Sepsis biomarkers. Value and limitations.

Use of biomarkers has flourished in many fields of medicine, and there is no doubt they will have an increasingly important role to play in patient management in the future. Sepsis biomarkers have three principal applications. First, they can be used to rule out infection. It is often believed that these markers can help identify the presence of infection, but this is not their real value. Indeed, no sepsis biomarker can be entirely specific for infection, because similar pathways can be activated in the absence of an infection; for example, in situations such as trauma or surgery (1). It is rather the negative predictive value, suggesting absence of infection, that can be most useful, encouraging the physician to withhold antibiotics or to discontinue them sooner rather than later. This use of biomarkers has been demonstrated in many studies during the last 10 years, from the initial landmark study by Christ-Crain and colleagues, showing that the use of procalcitonin (PCT) levels could reduce antibiotic therapy in suspected lower tract infections (2), to the more recent analysis of the Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients with Lower Respiratory Tract Infections (ProHOSP) study, which showed that PCT use could decrease antibiotic prescription in patients with heart failure presenting to an emergency department (3). Importantly, and in the same context (that biomarkers can be useful to rule out, rather than rule in, infection), a sepsis marker should not be used to escalate antibiotic therapy; this approach has been shown to be associated with increased organ failure (4). Second, sepsis biomarkers are also markers of disease severity, which is information that can be useful in patient triage, and especially when making decisions about possible intensive care unit admission (5). PCT is a particularly good severity marker in sepsis, with levels well related to mortality rates (6). Third, repeated measurements can be helpful to evaluate a patient’s clinical course and, therefore, suggest a need for treatment review if levels are not decreasing. A substantial decline in sepsis markers can be used to encourage earlier discontinuation of antibiotic therapy (7, 8). Could this latter application be used to create simple algorithms to guide patient management? In this issue of the Journal, Shehabi and colleagues (pp. 1102–1110) temper our enthusiasm about this possibility (9). In a fairly large study of almost 400 patients enrolled in 11 Australian intensive care units, use of an algorithm that included a PCT cutoff value of 0.1 ng/ml for stopping antibiotics did not influence the total duration of antibiotic therapy. The study was well-designed and conducted, so the quality of the data is not in question. Why, then, did this approach, based on a sound underlying principle, not work? Were the negative results perhaps related to the chosen cutoff value? Would another threshold have resulted in more positive findings? This proposition is far from established. This study may simply just represent another failure of a simple protocol to influence outcomes, particularly when the standard level of care is already good, as was probably the case in these Australian centers. Should we, therefore, write off PCT measurements? Of course not. It is, in fact, reassuring to see that PCT levels were higher in patients with positive than in those with negative cultures, and that the time course of PCT levels was strongly associated with outcome. Hence, these blood tests make sense. The study, rather, reminds us of the complexity of the problem. The underlying concept is valid, in that the duration of antibiotic therapy should not be identical in all patients, not only because the virulence of the microorganism and the site of infection will influence response to antibiotics but also because the host immune response may vary among patients; this is precisely why monitoring a marker of the patient’s response can be important. However, the decision to stop antibiotic therapy should be based on a composite of bacteriological information, source of infection, duration of antibiotic therapy, clinical evolution (including fever and organ function), and the time course of biomarker levels. Within the complex framework of sepsis, attempting to influence our strategies using a specific cutoff value of a single biomarker is unlikely to be effective; the key message is that a sepsis biomarker should never be used alone to dictate patient management. Among the more than 170 sepsis markers that have been proposed (10), PCT is one of the best, and it is certainly the most widely studied, but there is nothing magic about it, and it is definitely not perfect. Combining information collected from several biomarkers may be more useful (11), and adding circulating biomarker levels to information about the cellular response (12) and the degree of cell activation (13) may be a valuable future approach to help optimize our anti-infective strategies. n