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Procalcitonin Levels in Survivors and Nonsurvivors of Sepsis: Systematic Review and Meta-Analysis

Arora, Shubhangi*; Singh, Prashant; Singh, Preet Mohinder; Trikha, Anjan

doi: 10.1097/SHK.0000000000000305
Review Article
Free

ABSTRACT Procalcitonin (PCT) is an acute-phase reactant that has been used to diagnose and potentially track the treatment of sepsis. Procalcitonin values rise initially as the infection sets in and eventually fall with resolution. Its level has been reported to be significantly higher in potential nonsurvivors of a septic episode than among survivors. However, there is also a significant amount of evidence against this. We thus conducted a meta-analysis to pool data from all the available studies regarding PCT levels in survivors and nonsurvivors of sepsis. An extensive literature search was conducted using the key words “procalcitonin,” “sepsis,” and “prognosis.” The references of the relevant studies were also scanned. The data from the eligible studies were extracted and analyzed for any significant pooled mean difference between survivors and nonsurvivors both on days 1 and 3. The mean difference in the day 1 PCT values between survivors and nonsurvivors was found to be statistically significant (P = 0.02). The mean difference on day 3 was also statistically significant (P = 0.002). However, in a subgroup consisting of studies on patients with severe sepsis and septic shock, day 1 difference was not found to be significant (P = 0.62). We found heterogeneity of 90% in our study population, which decreased to 62% after exclusion of studies conducted in emergency department patients. Procalcitonin levels in early stages of sepsis are significantly lower among survivors as compared with nonsurvivors of sepsis.

*Department of Medicine, Brigham and Women’s Hospital; and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Anaesthesiology, All India Institute of Medical Sciences, New Delhi, India

Received 12 Oct 2014; first review completed 27 Oct 2014; accepted in final form 12 Nov 2014

Address reprint requests to Preet Mohinder Singh, MD, DNB, Department of Anaesthesiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India. E-mail: preetrajpal@gmail.com.

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INTRODUCTION

Procalcitonin (PCT) is a precursor of calcitonin originally isolated from rat medullary carcinoma cell lines (1–3). This molecule is usually undetectable in healthy individuals, and its production is induced by triggers like infection (4–8), especially bacterial (9), burns (10–13), trauma (14–17), surgery (18–20), cancer (21), and heat stroke (22). Although it is not yet clear what tissue produces the molecule, evidence suggests a role of macrophages and hepatocytes (23). Its primary role in the body is not yet clear (24, 25), although it seems that it acts as one of the downstream secondary mediators of inflammation that augments rather than initiates the inflammatory response in tissues already primed by other inflammatory mediators (26, 27). In vitro, it has been shown to ameliorate the tumor necrosis factor-α– and interferon-γ–mediated inducible nitric oxide synthase induction and, thus, nitric oxide production, which is known to cause vasodilation and, hence, hypotension (28). Thus, it seems to exert some anti-inflammatory effects (29). However, it has also been shown that its levels fall as the infection resolves (30–33).

In 1993, Assicot et al. were the first to describe the association of increased PCT level with the severity of invasive infection in children (34). Since then, there has been a lot of literature evaluating the role of PCT in diagnosis and prognosis in infected patients (35–41). A recently conducted meta-analysis has established the usefulness of PCT in the early diagnosis of sepsis (42). Procalcitonin may also help to safely reduce the duration of antibiotic therapy (43–47) while reducing the economic burden caused by the antibiotics (48, 49). Another meta-analysis has shown that PCT-guided therapy decreases the duration of antibiotic therapy without providing any mortality benefit (50). However, whether or not PCT can predict prognosis in patients with sepsis is not very clear (51–62).

Most of the studies have shown a lower level of PCT in patients who survived the septic or infectious episode than in those who did not (51–68). However, there have been some that have not (69–78). The primary objective of this meta-analysis was to pool the results of all the available studies and find out if there was any difference between the PCT level on the day of admission to the hospital among the survivors and nonsurvivors of sepsis. Difference in PCT levels on day 3 was the secondary objective.

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MATERIALS AND METHODS

Literature search

An extensive search of PubMed, EMBASE, and Cochrane registry of trials from 2000 to 2014 was carried out. The search terms used were “procalcitonin,” “sepsis,” and “prognosis.” References from relevant articles were also reviewed.

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Study selection

Two reviewers (Shubhangi Arora and Prashant Singh) independently evaluated the studies for their eligibility to be included and resolved any discrepancies by consensus or by consulting an alternate author (Preet Mohinder Singh). A study was considered eligible if it was a clinical observational study, conducted in patients suffering from sepsis (including severe sepsis and septic shock), and compared the plasma PCT levels in survivors and nonsurvivors on day 1 of the diagnosis of sepsis. Only English language articles and foreign language articles whose abstracts contained the pertinent information were included. Published abstracts were also included if they carried the pertinent information. Studies done on pediatric patients, trauma patients, and postoperative patients were excluded because these factors can affect the baseline PCT levels (10, 14, 18).

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Data extraction

The following data were extracted from each study: year of publication, definition of nonsurvivor, site of conduct of study, severity of sepsis, time of first sample, PCT levels on the day of admission/recruitment and on follow-up in survivors and nonsurvivors (expressed as mean and SD or as median and range), and the method of PCT assay.

If the PCT levels were expressed as median and range, the mean and SD were estimated using the method described by Hozo and colleagues (79). If the study provided with median and interquartile range (IQR), the authors were contacted by e-mail and requested to provide either the mean and SD or the full range. However, if authors did not reply, as a last resort, we estimated the mean using the validated formula: Mean = (2m + a + b)/4, where m is the median and a and b are the 25th and 75th centiles, respectively (80). The SD was estimated by the formula given by the Cochrane collaboration: IQR = 1.35 SD (81, 82).

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Statistical analysis

Statistical analysis was done using Review manager 5.3 by Cochrane collaboration. Heterogeneity was explored using the statistic I2. Pooled mean difference and the 95% confidence interval (95% CI) were calculated using the random-effects model when the between-study heterogeneity was significant (I2 > 56%). Fixed-effect model was used otherwise. Pooled mean difference was considered significant if the value of P < 0.05. The publication bias was explored using Eggar test by funnel plot, with P < 0.05 indicating a significant bias.

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RESULTS

The initial search revealed 853 articles. Of these, 711 articles were rejected on the basis of title. Duplicates were removed electronically. Of the remaining 142 studies, 40 were rejected on the basis of abstract. Another 14 studies were conference abstracts, in non-English languages, or their abstract did not carry the necessary information. For one study, the full text could not be found (83). Full texts of the remaining 87 studies were reviewed. Of these, 59 were excluded because they did not have the information pertinent for this meta-analysis or were done on pediatric, burn, postoperative, or trauma patients. One study was excluded because the results were reported in the form of median (95% CI), and the authors could provide neither the mean nor the range or IQR (84); one was excluded because the data were reported in the form of median and IQR without the actual 25th and 75th centiles, and the authors failed to respond to the e-mail correspondence (85). Hence, it was not possible to estimate the mean in the above two. Another study was excluded because it only included septic patients with PCT concentration of more than 10 ng/mL in their study (86). The remaining 25 studies were included.

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Study characteristics

Tables 1 and 2 describe the characteristics of each study. As is clear from Table 1, all of the studies were prospective in design. The definition of nonsurvivor in most of the studies was death within 28 (54, 56, 58, 59, 62, 75, 76, 87–89) or 30 (57) days. In other studies, no time duration was specified (51–53, 55, 60, 61, 69–74, 90, 91). Most of the studies involved intensive care unit (ICU) patients (51–54, 59, 60, 69, 70, 73–75, 85, 87–91). Four studies were in patients from the emergency department (ED) (55, 57, 58, 61). Three studies were in inpatients but did not mention the site of the patients in the hospital (56, 71, 72). The study by Oberholzer et al. (76) included inpatients from 33 hospitals but did not describe the exact location. Although most of the studies were conducted on patients suffering from sepsis and spanning the whole paradigm of “sepsis–severe sepsis–septic shock,” four of the studies were exclusively on septic shock patients (52, 53, 70, 74). Three studies were conducted only on patients with severe sepsis and septic shock (69, 76, 88). The mortality in these 25 studies varied widely from 19% to 69%.

Table 1

Table 1

Table 2

Table 2

The methods used for measurement of PCT were immunoluminometric assay, enzyme-linked immunosorbent assay (ELISA), enzyme fluorescence, immunofluorescence, and electrochemiluminescence (Table 2). The lower limit of measurement of all of these tests was 0.1 ng/mL or less.

The source of sepsis was explored in 17 studies (51–54, 56, 57, 59, 61, 62, 69, 70, 72–74, 87, 89, 91). These 17 studies included a total of 1,363 patients with 1,433 described sources of infection (Table 3). The most frequent sources of infection were the lungs (42.4%), followed by the abdomen (23.5%) and the urinary tract (12.3%). Skin and soft tissue infections were contributory only in 4% of cases.

Table 3

Table 3

In our meta-analysis, 2,353 patients from 25 studies were included, with 1,626 survivors and 727 nonsurvivors. The pooled mean difference between PCT levels in survivors and nonsurvivors was significant (P = 0.003). The weighted mean difference of PCT between the two groups was −6.02 ng/mL (−10.01 to −2.03) (Fig. 1).

Fig. 1

Fig. 1

We used the random-effects model for calculation of the mean difference between the survivors and nonsurvivors on day 1. The data showed heterogeneity with an I2 of 90%. We carried out a subgroup analysis to explore heterogeneity. We divided the studies into two groups: studies conducted in inpatients/ICU patients (21 studies) and those in patients coming to the ED (four studies). The heterogeneity in the studies conducted in the inpatient population was 62%. The pooled mean difference between the survivors (n = 995) and nonsurvivors (n = 511) was calculated as −3.78 ng/mL (−7.27 to −0.29) (P = 0.03) (Fig. 2).

Fig. 2

Fig. 2

The heterogeneity in the ED group came out to be 98%, and the pooled mean difference as −11.53 (−29.16 to 6.10) (P = 0.20) (Fig. 3).

Fig. 3

Fig. 3

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Pooled mean difference of PCT levels in patients with severe sepsis and septic shock

We also did a subgroup analysis with the studies reporting data from patients of severe sepsis and septic shock. There were seven studies involved, with a total of 459 patients, that did not show any significant difference between the PCT levels among the survivors and nonsurvivors (pooled mean difference, −1.71 [−10.16 to 6.73]; P = 0.69) (Fig. 4).

Fig. 4

Fig. 4

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Pooled mean difference of PCT levels on day 3

Only eight studies including 449 patients had provided day 3 levels of PCT. Again, the day 3 levels in the survivors were significantly lower as compared with the nonsurvivors, with a weighted mean difference of −5.96 ng/mL (95% CI, −2.15 to −9.78 ng/mL) (P = 0.002). All these studies were conducted in ICU or on inpatients (location not specified) (Fig. 5).

Fig. 5

Fig. 5

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Diagnostic value of PCT in predicting mortality

Of all the studies that we included, only 10 had done a receiver operating characteristic analysis for the ability of PCT to predict mortality (Table 4). Of these, only eight provided data on the sensitivities and specificities. Only five of these provided the cutoffs (51–54, 58, 62). However, the cutoff described by each study was different. Two studies by the same author had a cutoff of 6 ng/mL. One each had a cutoff of 3, 3.87, 9.47, and 10.65 ng/mL. Because of such a wide range of cutoffs, the data for prediction of mortality from each study could not be pooled.

Table 4

Table 4

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Publication bias

Figure 6 shows the funnel plot assessing the publication bias among the included 20 studies. Although the distribution of studies was generally symmetrical, all of the studies were gathered at the top, which suggests that studies with high variance (possibly smaller studies) did not get published.

Fig. 6

Fig. 6

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DISCUSSION

Our results showed that PCT levels on day 1 of diagnosis of sepsis differ significantly between surviving and nonsurviving patients of sepsis. The weighted mean difference between the PCT levels between survivors and nonsurvivors was significant, with a mean difference of −6.02 ng/mL (−10.01 to −2.03 ng/mL). This difference continues to be significant on day 3 of diagnosis of sepsis. The weighted mean difference between the PCT levels between survivors and nonsurvivors on day 3 was significant, with a mean difference of −5.96 ng/mL (95% CI, −2.15 to −9.78 ng/mL).

Ours is the first meta-analysis showing that PCT levels were significantly different among survivors and nonsurvivors on day 1 of diagnosis of sepsis. Other inflammatory markers like C-reactive protein have been shown to not differ significantly between survivors and nonsurvivors among the critically ill patients during early periods of critical illness (<48 h) (92). In vitro, PCT has been shown to have anti-inflammatory properties (28, 93), and its higher levels in neutropenic patients have been associated with response to antibiotic therapy (30, 94). However, its levels have been shown to go down as the infection resolves, with persistent high levels associated with higher mortality (31, 32, 34, 95–99). Thus, it seems that, early on in the infection, it does have a protective role, while, later on, it acts more or less as an inflammatory biomarker. In our meta-analysis, PCT levels have been shown to be significantly lower in survivors as compared with nonsurvivors even on day 1 of admission, with a pooled mean difference of −6.02 (−10.01 to −2.03). The possible explanation for this could be that, by the time these patients have presented to the hospital, they were no longer in early phases of sepsis and PCT correlates more or less with the inflammatory damage to the body.

There was a lot of overall variability in our study sample, with heterogeneity of 90%, while calculating the mean pooled difference of PCT levels on day 1. Subgroup analysis gave us two groups: one with studies done in inpatients and ICU patients, with a heterogeneity of 62%, and another with studies done in the ED, with a heterogeneity of 98%. Thus, this only partially explains the heterogeneity in our study population. Also, of note is the fact that the population coming to the ED is very heterogeneous. This may be because the population of patients presenting to the ED possibly included some trauma or postsurgical patients as well. As mentioned previously, trauma is known to cause modest increases in PCT levels (14, 16, 100). Also, the severity of illness may be highly heterogeneous among ED patients, varying from those who are fit to be discharged home on oral antibiotics to those for whom death is imminent in the next few hours. Also, the timing of measurement of PCT levels in ED patients might be slightly earlier on than in patients who are hospitalized in wards or the ICU.

Another factor that may be contributing to the heterogeneity may be the wide range of mortality in various trials. Most of the trials are from China and Europe. However, if we look at the mortality as per the continent where the trial was conducted, there is no obvious pattern of distribution (Table 1). We made an attempt to explore the heterogeneity on the basis of mortality rate. The studies with mortality less than 30% when grouped together still had a heterogeneity of 96%; however, in those with mortality more than 30%, the heterogeneity decreased to 73%. Further increasing the cutoff to 40% decreased the heterogeneity of the higher mortality studies to 58%, whereas that of the lower mortality ones remained high at 94%. Thus, this wide range of mortality that may point toward a difference in the population presenting to various tertiary care hospitals may only partially explain the heterogeneity.

Interestingly, when we separately analyzed the studies involving patients with severe sepsis and septic shock only, we did not find any significant difference between survivors and nonsurvivors in terms of the day 1 PCT levels. This can be a true lack of difference at such an early stage of sepsis. It can be expected that patients suffering from severe sepsis and septic shock would have higher degrees of inflammation, which would resolve during a longer period compared with less severe forms of sepsis. Thus, the PCT levels so early on in the course of the disease may not differ significantly between the patients who would eventually survive and those who would not. However, as can be seen, the sample size of this cohort of studies is very small; hence, we cannot rule out an inadequate sample size (459 patients), which may not have allowed a small but true difference to manifest. However, no study population with less severe forms of sepsis (excluding severe sepsis and septic shock) was available to conduct a separate subgroup analysis on patients with less severe forms of sepsis.

When we observe the results for day 3, we find that the PCT difference between survivors and nonsurvivors remains significant at −5.96 ng/mL (−2.15 to −9.78 ng/mL). This may be a diminished representation of the actual difference because of the effect of survivorship bias. Patients surviving until day 3 could have had lower PCT levels compared with those dying early in the course of their illness and thus could have resulted in a lower gap between survivors and nonsurvivors. A meta-analysis on critically ill patients showed a significant difference in late C-reactive protein levels (>48 h) between survivors and nonsurvivors (92), which is understandable because both these molecules are markers of inflammation.

This meta-analysis was not without its limitations. We could only include 25 studies in the meta-analysis. This was because of the stringent selection criteria that we used. Our primary objective was to find out if there was any difference in PCT levels early on in the course of sepsis (day 1); we could include only those studies that had measured a day 1 PCT level. Apart from studies done in pediatric patients, we also excluded those done exclusively on burn, postoperative, and trauma patients because such tissue injury is known to increase the PCT levels (10, 14, 18). We did not have any studies on patients with less severe forms of sepsis (no severe sepsis or septic shock) so we could not conduct a true subgroup analysis on our study population, separating it into mild and severe forms of sepsis (severe sepsis and septic shock). Also, our initial study population suffers from large degrees of heterogeneity, which cannot be fully explained on the basis of inclusion of studies conducted in the ED and the wide range of mortality among the studies included. This wide variation in mortality rates among the trials included could point toward different protocols and health systems in place internationally. Another reason could be the difference in the pattern and degree of multidrug-resistant flora all over the world. Although it is an important confounder in our meta-analysis, this degree of variation is inevitable when studies from all over the globe are pooled. Another potential for error is the lack of a single method of measurement of PCT. The lowest value of PCT that could be measured using different kits varied between 0.02 and 0.1 ng/mL. Because septic patients are expected to have values higher than this (2), this was considered acceptable. It would also be clinically more useful to find out the diagnostic value of PCT in the prediction of mortality among patients with sepsis. In conclusion, our meta-analysis does prove that there is a significant difference between PCT levels as early as day 1 between survivors and nonsurvivors among patients suffering from sepsis. This difference persists in later stages (day 3) as well.

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Keywords:

Procalcitonin in sepsis; mortality and procalcitonin in sepsis; procalcitonin in nonsurvivors

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