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Original Article

Differentiating sepsis from non-infective systemic inflammatory response syndrome: Comparison between C-reactive protein and Leptin

Farag, N. A.a; Taema, K. M.b,*; Abdel-Latiff, E.b; Hamed, G.b

Author Information
The Egyptian Journal of Critical Care Medicine: September 2013 - Volume 1 - Issue 3 - p 111-118
doi: 10.1016/j.ejccm.2013.11.003
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Abstract

Introduction

Despite the use of modern management strategies, sepsis is a leading cause of death in critically ill patients [1]. The septic response is an extremely complex chain of events involving inflammatory and anti-inflammatory processes, humoral and cellular reactions and circulatory abnormalities [2,3].

The diagnosis of sepsis and evaluation of its severity are complicated by the highly variable and non-specific nature of the signs and symptoms of sepsis [4]. However, the early diagnosis and stratification of the severity of sepsis are very important, increasing the possibility of starting timely and the specific treatment [5,6].

Leptin is an adipokine that reveals pleiotropic neurohumoral function, which regulates appetite and energy expenditure via the hypothalamic–pituitary–adrenal axis, vascular function, bone and cartilage growth, and pregnancy. It is also an important immunoregulatory hormone that enhances a number of immune responses, including macrophage effector functions and cytokine synthesis [7]. Leptin level was found to increase in response to infection and inflammatory stimuli [8].

We sought to evaluate the value of Leptin in critically ill patients and to compare it with the C-reactive protein for early diagnosis and differentiation between sepsis and non-infectious systemic inflammatory response syndrome (SIRS).

Patients and methods

This is a prospective study that was conducted on 30 adult critically ill patients staying for more than 24 h in the ICU (surgical/medical) department, El Sahel Teaching Hospital, Cairo, Egypt. We included in the study patients diagnosed with SIRS based on the 1991 ACCP/SCCM Sepsis Directory [9] and the diagnostic criteria advanced by the 2001 International Sepsis Definition Conference [10], exhibiting two or more of the following signs: (1) temperature of >38 or <36 °C, (2) pulse rate of >90 beats/min, (3) respiratory rate of >20 breaths/min or hyperventilation with a partial pressure of arterial carbon dioxide (PaCO2) of <32 mmHg, or (4) white blood cell (WBC) count of >12,000 or <4000 μL−1, or >10% immature cells.

We excluded from the study, patients who received anti-inflammatory drugs or corticosteroids before admission, patients who had immunosuppressive illness, and patients who had received massive blood transfusion.

The presence of infection was defined according to the clinical and microbiological criteria of the CDC definitions [11] and was held as a gold standard and determined by three independent experts who were blinded to the serum Leptin and CRP results and examined the patients daily for the 1st 48 h of admission. According to the presence or absence of infection, our patients were divided into two groups; group A included patients with non-infectious SIRS (SIRS group) and group B included patients with infection (sepsis group).

The study protocol was approved by the institutional review board at Cairo University together with representatives of study conduction site, and a written informed consent to participate was obtained from all participating patients or first degree relatives.

For all cases the following were performed

Full history taking and meticulous physical examination, with sequential organ failure assessment (SOFA) score to be assessed on admission, and days 2 and 4.

Routine laboratory investigations (e.g. complete blood count, blood urea nitrogen, blood sugar, serum sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, INR, albumin) were done in the patients. Serum biomarkers (Leptin and CRP levels) were done on admission, and days 2 and 4. Routine cultures of blood, sputum, urine, and suspected sites of infection were obtained.

All patients were managed by conventional supportive measures for critically ill patients including fluids, oxygen therapy, and ventilatory support whenever required. However, whenever criteria of infection appeared or suspected (according to CDC and guided by Surviving sepsis campaign guidelines), antibiotics were immediately instituted even in SIRS patients.

Leptin assay

Blood samples were collected aseptically by venipuncture 3 times (on admission and on days 2 and 4 of admission). The blood was then left to clot then centrifuged for 15 min at 5000 rpm. The sera were separated and stored at −20 °C until the time of the assay.

Serum Leptin was determined by quantitative sandwich enzyme immunoassay (USA) according to the manufacturer's instructions. The assay is an ELISA format, performed in microwells coated with anti-Leptin antibody (monoclonal). Leptin present in a measured volume of sample or calibrator will bind to the anti-Leptin antibody on the microtitre plate.

Non-bound material was removed by washing. Subsequently, a horseradish peroxidase (HRP) conjugated antibody to Leptin is added. After removal of non-bound conjugate by washing, substrate solution is added to the wells. The color that develops is proportional to the amount of Leptin present in sample or calibrator.

The enzymatic reaction is stopped chemically and the color intensity is read at 450 nm in an ELISA reader. From the absorbance of the samples and those of a calibration curve, the concentration of Leptin is determined by interpolation.

Statistical analysis

Data were prospectively collected and coded prior to analysis using the professional statistical Package for Social Science (SPSS version 16). Continuous variables were expressed as mean and standard deviation (SD). Categorical variables were expressed as frequency and proportion. Student-t Test (t) was used for comparison between two groups as regards normally distributed (parametric) quantitative data. Chi-Square Test (χ2) was used for comparison between two groups as regards qualitative data. Results were considered statistically significant if P ≤ 0.05. A receiver operating characteristic (ROC) analysis was performed to define a cutoff value of different markers.

Results

During the period between August 2011 and February 2012, thirty critically ill patients with expected length of stay more than 24 h in the surgical/medical ICU in El Sahel Teaching Hospital were enrolled in the study. Our patients had a mean age of 52.3 ± 18.6 year old, including 10 males (33.3%) and 20 females (66.6%). After enrollment, our patients were classified into two groups according to the diagnosis that included non-infective SIRS group and sepsis group.

Each group comprised 15 patients; patients' demographics and baseline clinical data are shown in Table 1. The presence or absence of co-morbid conditions as well as cause of ICU admission being medical or surgical was similar in both groups (Table 1). The causes of ICU admission are illustrated in Table 2.

Table 1
Table 1:
Baseline demographic and clinical data.
Table 2
Table 2:
Causes of admission in both groups.

As shown in Table 3, there was no significant difference between both groups regarding clinical and laboratory data, except higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and P/F ratio and lower heart rate (HR), respiratory rate, serum creatinine, and INR in SIRS group compared to sepsis group.

Table 3
Table 3:
Baseline clinical and laboratory data.

We found that the serum Leptin levels on days 2 and 4 in the SIRS group were positively correlated with the SOFA score (r = 0.76, P = 0.002 and r = 0.67, P = 0.006 respectively). Meanwhile, all three samples of serum CRP levels (on admission and on days 2 and 4) were correlated positively with the SOFA score (r = 0.75, P = 0.002; r = 0.67, P = 0.009; and r = 0.64, P = 0.01 respectively). On the other hand, in the sepsis group, neither the Leptin nor the CRP revealed a correlation with the SOFA score (r = 0.39, P = 0.2; r = 0.36, P = 0.2; and r = 0.15, P = 0.6 for admission and days 2 and 4 of Leptin respectively and r = 0.38, P = 0.2; r = 0.4, P = 0.13; and r = 0.22, P = 0.43 for CRP respectively).

Table 4 shows a higher incidence for the need of mechanical ventilation and use of inotropic and/or vasoactive support in the sepsis group than in the SIRS group. There was also significantly higher SOFA score in the sepsis group.

Table 4
Table 4:
Need of mechanical ventilation, use of inotropic and/or vasoactive support, and SOFA score in both groups.

Serum Leptin and serum CRP were compared in both groups on days 0, 2, and 4. Serum Leptin level on admission revealed a modest non significant higher level in the sepsis group (3.5 ± 0.9 μg/L vs. 3 ± 0.7 μg/L, P = 0.1) while on Day 2 the serum Leptin level was significantly higher in the sepsis group compared to the SIRS group (44.2 ± 17.7 μg/L vs. 31.1 ± 2.1 μg/L, P = 0.008). This significant difference disappeared again on day 4 where there was no significant difference between the two groups (18.2 ± 3.9 μg/L in sepsis group compared to 17 ± 1.4 μg/L in SIRS group, P = 0.23) (Fig. 1). Serum Leptin level of 38.05 μg/L on second day of admission was found to have a sensitivity of 93% and a specificity of 100% for the diagnosis of sepsis with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 94% (Fig. 2).

Figure 1
Figure 1:
Serum Leptin during days 0, 2, and 4 in both groups.
Figure 2
Figure 2:
ROC curve for cut-off value of serum Leptin of day 2.

Serum CRP level on admission was 61.2 ± 9 mg/L in the sepsis group compared to 48.9 ± 7.1 mg/L in the SIRS group which is a statistically significant difference (P < 0.001) (Fig. 3). Day 2 and day 4 serum levels of serum CRP were also significantly higher in the sepsis group than in the SIRS group (71.5 ± 9.6 mg/L and 196.8 ± 39.8 mg/L vs. 56.9 ± 8 mg/L and 73.7 ± 32.5 mg/L respectively, P < 0.001 for both) (Fig. 3). We found a serum CRP level of 51 mg/L on the day of admission to have 93% sensitivity, 80% specificity, 82% PPV, and 92% NPV for the diagnosis of sepsis (Fig. 4) and a level of 67.5 mg/L on day 2 to have 87% sensitivity, 93% specificity, 93% PPV, and 88% NPV for the diagnosis of sepsis (Fig. 5). The serum CRP on day 4 of 95.5 mg/L has a sensitivity and specificity of 93% and PPV and NPV of 93% for the diagnosis of sepsis (Fig. 6).

Figure 3
Figure 3:
Serum CRP during days 0, 2, and 4 in both groups.
Figure 4
Figure 4:
ROC curve for cut-off value of serum CRP of day 0.
Figure 5
Figure 5:
ROC curve for cut-off value of serum CRP of day 2.
Figure 6
Figure 6:
ROC curve for cut-off value of serum CRP of day 4.

Only 2 patients (in the sepsis group) died in our study and had a Leptin of 3.1 and 38.5 μg/L and a CRP of 65 and 73 mg/L on admission and day 2.

Discussion

Severe sepsis is the most common cause of death for patients admitted to the critical care units [1]. The early diagnosis of sepsis, the identification of its origin, and an adequate therapeutic management are crucial to overcome sepsis-associated mortality. So, the matter at heart in the early differentiation between Sepsis and non-infectious SIRS is the impact on outcome.

The adipokine Leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects toward T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of Leptin in the setting of an acute systemic inflammation [7,12]. Some studies found that serum Leptin is a powerful biomarker that helps to differentiate sepsis from the non-infectious SIRS in critically ill patients with higher levels in sepsis [8,13–15].

We intended in this study to evaluate the value of monitoring serum Leptin in critically ill patients and to compare it with serum CRP for early diagnosis of sepsis and its differentiation from non-infectious SIRS.

Both groups of the study had comparable demographic data and comorbidities, however data of disease severity were significantly worse in the sepsis group e.g. HR, MAP, RR, and need of mechanical ventilation and vasoactive support that was reflected on higher SOFA score. Higher heart rate and lower blood pressures were also reported by many investigators in patients with definite bacterial infection [16–18]. This was attributed by many authors to the well known systemic vasodilation and myocardial depression that occurs in sepsis. Endothelium dysfunction, inflammatory cytokines release, and inducible NO synthase mediated NO release are involved in sepsis associated profound vasodilation and biventricular failure [19–21].

Respiratory rate was significantly higher in sepsis than SIRS groups and this is in agreement with other studies in which patients with sepsis had higher RR and rapid shallow breathing index [18,22]. They explained this by reduced respiratory muscle capacity and increased load. The negative impact of sepsis on respiratory muscle function was attributed to circulating mediators [23], changes in intracellular calcium [24], oxygen metabolism [25], or changes in respiratory muscle ultrastructure [26]. These effects, however, could happen in critical illness irrespective of sepsis.

According to these differences in blood pressures, heart rate, and respiratory rate, it is not surprising that the use of inotropic and vasoactive supports and the need for mechanical ventilation and subsequently SOFA score were significantly higher in the sepsis group. Higher SOFA score in sepsis was reported in some other studies [8,27,28]. Despite these significant differences of clinical and laboratory data that were observed in our study and in others', Shapiro et al, [29] showed that these data are not pathognomonic for infection and may also be observed in a wide variety of noninfectious inflammatory conditions. In addition, they may be absent in patients with serious infections, especially in elderly individuals [29].

Our results showed that serum Leptin level on 2nd day and not on admission can differentiate between sepsis and non-infectious SIRS. We found a serum Leptin level of 38.05 μg/L on second day of admission to diagnose sepsis in patients admitted with SIRS with a sensitivity of 93% and a specificity of 100%.

Torpy et al., [13] reported a higher Leptin level in septic patients on the day of admission. Arnalich et al., [14] even found that the admission serum Leptin was higher in patients with septic shock than patients with severe sepsis without shock [14].

Similar to our results, Yousef et al, [8] showed that the admission serum Leptin was nearly equal among patients in the sepsis, SIRS, and non-SIRS groups and that the second day levels significantly increased in septic and SIRS patients compared to non-SIRS patients. They detected a cut-off serum Leptin level of 38 μg/L with a sensitivity of 91.2% and a specificity of 85% to identify sepsis from SIRS [8]. Cesur et al, [15] also stated that there was no statistically significant difference between the patient group with sepsis and the control group in terms of serum Leptin levels on admission but Leptin was higher in patient group with sepsis on days 3 and 5.

This reported rise in serum Leptin concentration following acute infection suggests that it may actively participate in the immune response and host defense. Leptin and its receptors have structural similarities with cytokine family that includes IL-6 and IL-12 [30,31], so it should not be surprising that it acts as a pro-inflammatory cytokine. Leptin itself was shown by some authors to increase the production of TNF α and IL-6 from macrophages [12].

Contrary to these results, Carlson et al showed that sepsis was not associated with significant change in serum Leptin concentration [32]. The population of this study was however not comparable with ours as patients were enrolled in the study after about 14 days of sepsis diagnosis. This delay in time of enrollment relative to sepsis onset could explain these differences as other authors had identified an increase in serum Leptin concentration for only the first 5 days following prolonged administration of IL-1α [33]. On the other hand, many of the studies that concluded an elevated serum Leptin in response to sepsis including ours did not report on body composition or feeding regimens that might conceivably have influenced the results.

On the extreme, Langouche et al in [34] even showed low serum Leptin levels in critically ill patients that were postulated by the authors to be due to an acute stress response. This study was planned to evaluate the effect of conventional and intense insulin therapy on serum Leptin. So, like Carlson and coworkers [32], they screened prolonged critically ill patients and an early effect may have been missed. Another explanation of this discrepancy could be attributed to differences in illness severity between their population and ours. Langouche and his colleagues [34] reported high death rates that were 51.5% in patients with sepsis while only two of our sepsis group population died (13.3%). Many authors showed an association between low serum Leptin level and mortality [14] as Leptin was found to stimulate proliferation of lympho-hematopoetic cells and phagocytic activity of macrophages [35].

We detected in this study that the serum CRP levels on admission, 2nd day, and 4th day following admission were significantly higher in sepsis compared to non-infectious SIRS. Many other studies [17,27,36] showed that a high serum CRP concentration in patients within 24 h of admission to hospital is indicative of sepsis and can differentiate septic patients from non-infectious SIRS. Yousef et al, [8] however showed that despite the mean values of CRP on admission cannot differentiate between the two groups, the CRP level on the 4th day of admission was significantly higher in sepsis compared to non-infectious SIRS groups [8].

C reactive protein production is a part of a larger picture of the acute phase response. This is principally regulated by the cytokines IL-6 [37], Tumor necrosis factor α, and IL-1β are also regulatory mediators of CRP synthesis [38]. C-reactive protein is directly involved in clearance of microorganisms [39]. It causes activation of neutrophils and enhances NK cell activity [40,41].

We detected a CRP level of 51 mg/L on the day of admission to have 93% sensitivity and 80% specificity for the diagnosis of sepsis. Many other investigators described CRP cut-off values for detection of sepsis. Povoa et al detected also a level of 50 mg/L with sensitivity of 98.5% and specificity of 75% [42]. Liu et al, [17] found a value of 60 mg/L with a sensitivity of 80.7% and specificity of 96.0% for diagnosing bacterial infection. Higher cut-off values were reported by other authors. Sierra et al, [43] showed the cut-off value of 80 mg/L is 94.3% sensitive and 87.3% specific for sepsis [43] however Miller and his colleagues reported a higher value of 170 mg/L for CRP with 100% specificity [44].

In a study on postoperative patients, the investigators found that the CRP started to be elevated 12 h and peaked 36 h after the operation [45]. Other authors reported that the CRP starts to elevate within 4–6 h of stimulus and doubles every 8 h to reach a peak at 36–50 h [39]. On the other hand, Leptin was found to start being elevated and peaked 24 h after stimulus [45]. This could explain the lack of significance of serum Leptin between both groups in our study on admission and on day 4 but the only significance was on day 2.

Despite the detection of an early serum CRP on admission of 51 mg/L to have 80% specificity for the diagnosis of sepsis, the later serum Leptin on day 2 of 38.05 μg/L was found to have 100% specificity. The late yet more specific elevation of serum Leptin level in sepsis needs to be further evaluated.

Conclusion

Serum CRP level can differentiate early between sepsis and non infectious SIRS on admission, however on the second day of admission the use of elevated serum Leptin level may be more specific than elevated CRP level either on admission or on second day in identifying sepsis patients.

Study limitations

Limitations of this study included the limited number of samples of the biomarkers (only three samples) that may have missed higher levels. Some other studies screened Leptin in 6 h intervals; however we aimed at evaluating the patients on admission. Another limitation was the limited number of patients included in the study; further studies are needed to confirm our results. Finally, Antibiotics had to be given early in some patients with SIRS with no obvious infection, for the possibility of hidden infection, which may have had an impact on the markers. In other patients in which infection appeared later could have had an occult infection that aggravated rather than a superadded infection, and may not have been appropriately assigned.

Conflict of interest

None declared.

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Keywords:

Sepsis; SIRS; Leptin; CRP

© 2013 by Lippincott Williams & Wilkins, Inc.