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.
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).
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).
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).
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).
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).
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.
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.
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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