Sepsis is an infectious condition with systemic inflammation that can lead to severe organ failure and death (1, 2). If sepsis progresses either to severe sepsis or septic shock, it has a very high mortality rate even with intensive therapeutic intervention (3, 4). Although novel treatments are improving the survival rate, the incidence of sepsis has been increasing substantially for several decades (1, 3).
To effectively treat sepsis, early and appropriate diagnosis is crucial because prompt antimicrobial treatment and resuscitation improve outcome (5). The diagnosis of sepsis, however, is often complicated because clinical manifestations are not specific for sepsis and systemic inflammatory signs are not obvious in many patients (6).
Inflammatory biomarkers have been studied for early diagnosis and prognostication of sepsis patients (7). Among these, procalcitonin (PCT), the prohormone of calcitonin, is a relatively sensitive marker of sepsis compared with white blood cell counts and C-reactive protein (CRP) (8). In general, serum levels of PCT are undetectable in healthy people, and PCT can rise markedly in the case of systemic infections (9). There have been studies on its utility to differentiate between sepsis and noninfectious conditions, to predict bacteremia in various infectious diseases, to predict outcomes in sepsis patients, and to guide antibiotic therapy (10–14).
Although an elevation in PCT level can increase the physician's suspicion of sepsis, its usefulness and the requirement for its routine measurement in critically ill patients remain controversial (12, 15). In particular, PCT levels have been shown to vary drastically over a short amount of time, and a single reading may not provide an accurate picture of the average PCT level. For this reason, and the fact that some patients may show low PCT levels despite severe infection, low PCT levels should be cautiously interpreted in a clinical context (9, 16). Accordingly, we evaluated the prevalence of low PCT levels among patients clinically diagnosed with severe sepsis or septic shock in the emergency department (ED). We also investigated outcomes and clinical characteristics associated with low PCT levels.
Data were collected from the sepsis registry, which included patients who presented to the ED and met the criteria for severe sepsis or septic shock. These data have been collected at Samsung Medical Center (a 1,960-bed, university-affiliated, tertiary referral hospital with approximately 70,000 annual ED visits, in Seoul, South Korea) since 2008, and have been used in previous studies from our laboratory (17–20). This study was approved by the institutional review board of Samsung Medical Center. Informed consent was waived because of the retrospective, observational, and anonymous nature of the study.
We included patients who were 18 years of age or older, presented with septic shock or severe sepsis, had blood lactate concentrations of ≥2.0 mmol/L at the time of diagnosis, and were at the ED between April 2012 and September 2014. Exclusion criteria were as follows: terminal malignancy, patients who previously signed “Do Not Resuscitate” orders or patients who refused invasive interventions, and patients who did not undergo initial measurements of PCT in the ED. Finally, we classified patients into two groups according to a specific PCT cutoff value: a low PCT group, PCT <0.25 ng/mL; and a high PCT group, PCT ≥0.25 ng/mL. This cutoff value has been used in other clinical trials for antibiotic stewardship (10) and showed the highest statistical significance with respect to differences in 28-day mortality in the cohort of this study. The primary endpoint was 28-day mortality.
Sepsis was defined as a suspected or confirmed infection in the presence of two or more systemic inflammatory response syndrome criteria (21). Severe sepsis was defined as sepsis associated with acute organ dysfunction. Septic shock was defined as sepsis that presented with hypotension (systolic blood pressure <90 mmHg, mean arterial pressure <60 mmHg, or a reduction in systolic blood pressure of >40 mmHg from baseline) despite adequate fluid resuscitation (22).
Measurement and data collection
PCT concentrations were measured by an enzyme-linked immunofluorescence assay (VIDAS BRAHMS PCT Assay; bioMérieux, Marcy-l’Étoile, France) at the time of initial ED evaluation. During the study period, there was no formal protocol for diagnosis or management of sepsis guided by PCT concentrations. Resuscitation was performed for patients with severe sepsis or septic shock based on the protocols of Rivers et al. and the 2008 or 2012 Surviving Sepsis Campaign guidelines (5, 23, 24).
The following data were obtained from the sepsis registry and electronic medical records: patient characteristics, comorbidities, initial vital signs, site(s) of infection, laboratory data, results of microbial culture from blood, disposition at the ED, hospital length of stay (LOS), LOS in the intensive care unit (ICU), 28-day mortality, and in-hospital mortality. Body mass index (BMI) values were categorized into an underweight group (BMI <18.5 kg/m2), a normal weight group (18.5 ≤ BMI < 25 kg/m2), and an obese group (BMI ≥ 25 kg/m2), according to Asia Cohort Consortium criteria (25). Sequential Organ Failure Assessment (SOFA) scores were calculated at the time that severe sepsis or septic shock was diagnosed, and the Acute Physiology and Chronic Health Evaluation II score was also determined (26, 27). A SOFA score ≥2 for any target organ was defined as organ failure (respiratory failure, nervous system failure, hepatic failure, coagulation failure, or renal failure).
Data are presented as medians with interquartile ranges (IQR) for numeric data, and numbers with percentages for categorical data. Categorical variables are expressed as numbers (percentages) of patients. Continuous variables were compared using the Kruskal–Wallis rank test or the Wilcoxon rank-sum test according to the number of groups. Categorical variables were compared with the chi-square test.
A multivariable logistic regression model was used to evaluate independent factors associated with low PCT. We adjusted for age, sex, and variables that were found to be statistically significant at P < 0.20 using univariate analysis. Collinearity between variables was assessed to ensure that no significant collinearity was present. The results are described as the odds ratio (OR) with a 95% confidence interval (CI). The adjusted odds ratio of the low PCT value for 28-day mortality was calculated by a logistic model adjusting for factors including age, gender, initial serum lactate, SOFA score, and baseline variables that were found to be statistically significant at P <0.20. A P value less than 0.05 was considered significant. STATA 13.0 (STATA Corporation, College Station, TX) was used for statistical analysis.
A total of 1,212 patients were included in this study (Fig. 1). The overall 28-day mortality was 12.4%, and the in-hospital mortality was 14.7%. There was no significant difference in 28-day mortality initial lactate levels between the included and excluded groups (12.4% vs. 13.5% for 28-day mortality, P = 0.69; 3.1 mmol/L [2.3–4.5] vs. 2.9 mmol/L [IQR, 2.4–4.5], P = 0.87 for lactate levels).
Prevalence of low PCT
Of the eligible patients, 154 (12.7%) were assigned to the low PCT group and 1,058 (87.3%) to the high PCT group. Among patients with bacteremia (n = 421), 16 (10.4%) had low PCT levels. Among patients presenting with septic shock or high lactate concentrations (≥4 mmol/L; n = 678), 43 (6.3%) had low PCT levels. In the low PCT group, there were 28 (2.3%) patients with PCT levels less than 0.1 ng/mL.
Comparison of baseline characteristics
The median PCT level was 2.26 ng/mL (IQR, 0.45–13.13) in the overall population, 0.15 ng/mL (IQR, 0.11–0.2) in the low PCT group, and 3.61 ng/mL (IQR, 0.78–16.61) in the high PCT group. A comparison of baseline characteristics of the two PCT groups is summarized in Table 1. Between the two groups, there were significant differences in comorbidities (chronic lung disease and hematologic malignancy), focus of infection, initial vital signs (mean arterial pressure), laboratory tests (leukocytosis, C-reactive protein [CRP] levels, and lactate levels), the presence of bacteremia, SOFA score, the presence of organ failure (cardiovascular, renal, hepatic, and coagulation failure), initial presentation with septic shock, use of vasopressors, and Acute Physiology and Chronic Health Evaluation II score.
Comparison of outcomes
The 28-day mortality was 4.6% in the low PCT group and 13.5% in the high PCT group (P < 0.01) (Table 2). In patients presenting with septic shock or high lactate concentrations (≥ 4 mmol/L), the 28-day mortality was 4.7% in the low PCT group (n = 43) and 16.1% in the high PCT group (n = 635) (P = 0.04). In-hospital mortality and ICU admission rate were lower in the low PCT group. There was no significant difference in ICU LOS or hospital LOS.
In a multivariable logistic regression model, low PCT level was independently associated with 28-day mortality (adjusted OR, 0.43; 95% CI 0.19–0.98; P = 0.04), as were metastatic cancer, the source of infection, lactate level, and SOFA score (Table 3).
Factors associated with low PCT
The logistic regression model revealed significant factors associated with low PCT (Table 4). Factors associated with low PCT included pneumonia as a primary source of infection (OR 2.65; 95% CI, 1.52–4.63; as opposed to an intra-abdominal infection); lower CRP levels (OR 0.84; 95% CI 0.81–0.88); lower lactate levels (OR, 0.71; 95% CI 0.60–0.83); the absence of bacteremia (OR, 0.20; 95% CI, 0.11–0.36); and the absence of organ failure, including cardiovascular (OR, 0.23; 95% CI, 0.12–0.46), renal (OR, 0.37; 95% CI, 0.14–0.94), and hepatic failure (OR, 0.28; 95% CI, 0.14–0.56). Intra-abdominal infection (OR for the low PCT group, 0.38; 95% CI, 0.22–0.66; as opposed to pneumonia) and obesity (OR for the low PCT group, 0.59; 95% CI, 0.36–0.98; as opposed to normal body weight) were significantly associated with high PCT.
Outcomes according to PCT category
When PCT levels were categorized into five groups (PCT <0.25 ng/mL; 0.25 ng/mL ≤ PCT <0.5 ng/mL; 0.5 ng/mL ≤ PCT < 2.0 ng/mL; 2.0 ng/mL ≤ PCT < 10.0 ng/mL; 10.0 ng/mL ≤ PCT), there were significant differences and increasing trends regarding bacteremia and initial presence of septic shock (Table 5). The 28-day mortality of the low PCT group was significantly lower than that of the other groups. However, there were no significant differences among the four higher groups (P = 0.81). Additionally, when PCT levels were categorized into quintile groups (Quintile 1, 0.03 ng/mL to 0.36 ng/mL; Quintile 2, 0.37–1.11 ng/mL, Quintile 3, 1.12–4.67 ng/mL; Quintile 4, 4.68–18.79 ng/mL; Quintile 5, 18.80–619.87 ng/mL), the results were similar (7.7%, 13.1%, 12.8%, 14.9%, and 13.6% for 28-day mortality; 14.5%, 28.7%, 32.1%, 44.2%, and 55.6% for bacteremia; and 12.1%, 21.1%, 35.4%, 40.5%, and 58.7% for septic shock, respectively).
Our study showed that a significant number of patients had low PCT concentrations (<0.25 ng/mL), although they were clinically diagnosed with severe sepsis and septic shock in the ED. The low PCT cutoff might be useful to identify low-risk patients. However, there was no stepwise trend of increasing mortality among patients with higher PCT levels, although there were trends of increasing incidences of bacteremia or septic shock.
There are many biomarkers for diagnosis of sepsis or prediction of outcome, but there is no single biomarker that is 100% reliable. PCT is a potential biomarker that could be added to the physician's tool box in that it is correlated with the severity of infection, the development of severe sepsis or septic shock, and associated mortality (11). To increase diagnostic yields, PCT might be used with other clinical variables and traditional laboratory tests. The present study elucidates the benefits and limitations of PCT as a biomarker, and these should be considered for appropriate interpretation during initial diagnosis of severe sepsis or septic shock in the ED.
There are clinical factors that may influence PCT levels, including trauma, surgery, presence of tumors, noninfectious inflammatory conditions, and renal failure (8, 11). In the present study, we showed that several factors were associated with low PCT levels, including the presence of pneumonia as a source of infection. Although we could not fully explain the causalities, the results were likely due to the more highly localized infection of patients with pneumonia. In addition, intra-abdominal infection was associated with high PCT levels, unlike pneumonia. The high PCT levels associated with intra-abdominal infection were likely due to higher rates of bacteremia. These results suggest that PCT concentrations should be interpreted differently according to the source of infection. Other significant factors associated with high PCT levels were higher CRP levels, higher lactate concentrations, and the presence of organ failure. These results are similar to those of previous studies showing correlations between PCT level and the severity of sepsis (28–31).
Interestingly, our study showed that obesity was significantly associated with high PCT. According to additional analysis, their overall PCT values were relatively higher than those of patients without obesity, albeit with marginal statistical significance. These findings suggest that obesity might augment PCT levels so as to exceed a cutoff value, although the absolute changes might be small. The results were consistent with a previous study that found that PCT concentrations were positively associated with BMI, and that adipose tissue could secrete PCT (32). We suggest that obesity might be a factor that should be considered for interpretation of PCT levels. Additional study will be needed to verify this.
PCT levels had a correlation with CRP levels in this study, and we found no significant differences predicting 28-day mortality in additional analysis comparing 28-day mortality with CRP. However, PCT might have some advantages as an inflammatory biomarker. PCT might have a closer correlation than does CRP with the severity of infection and organ dysfunction (33). In this study, additional analysis also found that PCT had a stronger association with bacteremia, diagnosis of septic shock, and organ failure, suggesting that PCT might have additional clinical significance.
There have been various studies showing the usefulness of PCT in the evaluation of sepsis (8, 12, 13), as well as studies reporting that PCT had poor diagnostic performance (15, 16, 34). Recently, several studies have proposed that PCT clearance could be used as a prognostic marker instead of static PCT measurement (9, 35). In this study, we used initial values of PCT for analysis, and so dynamic changes in PCT concentrations were not analyzed, due to insufficient data. PCT levels were remeasured in 15 patients of the low PCT group within 72 h, and all these patients had increased PCT levels, 9 of whom had PCT > 0.25 ng/mL; there was no mortality among them. The lack of analysis of dynamic changes in PCT is one of the limitations of the present study; nonetheless, given the importance of early and appropriate decision-making at the time of initial evaluation, the results of our study might provide helpful information relevant to the interpretation of initial PCT levels in EDs.
Our study had several limitations as a retrospective study at a single center. First, our findings may not be generalizable to other settings, and the results should therefore be cautiously interpreted at other EDs. Second, patients with less severe sepsis were included, and there could have been a few patients with other clinical diagnoses. Diagnosis of sepsis, however, is often complicated and can be based on clinical suspicion. We included patients according to the current sepsis definition, with the presence of intermediate or high lactate levels or organ failure. Patients confirmed with noninfectious diagnoses were not included in the registry. Third, we analyzed the PCT concentrations, not as a continuous variable, but as a categorical variable using cutoff values used in other studies. The distribution of PCT levels was too wide for appropriate analysis and there was no clinically significant cutoff value regarding prognosis at higher PCT levels. Fourth, we could not fully evaluate clinical factors that might affect PCT concentrations. Thus, we could not investigate the pathophysiologic association between clinical characteristics and PCT levels. Finally, there might be a selection bias because PCT levels were not measured in all patients with severe sepsis or septic shock during the study period.
In conclusion, low PCT levels were common among patients diagnosed with severe sepsis or septic shock in the ED. The prevalence of low PCT levels was significantly different according to obesity, the source of infection, CRP levels, lactate levels, bacteremia, and organ failure. Low PCT levels were significantly associated with a low-risk of 28-day mortality, but there was no trend of increasing mortality among patients with higher PCT levels.
The authors thank Jae Sun Lee, EunByulAhn, and Dareum Kim, clinical research coordinators, for their assistance with data collection.
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