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Review
The role of immune and metabolic biomarkers for improved management of sepsis patients Expert Rev. Clin. Immunol. 10(9), 1255–1262 (2014)
Philipp Schuetz* and Beat Mueller Department of Endocrinology, Diabetes and Clinical Nutrition, Medical University Clinic, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland and Department of Internal Medicine, Medical University Clinic, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland *Author for correspondence: Tel.: +41 628 389 524 [email protected]
Sepsis, the body‘s overwhelming response to systemic infections, is responsible for significant morbidity, mortality, and financial burden. Pathogens and their antigens stimulate pro- and anti-inflammatory mediators and immune markers which characterize the host defense and orchestrate leukocyte recruitment to the acute site of infection. Different immune and metabolic biomarkers have been studied in relation to sepsis for their diagnostic and/or prognostic aid. Recent studies have provided abundant evidence that specific immune and metabolic biomarkers improve a physician‘s ability to guide early sepsis recognition, severity assessment and therapeutic decisions in individual patients. This may allow for a transition from bundled sepsis care (protocols combining several medical practices) to more individualized management. First, lactate has now been widely used for risk stratification and guidance of fluid resuscitation. Second, procalcitonin correlates with risks of bacterial infections and helps guide therapeutic decisions about initiation and withdrawal of anti-microbial therapy. Third, prognostic markers such as pro-adrenomedullin improve early mortality prediction and thereby site-of-care decisions in respiratory infections. For these markers interventional trials have documented their value when integrated in clinical protocols. KEYWORDS: adrenomedullin • antibiotic guidance • biomarker • lactate • pro-ADM • procalcitonin • sepsis
Sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection [1]. In bacterial sepsis, pathogens and their antigens stimulate proinflammatory and anti-inflammatory immune and metabolic mediators that characterize the host defense and coordinate leukocyte recruitment to the acute site of infection [2]. These molecules thereby have a plenitude of adaptive and maladaptive functions including the regulation of osmolality and volume status, appetite, blood circulation and food intake among others [3]. Precursors, mature forms and degradation products of these various mediators penetrate from the original site of action into the circulation, where, theoretically, they can all be measured. As surrogate immune biomarkers, these substances mirror the extent and severity of an infection [4]. Significant attempts have been made to correlate the levels of different mediators with the presence of sepsis as potential diagnostic markers of sepsis [5–7]. informahealthcare.com
10.1586/1744666X.2014.932250
The recognition over 25 years ago that the host response played an exquisite role in sepsis led to the definition of sepsis that is still the standard today [1]. Unfortunately, the systemic inflammatory response syndrome (SIRS) variables (i.e., body temperature, heart rate, tachypnea and white blood count) turned out to be less useful than anticipated, lacking sensitivity, specificity and ease of clinical application [8]. Had the host response biomarker procalcitonin (PCT) been available when the SIRS criteria were put forth, it arguably would have been preferable to white blood cell count as a laboratory-based SIRS criterion. This is particularly true when considering the greater sensitivity and specificity demonstrated in the impressive body of literature linking PCT levels to bacterial infections [2,6,9–12]. Despite recent advances in diagnosis and medical therapy, mortality and morbidity attributable to sepsis remain considerable [1]. There is convincing evidence linking the early
2014 Informa UK Ltd
ISSN 1744-666X
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start of fluid resuscitation and early initiation of appropriate antimicrobial therapy to improved outcomes in patients with sepsis [1,13,14]. For this reason, the updated Surviving Sepsis Campaign (SSC) included, among others, the following key recommendations based on current evidence [1]: early quantitative resuscitation of the septic patient during the first 6 h after recognition, administration of broad-spectrum antimicrobial therapy within 1 h of recognition of septic shock and reassessment of antimicrobial therapy daily for de-escalation when appropriate. In a recent study including patients with septic shock who were treated with an emergency department-based early resuscitation, no increase in mortality was found with each hour delay to administration of antibiotics after triage; yet, a delay in antibiotics until after shock recognition was associated with increased mortality [15]. This demonstrates the importance of early recognition of severe sepsis and initiation of therapeutic measures. Because many other adjunct sepsis therapies (i.e., systemic corticosteroids, tight glucose control) have, despite early allegedly ‘promising’ data, not proven to be beneficial in recent trials [16,17], early recognition is the main focus of current sepsis management. While clinical parameters such as the SIRS criteria are still the cornerstone of the sepsis definition, these clinical parameters lack specificity toward sepsis etiology [8]. To fill this gap, specific immune and metabolic biomarkers measured on admission and during follow-up have been suggested to improve early sepsis recognition, severity assessment and therapeutic decision-making for individual patients and may thereby allow transformation of bundled sepsis care to more individualized patient management [18–20]. While multiple ‘promising’ immune biomarkers have been posited in observational studies within the last several years, only a few of them have been evaluated in prospective randomized controlled intervention trials. Thus, efficacy and safety of these markers when used in clinical routine remain unproven. Yet, this is the decisive step before using these immune biomarkers in clinical practice. For this reason, the current review focuses on three immune and metabolic biomarkers that have been evaluated in such intervention trials which may allow physicians to make more proactive decisions in individual patients. Particularly, this review focuses on lactate for guidance of fluid resuscitation, PCT, a marker that facilitates assessing the risk of bacterial infections and guidance of therapeutic decisions, and proadrenomedullin (pro-ADM), an inflammatory prognostic marker that improves mortality prediction and – in a pilot intervention study – improved site-of-care decisions in patients with different types of respiratory infections. Risk stratification & fluid management based on lactate levels
As of today, lactate may be the most widely used metabolic biomarker in sepsis. Sepsis-induced tissue hypoperfusion is typically characterized by infection-induced hypotension, leading to elevated lactate levels and oliguria. Lactate thus improves identification of patients needing early and aggressive fluid 1256
resuscitation. Many arguments favor the use of lactate to assess septic patients in clinical routine as an inexpensive and easily measurable biomarker. As demonstrated in correlation studies, lactate levels derived from venous samples correspond well with arterial measurements obviating the immediate need for an arterial line [21]. In sepsis management, the metabolic marker lactate has been used for identification of patients in need of early fluid resuscitation and for assessing a patient’s response to therapy [22]. According to the SSC guidelines [1,23], an initial lactate >4 mmol/l should prompt immediate protocolized resuscitative efforts despite the fact that lactate concentration per se lacks precision as a measure of tissue metabolic status. The proposed cut-off was suggested by Rivers and colleagues in the original Early Goal-Directed Therapy study [13]. Whether patients with lower levels than 4 mmol/l would also benefit from early resuscitation remain unclear. Important in this regard, previous studies have shown a linear relationship of blood lactate and mortality in patients with sepsis; the risk of mortality increased from 15% with levels 24 h)
630
47% adherence
[63]
AB-free days alive: 27%; Duration: -33% 12/50 (24%) vs 8/51 (15.7%) 1 month 101 VAP when intubated for >48 h
not reported
[62]
Duration: -25% 14/53 (26.4%) vs 15/57 (26.3%) Hospital stay 110 Suspected bacterial infections and >1 SIRS criteria
not reported
[61]
Duration: -20% 3/13 (23.1%) vs 3/14 (21.4%) not reported Hospital stay 27 Single center, Germany, surgical ICU Schroeder et al. (2009)
Severe sepsis following abdominal surgery
[60]
Duration: -37% 12/40 (30%) vs 8/39 (20.5%) 81% adherence 79 Single center, Switzerland; medical ICU Nobre et al. (2008)
Suspected severe sepsis or septic shock
1 month
Ref. Efficacy endpoint: relative reduction in antibiotic exposure Safety endpoint: mortality (control patients vs PCT group) Adherence to PCT algorithm in PCT group Follow-up time Patients (n) Type of trial, country, setting
Inclusion criteria
Review
Study (year)
sensitivity and to rule out other infections not requiring antibiotic therapy are largely lacking. Immune biomarkers, such as PCT, which mirror the host response to the infection and thus directly correlate with the severity and extent of the infection are of interest. PCT is released ubiquitously in virtually all tissues in response to endotoxin or mediators such as IL-1b, TNF-a and IL-6 [29]. Upregulation of PCT, however, is attenuated by cytokines released in response to viral infections (i.e., IFN-g) [30]. PCT is thus more specific for bacterial infections and helps distinguish bacterial infections from viral illnesses. ICU studies including patients with only viral or both viral and bacterial pneumonia during the H1N1 outbreak [31–33] found higher PCT levels in the latter group with high discriminatory accuracy area under the curve [AUC] of 0.90, sensitivity and specific at the PCT cut-off of 0.8 mg/l 91 and 68%. PCT’s kinetic profile shows a prompt increase within 6–12 h of infection, and circulating PCT levels are cut in half daily when the infection is controlled. PCT has prognostic implications and correlates with bacterial load [34–36] and severity of infection [10,12,37]. The dual function of PCT as a precursor peptide from the hormone calcitonin and a cytokine mediator, which is elevated upon systemic bacterial infections in line with other cytokines, has coined the term ‘hormokine’ mediator [2]. Due to these characteristics, PCT has been presented as a promising immune marker for sepsis diagnosis and for antibiotic stewardship in sepsis. A 2007 meta-analysis including 17 observational studies with a total of more than 2000 patients found a high discriminatory value of PCT (AUC: 0.84; pooled sensitivity: 0.77 [95% CI: 0.72–0.81] and pooled specificity: 0.79 [95% CI: 0.74–0.84]) for bacteremia, with blood culture as the gold standard [8,38]. Different trials have investigated the effects of PCT use embedded in clinical guidelines with cut-offs adapted to the clinical setting (TABLE 1 & TABLE 2). The efficacy and safety of PCT protocols to guide antibiotic decisions have been demonstrated in more than 14 randomized controlled trials in different clinical settings and including infections of varying severity [19,39,40]. The PCT protocols used were all similar and based on the same intuitive concept: recommendations for or against initiation or continuation of antibiotic therapy were based on initial PCT levels, the kinetics of PCT over time or both as well as the clinical picture of the patient [41]. The cut-offs differed depending on the clinical setting and the acuity of presentation [39]. These protocols proved to be safe and highly effective in terms of lowering antibiotic exposure. In fact, for lower severity patients such as bronchitis and upper respiratory infections, prescription rates lowered by 60–70% were found [19,39,40]. In higher severity patients, PCT guidance resulted in a relative reduction in the duration of antibiotic treatment by 40% in pneumonia and by 25% in the critical care setting. In addition, reductions in antibiotic exposure also resulted in lower antibiotic side effects and costs.
Table 1. Overview of studies examining procalcitonin to guide antibiotic treatment in the ICU setting according to a recent meta-analysis.
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Table 2. Use of procalcitonin to guide antibiotic duration in intensive care unit patients. Use of procalcitonin on admission to the ICU
Use of procalcitonin during follow up in the ICU (every 1–2 days)
PCT range initial measurement
Recommendation on antibiotics
PCT range follow up measurements
Recommendation on antibiotics
PCT 1.0 mg/l
Stopping antibiotics discouraged, consider treatment failure
ICU: Intensive care unit; PCT: Procalcitonin. Data taken from [39].
Based on this body of evidence, recent lower respiratory tract infection guidelines emphasize the concept of using a biomarker to guide antibiotics and state that ‘.. biomarkers can guide treatment duration by the application of predefined stopping rules for antibiotics. It has been shown that such rules work even in most severe cases, including pneumonia with septic shock…’ [42]. In addition, the recent updated SSC guidelines now include a statement about PCT as a marker to de-escalate therapy in patients with clinical signs of recovery [1]. Site-of-care decisions based on pro-ADM
Recently, a multitude of prognostic markers from various pathways has been proposed for patients with sepsis. This potentially enables clinicians to early predict adverse clinical course and case fatality, thereby improving decisions about initial site of care, hospital or ICU admission, the extent of diagnostic work-up necessary, the choice and route of antimicrobial agents and the evaluation for early discharge. Prognostic markers may help to select specific medical therapies for patients most likely benefiting from them, namely in resource-deprived settings (e.g., busy shifts and/or shortage of emergency room staffing). One immune marker that has been tested in a randomized controlled trial for this question is pro-ADM. This precursor peptide of adrenomedullin is derived from the calcitonin gene family and is a very potent vasodilating agent with additional immune modulating and metabolic properties [43]. Adrenomedullin is a potent vasodilator with its widespread production in tissues helping to maintain blood supply to individual organs and has bactericidal activity [43,44]. A strong body of evidence also suggests that this molecule is able to act as an autocrine, paracrine or endocrine mediator in a number of biological pathways including the endothelial regulation of blood pressure 1258
(vasodilation) with protection against organ damage, control of blood volume through regulation of thirst among others. Although the molecular mechanisms linking this marker to mortality and adverse outcomes remain somewhat ill defined, the observation of increasing levels measured in plasma in direct correlation with disease progression in several disease states, however, may be the most important characteristic of this marker for use in patients [43,44]. In patients with communityacquired pneumonia and other lower respiratory tract infections, pro-ADM levels measured on admission were significantly associated with disease severity and outcome with AUCs for mortality of 0.76–0.88 and for treatment failure of 0.71–0.76 [4,45,46]. Pro-ADM has also been shown to significantly improve the usefulness of clinical severity scores (such as the confusion, urea, respiratory rate, blood pressure, age over 65 years CURB-65), thereby providing an additional margin of safety [45]. In a recent multicenter trial, an improved assessment of community-acquired pneumonia has been proposed based on CURB-65 and pro-ADM cut-off levels. Patients were stratified into three risk classes with estimated mortality rates ranging from 0.65 to 9.8% (FIGURE 1) [45]. Importantly, in a recent randomized pilot study, this algorithm tended to reduce hospital length of stay without negatively affecting patient outcomes compared with patients stratified according to CURB-65 alone [47]. Other immune biomarkers for management of sepsis patients
Immune biomarkers from different pathways involved in the pathogenesis of sepsis have previously been evaluated observationally. For example, markers of endothelial cell activation were associated with sepsis severity, organ dysfunction and Expert Rev. Clin. Immunol. 10(9), (2014)
The role of immune & metabolic biomarkers
CURB65
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0–1 points: low risk
2 points: moderate risk
3–5 points: high risk
+
+
+
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ProADM
Overall risk (CURB65-A)
Estimated mortality recommendations
4%, inpatient stay, ICU?
1.5
High
>4%, inpatient stay, ICU?
4%, inpatient stay, ICU?
0.75–1.5
High
>4%, inpatient stay, ICU?
>1.5
(very) high
>4%, inpatient stay, ICU?
Figure 1. CURB-A score combining the traditional CURB-65 criteria with levels of pro-adrenomedullin for an improved risk stratification of patients with lower respiratory tract infections. Based on the CURB-A risk class, each patient is assigned an expected mortality risk and a recommendation for site-of-care decision (inpatient vs outpatient vs intensive care unit admission) CURB 65: Confusion, urea, respiratory rate, blood pressure, age over 65 years; ICU: Intensive care unit; Pro-ADM: Proadrenomedullin.
strong predictors of mortality [48,49]. Repeated measurements of endothelin-1 precursor peptides have been shown to be correlated with the disease course and to significantly improve risk assessment in pneumonia patients [50]. In addition to providing predictive information, endothelial immune biomarkers may also help physicians to select specific sepsis drugs for patients. Because antagonism of the endothelium system by bosentan has shown beneficial effects in experimental models of sepsis, it is tempting to hypothesize if these antagonistic therapies find their ways into clinical routine the measurement of endothelium activation may help to identify patients who might benefit most from endothelin receptor antagonist therapies. Another interesting immune monitoring marker is endotoxin activity assay, which not only measures blood endotoxin levels but also helps to monitor immunological reaction against the endotoxemia [51,52]. Other immune biomarkers may help to predict acute kidney injury such as neutrophil gelatinase-associated lipocalin. Such information may enable prophylactic renal-protective therapies in high-risk patients [53,54]. Similarly, B-type natriuretic peptide increases with sepsis severity and is associated with cardiac dysfunction [55]. Monitoring of B-type natriuretic peptide in early sepsis may thus help to identify cardiac dysfunction early, which may prompt earlier use of inotropic agents. Finally, vasopressin precursor levels (copeptin) may be an interesting marker for patients with pneumonia, particularly in cases with osmo and volume dysregulation such as in the case of hyponatremia in Legionella [56,57]. informahealthcare.com
Conclusions
Protocolized bundled sepsis care has been shown to improve outcomes in patients [58]. Because all medical therapies can have potentially harmful effects if used indiscriminately, selection of patients most likely benefitting from such therapies is pivotal. This was recently illustrated in a counterintuitive study from Africa where indiscriminately and excessively applied fluid boluses significantly increased 48-h mortality in children with shock [59]. The results of this study challenge the benefits of indiscriminative fluid resuscitation as a lifesaving intervention in all patients with possible sepsis. Overuse of antibiotics by overprescription in patients without infection and prolonged duration of treatment in patients with proven infection, results in an increase in antimicrobial drug-resistant bacteria and sometimes deleterious patient outcomes as recently found in a large ICU trial [28]. Prognostic immune biomarkers may facilitate selection of patients for whom early discharge is safe and may help to focus resources to the patients in need. Immune biomarkers may help physicians to identify patients who would, and would not, benefit from distinct therapies and thus may allow a transition from bundled sepsis care to more personalized approaches, which in turn could result in improved patient outcomes. Expert commentary
In bacterial sepsis, pathogens and their antigens stimulate proinflammatory and anti-inflammatory immune mediators 1259
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that characterize the host defense and coordinate leukocyte recruitment to the acute site of infection. Precursors, mature forms and degradation products of these immune mediators penetrate from the initial site of action into the circulation, where, in theory, they can all be measured. As surrogate biomarkers, these substances mirror the extent and severity of an infection and thus provide important surrogate information to clinical providers. In line with this, recent studies have provided evidence that specific immune markers improve a physician’s ability to detect sepsis early, assess severity and make therapeutic decisions in individual patients. Recently, several immune markers have been found to be helpful for individualized patient management with benefits for the patient such as lower drug exposure and lower risk of drug side effects. Markers such as lactate for risk stratification and guidance of fluid resuscitation, PCT for assessment of risk of bacterial infections and guidance regarding therapeutic decisions about initiation and ceasing antimicrobial therapy, and more recently prognostic markers such as pro-ADM for early mortality prediction and site-of-care decisions in respiratory infections, have been shown to improve patient management in interventional studies.
Five-year view
Several comprehensive effectiveness research studies are currently being carried out aiming to further validate these concepts in ‘real-world-settings’ and thereby improve patient care. Results of these trials may ultimately help to transition from bundled sepsis treatment strategies to more individualized patient care thereby reducing unnecessary drug exposure for the patients and providing better guidance for the allocation of limited patient and societal resources. Financial & competing interests disclosure
P Schuetz and B Mueller received support from B.R.A.H.M.S/Thermofisher and bioMe´rieux to attend meetings, fulfill speaking engagements and for unrestricted research grants. P Schuetz is supported by the Swiss National Science Foundation (SNSF Professorship, PP00P3_150531/1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors wish to thank D Bielawski (Wayne State University, Detroit, MI, USA) for language editing of the manuscript, which was funded by University of Basel (Switzerland) without external support. No writing assistance was utilized in the production of this manuscript.
Key issues • Every medical therapy has potential adverse effects, and selection of patients most likely to benefit is crucial, making more personalized approaches necessary. • Immune biomarkers measured on admission and during follow-up can guide/support the clinician’s early recognition of sepsis, severity assessment and therapeutic decisions in individual patients. • Biomarkers may allow transition from generalizing sepsis care bundles to a more tailored management in individual patients thereby reducing the risk for adverse treatment outcomes in patients who – based on their biomarker levels – do not likely benefit from therapy. • Lactate improves initial risk stratification and prompts early fluid resuscitation. • Lactate clearance may be used for assessing a patient’s response to fluids. • Procalcitonin facilitates assessment of bacterial infection risk. • Procalcitonin algorithms for guiding therapeutic decisions about initiation and duration of antimicrobial therapy have shown strong effects in regard to lower antibiotic consumption and appear to be safe regarding the results from interventional trials. • Proadrenomedullin is an inflammatory prognostic immune marker that improves early mortality prediction and might improve site-ofcare decisions in patients with respiratory infections.
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Schuetz P, Christ-Crain M, Zimmerli W, Mueller B. Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia. Intensive Care Med 2011; 37(6):970-80 Ikeda T, Ikeda K, Suda S, Ueno T. Usefulness of the endotoxin activity assay as a biomarker to assess the severity of endotoxemia in critically ill patients. Innate Immun 2014. [Epub ahead of print] Romaschin AD, Klein DJ, Marshall JC. Bench-to-bedside review: clinical experience with the endotoxin activity assay. Crit Care 2012;16(6):248 Shapiro NI, Trzeciak S, Hollander JE, et al. The diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin in the prediction of acute kidney injury in emergency department patients with suspected sepsis. Ann Emerg Med 2010; 56(1):52-9.e51 Bagshaw SM, Bennett M, Haase M, et al. Plasma and urine neutrophil gelatinaseassociated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 2010;36(3): 452-61 Turner KL, Moore LJ, Todd SR, et al. Identification of cardiac dysfunction in sepsis with B-type natriuretic peptide. J Am Coll Surg 2011;213(1):139-46.discussion 146-137
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Schuetz P, Haubitz S, Christ-Crain M, Pro HSG. Hyponatremia and anti-diuretic hormone in Legionnaires’ disease. BMC Infect Dis 2013;13:585
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Haubitz S, Hitz F, Graedel L, et al. Ruling out Legionella in community acquired
pneumonia. Am J Med 2014. [Epub ahead of print] 58.
Barochia AV, Cui X, Vitberg D, et al. Bundled care for septic shock: an analysis of clinical trials. Crit Care Med 2010;38(2): 668-78
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Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364(26):2483-95
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Nobre V, Harbarth S, Graf JD, et al. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008;177(5):498-505
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Schroeder S, Hochreiter M, Koehler T, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg 2009;394(2): 221-6
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Hochreiter M, Kohler T, Schweiger AM, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care 2009;13(3):R83
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Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in Ventilator Associated Pneumonia - a randomized study. Eur Respir J 2009;34(6):1364-75
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Expert Rev. Clin. Immunol. 10(9), (2014)
Review
The role of immune and metabolic biomarkers for improved management of sepsis patients Expert Rev. Clin. Immunol. 10(9), 1255–1262 (2014)
Philipp Schuetz* and Beat Mueller Department of Endocrinology, Diabetes and Clinical Nutrition, Medical University Clinic, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland and Department of Internal Medicine, Medical University Clinic, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland *Author for correspondence: Tel.: +41 628 389 524 [email protected]
Sepsis, the body‘s overwhelming response to systemic infections, is responsible for significant morbidity, mortality, and financial burden. Pathogens and their antigens stimulate pro- and anti-inflammatory mediators and immune markers which characterize the host defense and orchestrate leukocyte recruitment to the acute site of infection. Different immune and metabolic biomarkers have been studied in relation to sepsis for their diagnostic and/or prognostic aid. Recent studies have provided abundant evidence that specific immune and metabolic biomarkers improve a physician‘s ability to guide early sepsis recognition, severity assessment and therapeutic decisions in individual patients. This may allow for a transition from bundled sepsis care (protocols combining several medical practices) to more individualized management. First, lactate has now been widely used for risk stratification and guidance of fluid resuscitation. Second, procalcitonin correlates with risks of bacterial infections and helps guide therapeutic decisions about initiation and withdrawal of anti-microbial therapy. Third, prognostic markers such as pro-adrenomedullin improve early mortality prediction and thereby site-of-care decisions in respiratory infections. For these markers interventional trials have documented their value when integrated in clinical protocols. KEYWORDS: adrenomedullin • antibiotic guidance • biomarker • lactate • pro-ADM • procalcitonin • sepsis
Sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection [1]. In bacterial sepsis, pathogens and their antigens stimulate proinflammatory and anti-inflammatory immune and metabolic mediators that characterize the host defense and coordinate leukocyte recruitment to the acute site of infection [2]. These molecules thereby have a plenitude of adaptive and maladaptive functions including the regulation of osmolality and volume status, appetite, blood circulation and food intake among others [3]. Precursors, mature forms and degradation products of these various mediators penetrate from the original site of action into the circulation, where, theoretically, they can all be measured. As surrogate immune biomarkers, these substances mirror the extent and severity of an infection [4]. Significant attempts have been made to correlate the levels of different mediators with the presence of sepsis as potential diagnostic markers of sepsis [5–7]. informahealthcare.com
10.1586/1744666X.2014.932250
The recognition over 25 years ago that the host response played an exquisite role in sepsis led to the definition of sepsis that is still the standard today [1]. Unfortunately, the systemic inflammatory response syndrome (SIRS) variables (i.e., body temperature, heart rate, tachypnea and white blood count) turned out to be less useful than anticipated, lacking sensitivity, specificity and ease of clinical application [8]. Had the host response biomarker procalcitonin (PCT) been available when the SIRS criteria were put forth, it arguably would have been preferable to white blood cell count as a laboratory-based SIRS criterion. This is particularly true when considering the greater sensitivity and specificity demonstrated in the impressive body of literature linking PCT levels to bacterial infections [2,6,9–12]. Despite recent advances in diagnosis and medical therapy, mortality and morbidity attributable to sepsis remain considerable [1]. There is convincing evidence linking the early
2014 Informa UK Ltd
ISSN 1744-666X
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start of fluid resuscitation and early initiation of appropriate antimicrobial therapy to improved outcomes in patients with sepsis [1,13,14]. For this reason, the updated Surviving Sepsis Campaign (SSC) included, among others, the following key recommendations based on current evidence [1]: early quantitative resuscitation of the septic patient during the first 6 h after recognition, administration of broad-spectrum antimicrobial therapy within 1 h of recognition of septic shock and reassessment of antimicrobial therapy daily for de-escalation when appropriate. In a recent study including patients with septic shock who were treated with an emergency department-based early resuscitation, no increase in mortality was found with each hour delay to administration of antibiotics after triage; yet, a delay in antibiotics until after shock recognition was associated with increased mortality [15]. This demonstrates the importance of early recognition of severe sepsis and initiation of therapeutic measures. Because many other adjunct sepsis therapies (i.e., systemic corticosteroids, tight glucose control) have, despite early allegedly ‘promising’ data, not proven to be beneficial in recent trials [16,17], early recognition is the main focus of current sepsis management. While clinical parameters such as the SIRS criteria are still the cornerstone of the sepsis definition, these clinical parameters lack specificity toward sepsis etiology [8]. To fill this gap, specific immune and metabolic biomarkers measured on admission and during follow-up have been suggested to improve early sepsis recognition, severity assessment and therapeutic decision-making for individual patients and may thereby allow transformation of bundled sepsis care to more individualized patient management [18–20]. While multiple ‘promising’ immune biomarkers have been posited in observational studies within the last several years, only a few of them have been evaluated in prospective randomized controlled intervention trials. Thus, efficacy and safety of these markers when used in clinical routine remain unproven. Yet, this is the decisive step before using these immune biomarkers in clinical practice. For this reason, the current review focuses on three immune and metabolic biomarkers that have been evaluated in such intervention trials which may allow physicians to make more proactive decisions in individual patients. Particularly, this review focuses on lactate for guidance of fluid resuscitation, PCT, a marker that facilitates assessing the risk of bacterial infections and guidance of therapeutic decisions, and proadrenomedullin (pro-ADM), an inflammatory prognostic marker that improves mortality prediction and – in a pilot intervention study – improved site-of-care decisions in patients with different types of respiratory infections. Risk stratification & fluid management based on lactate levels
As of today, lactate may be the most widely used metabolic biomarker in sepsis. Sepsis-induced tissue hypoperfusion is typically characterized by infection-induced hypotension, leading to elevated lactate levels and oliguria. Lactate thus improves identification of patients needing early and aggressive fluid 1256
resuscitation. Many arguments favor the use of lactate to assess septic patients in clinical routine as an inexpensive and easily measurable biomarker. As demonstrated in correlation studies, lactate levels derived from venous samples correspond well with arterial measurements obviating the immediate need for an arterial line [21]. In sepsis management, the metabolic marker lactate has been used for identification of patients in need of early fluid resuscitation and for assessing a patient’s response to therapy [22]. According to the SSC guidelines [1,23], an initial lactate >4 mmol/l should prompt immediate protocolized resuscitative efforts despite the fact that lactate concentration per se lacks precision as a measure of tissue metabolic status. The proposed cut-off was suggested by Rivers and colleagues in the original Early Goal-Directed Therapy study [13]. Whether patients with lower levels than 4 mmol/l would also benefit from early resuscitation remain unclear. Important in this regard, previous studies have shown a linear relationship of blood lactate and mortality in patients with sepsis; the risk of mortality increased from 15% with levels 24 h)
630
47% adherence
[63]
AB-free days alive: 27%; Duration: -33% 12/50 (24%) vs 8/51 (15.7%) 1 month 101 VAP when intubated for >48 h
not reported
[62]
Duration: -25% 14/53 (26.4%) vs 15/57 (26.3%) Hospital stay 110 Suspected bacterial infections and >1 SIRS criteria
not reported
[61]
Duration: -20% 3/13 (23.1%) vs 3/14 (21.4%) not reported Hospital stay 27 Single center, Germany, surgical ICU Schroeder et al. (2009)
Severe sepsis following abdominal surgery
[60]
Duration: -37% 12/40 (30%) vs 8/39 (20.5%) 81% adherence 79 Single center, Switzerland; medical ICU Nobre et al. (2008)
Suspected severe sepsis or septic shock
1 month
Ref. Efficacy endpoint: relative reduction in antibiotic exposure Safety endpoint: mortality (control patients vs PCT group) Adherence to PCT algorithm in PCT group Follow-up time Patients (n) Type of trial, country, setting
Inclusion criteria
Review
Study (year)
sensitivity and to rule out other infections not requiring antibiotic therapy are largely lacking. Immune biomarkers, such as PCT, which mirror the host response to the infection and thus directly correlate with the severity and extent of the infection are of interest. PCT is released ubiquitously in virtually all tissues in response to endotoxin or mediators such as IL-1b, TNF-a and IL-6 [29]. Upregulation of PCT, however, is attenuated by cytokines released in response to viral infections (i.e., IFN-g) [30]. PCT is thus more specific for bacterial infections and helps distinguish bacterial infections from viral illnesses. ICU studies including patients with only viral or both viral and bacterial pneumonia during the H1N1 outbreak [31–33] found higher PCT levels in the latter group with high discriminatory accuracy area under the curve [AUC] of 0.90, sensitivity and specific at the PCT cut-off of 0.8 mg/l 91 and 68%. PCT’s kinetic profile shows a prompt increase within 6–12 h of infection, and circulating PCT levels are cut in half daily when the infection is controlled. PCT has prognostic implications and correlates with bacterial load [34–36] and severity of infection [10,12,37]. The dual function of PCT as a precursor peptide from the hormone calcitonin and a cytokine mediator, which is elevated upon systemic bacterial infections in line with other cytokines, has coined the term ‘hormokine’ mediator [2]. Due to these characteristics, PCT has been presented as a promising immune marker for sepsis diagnosis and for antibiotic stewardship in sepsis. A 2007 meta-analysis including 17 observational studies with a total of more than 2000 patients found a high discriminatory value of PCT (AUC: 0.84; pooled sensitivity: 0.77 [95% CI: 0.72–0.81] and pooled specificity: 0.79 [95% CI: 0.74–0.84]) for bacteremia, with blood culture as the gold standard [8,38]. Different trials have investigated the effects of PCT use embedded in clinical guidelines with cut-offs adapted to the clinical setting (TABLE 1 & TABLE 2). The efficacy and safety of PCT protocols to guide antibiotic decisions have been demonstrated in more than 14 randomized controlled trials in different clinical settings and including infections of varying severity [19,39,40]. The PCT protocols used were all similar and based on the same intuitive concept: recommendations for or against initiation or continuation of antibiotic therapy were based on initial PCT levels, the kinetics of PCT over time or both as well as the clinical picture of the patient [41]. The cut-offs differed depending on the clinical setting and the acuity of presentation [39]. These protocols proved to be safe and highly effective in terms of lowering antibiotic exposure. In fact, for lower severity patients such as bronchitis and upper respiratory infections, prescription rates lowered by 60–70% were found [19,39,40]. In higher severity patients, PCT guidance resulted in a relative reduction in the duration of antibiotic treatment by 40% in pneumonia and by 25% in the critical care setting. In addition, reductions in antibiotic exposure also resulted in lower antibiotic side effects and costs.
Table 1. Overview of studies examining procalcitonin to guide antibiotic treatment in the ICU setting according to a recent meta-analysis.
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Table 2. Use of procalcitonin to guide antibiotic duration in intensive care unit patients. Use of procalcitonin on admission to the ICU
Use of procalcitonin during follow up in the ICU (every 1–2 days)
PCT range initial measurement
Recommendation on antibiotics
PCT range follow up measurements
Recommendation on antibiotics
PCT 1.0 mg/l
Stopping antibiotics discouraged, consider treatment failure
ICU: Intensive care unit; PCT: Procalcitonin. Data taken from [39].
Based on this body of evidence, recent lower respiratory tract infection guidelines emphasize the concept of using a biomarker to guide antibiotics and state that ‘.. biomarkers can guide treatment duration by the application of predefined stopping rules for antibiotics. It has been shown that such rules work even in most severe cases, including pneumonia with septic shock…’ [42]. In addition, the recent updated SSC guidelines now include a statement about PCT as a marker to de-escalate therapy in patients with clinical signs of recovery [1]. Site-of-care decisions based on pro-ADM
Recently, a multitude of prognostic markers from various pathways has been proposed for patients with sepsis. This potentially enables clinicians to early predict adverse clinical course and case fatality, thereby improving decisions about initial site of care, hospital or ICU admission, the extent of diagnostic work-up necessary, the choice and route of antimicrobial agents and the evaluation for early discharge. Prognostic markers may help to select specific medical therapies for patients most likely benefiting from them, namely in resource-deprived settings (e.g., busy shifts and/or shortage of emergency room staffing). One immune marker that has been tested in a randomized controlled trial for this question is pro-ADM. This precursor peptide of adrenomedullin is derived from the calcitonin gene family and is a very potent vasodilating agent with additional immune modulating and metabolic properties [43]. Adrenomedullin is a potent vasodilator with its widespread production in tissues helping to maintain blood supply to individual organs and has bactericidal activity [43,44]. A strong body of evidence also suggests that this molecule is able to act as an autocrine, paracrine or endocrine mediator in a number of biological pathways including the endothelial regulation of blood pressure 1258
(vasodilation) with protection against organ damage, control of blood volume through regulation of thirst among others. Although the molecular mechanisms linking this marker to mortality and adverse outcomes remain somewhat ill defined, the observation of increasing levels measured in plasma in direct correlation with disease progression in several disease states, however, may be the most important characteristic of this marker for use in patients [43,44]. In patients with communityacquired pneumonia and other lower respiratory tract infections, pro-ADM levels measured on admission were significantly associated with disease severity and outcome with AUCs for mortality of 0.76–0.88 and for treatment failure of 0.71–0.76 [4,45,46]. Pro-ADM has also been shown to significantly improve the usefulness of clinical severity scores (such as the confusion, urea, respiratory rate, blood pressure, age over 65 years CURB-65), thereby providing an additional margin of safety [45]. In a recent multicenter trial, an improved assessment of community-acquired pneumonia has been proposed based on CURB-65 and pro-ADM cut-off levels. Patients were stratified into three risk classes with estimated mortality rates ranging from 0.65 to 9.8% (FIGURE 1) [45]. Importantly, in a recent randomized pilot study, this algorithm tended to reduce hospital length of stay without negatively affecting patient outcomes compared with patients stratified according to CURB-65 alone [47]. Other immune biomarkers for management of sepsis patients
Immune biomarkers from different pathways involved in the pathogenesis of sepsis have previously been evaluated observationally. For example, markers of endothelial cell activation were associated with sepsis severity, organ dysfunction and Expert Rev. Clin. Immunol. 10(9), (2014)
The role of immune & metabolic biomarkers
CURB65
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0–1 points: low risk
2 points: moderate risk
3–5 points: high risk
+
+
+
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ProADM
Overall risk (CURB65-A)
Estimated mortality recommendations
4%, inpatient stay, ICU?
1.5
High
>4%, inpatient stay, ICU?
4%, inpatient stay, ICU?
0.75–1.5
High
>4%, inpatient stay, ICU?
>1.5
(very) high
>4%, inpatient stay, ICU?
Figure 1. CURB-A score combining the traditional CURB-65 criteria with levels of pro-adrenomedullin for an improved risk stratification of patients with lower respiratory tract infections. Based on the CURB-A risk class, each patient is assigned an expected mortality risk and a recommendation for site-of-care decision (inpatient vs outpatient vs intensive care unit admission) CURB 65: Confusion, urea, respiratory rate, blood pressure, age over 65 years; ICU: Intensive care unit; Pro-ADM: Proadrenomedullin.
strong predictors of mortality [48,49]. Repeated measurements of endothelin-1 precursor peptides have been shown to be correlated with the disease course and to significantly improve risk assessment in pneumonia patients [50]. In addition to providing predictive information, endothelial immune biomarkers may also help physicians to select specific sepsis drugs for patients. Because antagonism of the endothelium system by bosentan has shown beneficial effects in experimental models of sepsis, it is tempting to hypothesize if these antagonistic therapies find their ways into clinical routine the measurement of endothelium activation may help to identify patients who might benefit most from endothelin receptor antagonist therapies. Another interesting immune monitoring marker is endotoxin activity assay, which not only measures blood endotoxin levels but also helps to monitor immunological reaction against the endotoxemia [51,52]. Other immune biomarkers may help to predict acute kidney injury such as neutrophil gelatinase-associated lipocalin. Such information may enable prophylactic renal-protective therapies in high-risk patients [53,54]. Similarly, B-type natriuretic peptide increases with sepsis severity and is associated with cardiac dysfunction [55]. Monitoring of B-type natriuretic peptide in early sepsis may thus help to identify cardiac dysfunction early, which may prompt earlier use of inotropic agents. Finally, vasopressin precursor levels (copeptin) may be an interesting marker for patients with pneumonia, particularly in cases with osmo and volume dysregulation such as in the case of hyponatremia in Legionella [56,57]. informahealthcare.com
Conclusions
Protocolized bundled sepsis care has been shown to improve outcomes in patients [58]. Because all medical therapies can have potentially harmful effects if used indiscriminately, selection of patients most likely benefitting from such therapies is pivotal. This was recently illustrated in a counterintuitive study from Africa where indiscriminately and excessively applied fluid boluses significantly increased 48-h mortality in children with shock [59]. The results of this study challenge the benefits of indiscriminative fluid resuscitation as a lifesaving intervention in all patients with possible sepsis. Overuse of antibiotics by overprescription in patients without infection and prolonged duration of treatment in patients with proven infection, results in an increase in antimicrobial drug-resistant bacteria and sometimes deleterious patient outcomes as recently found in a large ICU trial [28]. Prognostic immune biomarkers may facilitate selection of patients for whom early discharge is safe and may help to focus resources to the patients in need. Immune biomarkers may help physicians to identify patients who would, and would not, benefit from distinct therapies and thus may allow a transition from bundled sepsis care to more personalized approaches, which in turn could result in improved patient outcomes. Expert commentary
In bacterial sepsis, pathogens and their antigens stimulate proinflammatory and anti-inflammatory immune mediators 1259
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that characterize the host defense and coordinate leukocyte recruitment to the acute site of infection. Precursors, mature forms and degradation products of these immune mediators penetrate from the initial site of action into the circulation, where, in theory, they can all be measured. As surrogate biomarkers, these substances mirror the extent and severity of an infection and thus provide important surrogate information to clinical providers. In line with this, recent studies have provided evidence that specific immune markers improve a physician’s ability to detect sepsis early, assess severity and make therapeutic decisions in individual patients. Recently, several immune markers have been found to be helpful for individualized patient management with benefits for the patient such as lower drug exposure and lower risk of drug side effects. Markers such as lactate for risk stratification and guidance of fluid resuscitation, PCT for assessment of risk of bacterial infections and guidance regarding therapeutic decisions about initiation and ceasing antimicrobial therapy, and more recently prognostic markers such as pro-ADM for early mortality prediction and site-of-care decisions in respiratory infections, have been shown to improve patient management in interventional studies.
Five-year view
Several comprehensive effectiveness research studies are currently being carried out aiming to further validate these concepts in ‘real-world-settings’ and thereby improve patient care. Results of these trials may ultimately help to transition from bundled sepsis treatment strategies to more individualized patient care thereby reducing unnecessary drug exposure for the patients and providing better guidance for the allocation of limited patient and societal resources. Financial & competing interests disclosure
P Schuetz and B Mueller received support from B.R.A.H.M.S/Thermofisher and bioMe´rieux to attend meetings, fulfill speaking engagements and for unrestricted research grants. P Schuetz is supported by the Swiss National Science Foundation (SNSF Professorship, PP00P3_150531/1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors wish to thank D Bielawski (Wayne State University, Detroit, MI, USA) for language editing of the manuscript, which was funded by University of Basel (Switzerland) without external support. No writing assistance was utilized in the production of this manuscript.
Key issues • Every medical therapy has potential adverse effects, and selection of patients most likely to benefit is crucial, making more personalized approaches necessary. • Immune biomarkers measured on admission and during follow-up can guide/support the clinician’s early recognition of sepsis, severity assessment and therapeutic decisions in individual patients. • Biomarkers may allow transition from generalizing sepsis care bundles to a more tailored management in individual patients thereby reducing the risk for adverse treatment outcomes in patients who – based on their biomarker levels – do not likely benefit from therapy. • Lactate improves initial risk stratification and prompts early fluid resuscitation. • Lactate clearance may be used for assessing a patient’s response to fluids. • Procalcitonin facilitates assessment of bacterial infection risk. • Procalcitonin algorithms for guiding therapeutic decisions about initiation and duration of antimicrobial therapy have shown strong effects in regard to lower antibiotic consumption and appear to be safe regarding the results from interventional trials. • Proadrenomedullin is an inflammatory prognostic immune marker that improves early mortality prediction and might improve site-ofcare decisions in patients with respiratory infections.
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