significant information as part of an initial multi-modal clinical examination, and provide a more accurate method of assessing disease progression and the efficacy of therapeutic interventions compared to the use of conventional biomarkers or scoring systems [
30].
Based on the results of this study, two clinically important uses for MR-proADM can be proposed: (i) an early escalation of treatment in patients with MR-proADM concentrations ≥ 1.5 nmol/L, thus identifying an already high level of disease severity or a high potential for further development and progression, and (ii) a decreased number of hospital admissions allowing a safe increase in out-patient treatment in patients with MR-proADM concentrations < 0.9 nmol/L.
First, an early identification of further disease development and progression in patients with uncomplicated infections and minimal organ dysfunction is crucial in order to initiate, escalate or intensify treatment at the earliest opportunity. Our results identified a large patient population with few clinical or laboratory signs which would prompt an immediate and urgent therapeutic response. The presence of elevated MR-proADM concentrations in a subset of these patients, however, resulted in long lengths of hospitalisation, a high likelihood of mortality, increased ICU admission rates, and a high number of patients satisfying the composite endpoint for disease progression, compared to those with low MR-proADM levels. Such findings may facilitate specific interventions such as the rapid administration of antibiotics and fluids, the use of adjunctive sepsis therapies, or additional diagnostic testing in order to prevent potential cases of under-treatment or inappropriate discharge. In addition, a more personalised and tailored therapeutic approach may be most beneficial in patients with the highest MR-proADM concentrations (e.g. > 2.75 nmol/L [
19]), with the early admission onto a high dependency or intensive care unit to initiate aggressive therapeutic strategies, such as those targeting extravascular fluid accumulation, potentially decreasing further organ dysfunction or progression towards multiple organ failure [
20,
32]. Interestingly, MR-proADM concentrations > 2.75 nmol/L in our study (
N = 126; 10.7%) resulted in a 28-day mortality rate of 30.2%, similar to the 32.5% found in the intensive care study of Elke et al. [
19] in patients with corresponding concentrations (
N = 759; 73.7%).
Few studies have reported similar findings to ours. Indeed, numerous investigations have focussed on mortality and adverse event prediction in patients with community-acquired pneumonia (CAP), comparing MR-proADM performance to clinical scores such as CURB-65 and the Pneumonia Severity Index (PSI), with a moderate to good discriminatory performance found for both endpoints and similar cut-offs compared to our analysis [
33‐
38]. Similar results were also reported for mortality prediction outside the intensive care setting using SOFA and qSOFA scores in the recent sepsis-3 definitions [
2], thus partially confirming and validating results from our analysis.
Findings observed in our study may, in part, be explained by the rapidly induced kinetical profile of MR-proADM in response to LPS addition, compared to other parameters such as procalcitonin and C-reactive protein [
16]. Initial microcirculatory dysfunction due to infection is likely to drive the expected physiological development towards organ dysfunction and ultimate multiple organ failure [
39]. Hence, measurement of MR-proADM values upon ED presentation may provide an early indication concerning potential disease progression [
30]. Similar findings have also been observed in an intensive care setting in patients with high MR-proADM concentrations and initially low or moderate levels of organ dysfunction that progressed towards sepsis-related multiple organ failure [
19,
20,
40]. Indeed, continuously elevated concentrations, despite decreasing PCT levels over the first 24 h of treatment, indicated a high likelihood of subsequent treatment failure and disease progression, thus providing an early and independent prompt with which to change or modify treatment [
19]. The use of MR-proADM to identify the likelihood of infection-related disease progression may therefore be of significant clinical value irrespective of clinical setting or initial disease severity.
Second, a more accurate identification of uncomplicated infections with a low risk of further progression may improve initial hospitalisation and out-patient treatment decision-making. Our results found a similar performance of MR-proADM within both the derivation and validation cohorts, with comparable increases in outpatient numbers, a lack of subsequent mortality and decreased rehospitalisation rates.
Surprisingly, only few studies with relatively small patient populations have previously investigated the accuracy of hospitalisation and out-patient treatment decisions in infected patients using MR-proADM. Of these, Travaglino et al. [
41] observed a poor performance in 128 patients with high fever and mixed infections, as opposed to the high discriminatory performance found by Starre et al. [
42] in 321 urinary tract infection (UTI) patients. A recent secondary analysis of 313 UTI patients by Stalenhoef et al. [
24] found similar results to our analysis using a comparable cut-off, with increased out-patient treatment, no mortality and fewer cases of subsequent rehospitalisation. Conversely, Albrich et al. [
43] tested a novel algorithm combining CURB-65 and MR-proADM values in an interventional setting of 313 lower respiratory tract infection (LRTI) patients [
44], resulting in significantly increased out-patient numbers and decreased overruling and readmission rates compared to a control group triaged using CURB-65 alone [
45]. Results from our study are therefore derived from the largest sample size of patients with a suspected infection presenting to the ED with initial hospitalisation and out-patient treatment decision data to date. The high performance of MR-proADM as a stand-alone parameter as opposed to in combination with a clinical score may facilitate easier use in high patient settings such as the ED, although further observational and interventional studies with similarly large patient populations are required to confirm and validate our findings. The generation of corresponding health economic data would also be beneficial in highlighting potential cost savings from increased out-patient treatment.
Our study has several limitations. Firstly, the absence of subsequent biomarker and clinical score measurements after hospital admission only allow assumptions to be made concerning disease progression and sepsis development, according to current definitions [
2]. Similar studies investigating MR-proADM kinetics in LRTI patients over 72 h have previously shown a decreased survival probability in patients with increasing or continuously elevated concentrations [
46]. Nevertheless, future studies should be designed considering additional variables such as SOFA score kinetics between admission and either 48 or 72 h to investigate developing organ dysfunction and sepsis progression as relevant endpoints. In addition, the inclusion of hospitalisation duration as a variable in the composite endpoint for identifying uncomplicated infections and disease progression may not take numerous time-dependent internal and external clinical factors into account, and could result in different findings if an alternative discriminatory value is used. Secondly, clinical scores in the validation cohort could not be calculated due to the absence of key clinical data, thus, a direct comparison between cohorts was not possible. Finally, mortality and hospitalisation prevalence in other hospitals and clinical settings may significantly differ with one another, leading to the calculation of different negative and positive predictive values, and resulting in study results which are not directly transferrable.
We note several strengths. Firstly, the comparative use of two large, independent, multicentre patient populations ensured a high degree of internal validity, with similar patient demographics between cohorts. Nevertheless, future studies would greatly benefit from the inclusion of further EDs from alternative geographies, different income-settings and hospitals with significantly different triage procedures, in order to rule-out any significant influence on results and increase the reproducibility of the findings. Secondly, the use of optimised derivation MR-proADM cut-offs resulted in similar findings across both cohorts with regard to the identification of disease severity and out-patient treatment, strengthening its potential use in both areas.