systemic inammatory response syndrome: Comparison between C-reactive protein and Leptin N.A. Farag a , K.M. Taema b, * , E. Abdel-Lati b , G. Hamed b a Critical Care Medicine, Elsahel Teaching Hospital, Cairo, Egypt b Critical Care Medicine, Cairo University, Cairo, Egypt Received 15 May 2013; revised 15 November 2013; accepted 16 November 2013 Available online 5 December 2013 KEYWORDS Sepsis; SIRS; Leptin; CRP Abstract Background: Differentiation of sepsis from non-infectious SIRS is important in improv- ing sepsis outcome. We intended in this study to evaluate the role of serum Leptin and to compare it with CRP in differentiating sepsis from non-infectious SIRS. Methods: We included 30 patients with SIRS. According to the presence or absence of infection, our patients were classied into SIRS group and sepsis group. Leptin and CRP were evaluated in all patients on admission, day 2 and day 4. Results: Our patients had a mean age of 52.3 18.6 year old, 10 males (33.3%). There were no signicant differences regarding baseline demographic and clinical data apart from blood pressures which were lower in the sepsis group. Serum Leptin on Day 2 only was higher in the sepsis group (44.2 17.7 lg/L vs. 31.1 2.1 lg/L, P = 0.008) with no difference in days 0 and 4 of admission. We detected a serum Leptin level of 38.05 lg/L on day 2 to be 93% sensitive and 100% specic to diagnose sepsis. The three serum CRP levels were higher in sepsis compared to SIRS group (61.2 9 mg/L vs. 48.9 7.1 mg/L, P < 0.001 in day 0, 71.5 9.6 mg/L and 196.8 39.8 mg/ L in sepsis group vs. 56.9 8 mg/L and 73.7 32.5 mg/L in SIRS group for days 2 and 4 respec- tively, P < 0.001 for both). We found a CRP of 67.5 mg/L on day 2 having 87% sensitivity and * Corresponding author. Tel.: +20 1000412603. E-mail addresses: Khaled.toaima@kasralainy.edu.eg, Khaledtoai- ma@assih.com (K.M. Taema). Peer review under responsibility of The Egyptian College of Critical Care Physicians. Production and hosting by Elsevier The Egyptian Journal of Critical Care Medicine (2013) 1, 111118 The Egyptian College of Critical Care Physicians The Egyptian Journal of Critical Care Medicine http://ees.elsevier.com/ejccm www.sciencedirect.com 2090-7303 2013 Production and hosting by Elsevier B.V. on behalf of The Egyptian College of Critical Care Physicians. http://dx.doi.org/10.1016/j.ejccm.2013.11.003 93% specicity for the diagnosis of sepsis. Conclusion: We concluded that despite serum Leptin may not be benecial in early differentia- tion between sepsis and non infectious SIRS on admission; it may be highly specic on second day. 2013 Production and hosting by Elsevier B.V. on behalf of The Egyptian College of Critical Care Physicians. Introduction Despite the use of modern management strategies, sepsis is a leading cause of death in critically ill patients [1]. The septic re- sponse is an extremely complex chain of events involving inammatory and anti-inammatory 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-specic nature of the signs and symptoms of sepsis [4]. However, the early diag- nosis and stratication of the severity of sepsis are very impor- tant, increasing the possibility of starting timely and the specic treatment [5,6]. Leptin is an adipokine that reveals pleiotropic neurohumo- ral function, which regulates appetite and energy expenditure via the hypothalamicpituitaryadrenal axis, vascular func- tion, bone and cartilage growth, and pregnancy. It is also an important immunoregulatory hormone that enhances a num- ber of immune responses, including macrophage effector func- tions and cytokine synthesis [7]. Leptin level was found to increase in response to infection and inammatory stimuli [8]. We sought to evaluate the value of Leptin in critically ill pa- tients and to compare it with the C-reactive protein for early diagnosis and differentiation between sepsis and non-infec- tious systemic inammatory response syndrome (SIRS). Patients and methods This is a prospective study that was conducted on 30 adult crit- ically ill patients staying for more than 24 h in the ICU (surgi- cal/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 Denition Conference [10], exhibiting two or more of the fol- lowing 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 diox- ide (PaCO2) of <32 mmHg, or (4) white blood cell (WBC) count of >12,000 or <4000 lL 1 , or >10% immature cells. We excluded from the study, patients who received anti- inammatory drugs or corticosteroids before admission, pa- tients who had immunosuppressive illness, and patients who had received massive blood transfusion. The presence of infection was dened according to the clin- ical and microbiological criteria of the CDC denitions [11] and was held as a gold standard and determined by three inde- pendent 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 infec- tion, our patients were divided into two groups; group A in- cluded patients with non-infectious SIRS (SIRS group) and group B included patients with infection (sepsis group). The study protocol was approved by the institutional re- view 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 rst 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 as- sessed on admission, and days 2 and 4. Routine laboratory investigations (e.g. complete blood count, blood urea nitrogen, blood sugar, serum sodium, potas- sium, calcium, aspartate aminotransferase, alanine amino- transferase, 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 mea- sures for critically ill patients including uids, oxygen therapy, and ventilatory support whenever required. However, when- ever 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 en- zyme immunoassay (USA) according to the manufacturers 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. Subse- quently, 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 112 N.A. Farag et al. (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 (v 2 ) was used for comparison between two groups as regards qualitative data. Results were considered statistically signi- cant if P 6 0.05. A receiver operating characteristic (ROC) analysis was performed to dene 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 classied 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. As shown in Table 3, there was no signicant difference be- tween both groups regarding clinical and laboratory data, ex- cept 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. 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 respec- tively). 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 re- vealed 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 signif- icantly higher SOFA score in the sepsis group. 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 signicant higher level in the sepsis group (3.5 0.9 lg/L vs. 3 0.7 lg/L, P = 0.1) while on Table 1 Baseline demographic and clinical data. SIRS Sepsis P-value Age 51.3 16 53.3 21.3 0.77 Gender [N (%)] Male 6 (40%) 4 (26.7%) 0.35 Female 9 (60%) 11 (73.3%) BMI 23.9 2.4 24.3 3.7 0.7 HTN [N (%)] 8 (53.3%) 7 (46%) 0.8 DM [N (%)] 10 (66.7%) 7 (46%) 0.47 CVS [N (%)] 2 (13.3%) 1 (6.66%) 0.56 CRF [N (%)] 1 (6.66%) 2 (13.3%) 0.56 CHF [N (%)] 0 (0%) 1 (6.66%) 0.32 Co-morbidity 1 co-morbidity 3 3 0.68 2 co-morbidities 3 5 More than two co-morbidities 9 7 Cause of admission Medical 12 12 0.67 Surgical 3 3 BMI: body mass index, HTN: hypertension, DM: diabetes mellitus, CVS: cerebrovascular stroke, CRF: chronic renal failure, CLD: chronic lung disease, CHF: congestive heart failure. Table 2 Causes of admission in both groups. SIRS N (%) Sepsis N (%) Total Respiratory distress Pneumonia 0 (0 %) 7 (46.7 %) 7 (23.3 %) Acute lung injury 4 (26.7 %) 0 (0 %) 4 (13.3 %) Bronchogenic carcinoma 1 (6.7 %) 0 (0 %) 1 (3.3 %) Abdominal sepsis 0 (0 %) 1 (6.7 %) 1 (3.3 %) Suspected central line infection 1 (6.7 %) 1 (6.7 %) 2 (6.7 %) Soft tissue infection 0 (0 %) 1 (6.7 %) 1 (3.3 %) Urinary tract infection 0 (0 %) 2 (13.3%) 2 (6.7 %) DKA 3 (20 %) 0 (0 %) 3 (10 %) Post-operative 3 (20 %) 3 (20 %) 6 (20 %) Intestinal obstruction 1 (6.7 %) 0 (0 %) 1 (3.3 %) Hematologic malignancy 1 (6.7 %) 0 (0 %) 1 (3.3 %) CRF with volume overload 1 (6.7 %) 0 (0 %) 1 (3.3 %) Total 15 (100 %) 15 (100 %) 30 (100 %) DKA: diabetic ketoacidosis, CRF: chronic renal failure. Differentiating sepsis from non-infective systemic inammatory response syndrome 113 Day 2 the serum Leptin level was signicantly higher in the sepsis group compared to the SIRS group (44.2 17.7 lg/L vs. 31.1 2.1 lg/L, P = 0.008). This signicant difference dis- appeared again on day 4 where there was no signicant differ- ence between the two groups (18.2 3.9 lg/L in sepsis group compared to 17 1.4 lg/L in SIRS group, P = 0.23) (Fig. 1). Serum Leptin level of 38.05 lg/L on second day of admission was found to have a sensitivity of 93% and a specicity of 100% for the diagnosis of sepsis with a positive predictive va- lue (PPV) of 100% and a negative predictive value (NPV) of 94% (Fig. 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 signicant difference (P < 0.001) (Fig. 3). Day 2 and day 4 serum levels of serum CRP were also signicantly 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% specicity, 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% specicity, 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 sensitiv- ity and specicity of 93% and PPV and NPV of 93% for the diagnosis of sepsis (Fig. 6). Only 2 patients (in the sepsis group) died in our study and had a Leptin of 3.1 and 38.5 lg/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 identication of its origin, and an adequate thera- peutic management are crucial to overcome sepsis-associated mortality. So, the matter at heart in the early differentiation Table 3 Baseline clinical and laboratory data. SIRS Sepsis P-value HR 111.6 14.4 124.8 18.8 0.04 SBP 112.33 23.7 90.67 20.5 0.012 DBP 69.33 14.7 54 11.8 0.004 MBP 83.7 16.8 66.2 14.2 0.005 RR 25.7 3.7 34.5 8.7 0.001 Temperature 38 1 38.9 1.7 0.078 CVP 6.3 3.2 4 4.5 0.17 ScvO 2 72.3 6.3 67.4 14.8 0.25 Serum urea 67.3 52.8 91.2 79.9 0.34 Serum Creatinine 1.7 0.98 3.4 2.2 0.01 Na + 133.2 5.2 135.9 7.3 0.25 K + 3.9 0.8 3.5 0.5 0.095 Ca ++ 8.3 0.8 7.8 1.6 0.32 RBG 199.7 64.6 284.3 163.6 0.07 AST 78.9 110.4 95.9 106.9 0.67 ALT 38.2 22.4 88 118.1 0.12 Serum albumin 3.1 0.8 3.2 0.5 0.9 INR 1.4 0.32 1.97 0.86 0.04 Hemoglobin 11 2.8 10.9 2.3 0.85 Platelet count 199.3 107.9 226 137 0.55 TLC 14.8 5.9 19.3 8.5 0.09 P/F ratio 373.93 61.7 263.27 95.7 0.001 Table 4 Need of mechanical ventilation, use of inotropic and/or vasoactive support, and SOFA score in both groups. SIRS Sepsis P-value Mechanical ventilation [N (%)] Yes 0 (0 %) 9 (60 %) 0.002 No 15 (100%) 6 (40 %) Use of inotropic and/or vasoactive support [N (%)] Yes 2 (13.3 %) 7 (47 %) 0.05 No 13 (86.6 %) 8 (53 %) SOFA score Mean SD 5 3 8 3 0. 02 Figure 1 Serum Leptin during days 0, 2, and 4 in both groups. Figure 2 ROC curve for cut-off value of serum Leptin of day 2. 114 N.A. Farag et al. between Sepsis and non-infectious SIRS is the impact on outcome. The adipokine Leptin regulates energy expenditure, vascu- lar function, bone and cartilage growth as well as the immune system and systemic inammatory response. Several activating effects toward T cells, monocytes, endothelium cells and cyto- kine production have been reported suggesting a protective role of Leptin in the setting of an acute systemic inammation [7,12]. Some studies found that serum Leptin is a powerful bio- marker that helps to differentiate sepsis from the non-infec- tious SIRS in critically ill patients with higher levels in sepsis [8,1315]. We intended in this study to evaluate the value of monitor- ing 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 signicantly worse in the sepsis group e.g. HR, MAP, RR, and need of mechanical ventilation and vasoactive support that was reected on higher SOFA score. Higher heart rate and lower blood pressures were also reported by many investigators in patients with denite bacterial infection [1618]. This was attributed by many authors to the well known systemic vasodilation and myocardial depression that occurs in sepsis. Endothelium dysfunction, inammatory cytokines release, and inducible NO synthase mediated NO release are involved in sepsis associated profound vasodilation and biventricular failure [1921]. Respiratory rate was signicantly 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 respi- ratory muscle capacity and increased load. The negative im- pact 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 signicantly higher in the sepsis group. Higher SOFA score in sepsis was reported in some other studies [8,27,28]. Despite these signi- cant differences of clinical and laboratory data that were ob- served 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 inam- matory 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 lg/ L on second day of admission to diagnose sepsis in patients admitted with SIRS with a sensitivity of 93% and a specicity 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 Figure 3 Serum CRP during days 0, 2, and 4 in both groups. Figure 5 ROC curve for cut-off value of serum CRP of day 2. Figure 4 ROC curve for cut-off value of serum CRP of day 0. Differentiating sepsis from non-infective systemic inammatory response syndrome 115 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 signicantly increased in septic and SIRS patients compared to non-SIRS patients. They detected a cut-off serum Leptin level of 38 lg/L with a sensitivity of 91.2% and a spec- icity of 85% to identify sepsis from SIRS [8]. Cesur et al, [15] also stated that there was no statistically signicant 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-inammatory cytokine. Leptin itself was shown by some authors to increase the production of TNF a and IL-6 from macrophages [12]. Contrary to these results, Carlson et al showed that sepsis was not associated with signicant 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 identied an increase in serum Leptin concentration for only the rst 5 days following pro- longed administration of IL-1a [33]. On the other hand, many of the studies that concluded an elevated serum Leptin in re- sponse to sepsis including ours did not report on body compo- sition or feeding regimens that might conceivably have inuenced 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 cowork- ers [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 col- leagues [34] reported high death rates that were 51.5% in pa- tients 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 sig- nicantly 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 hos- pital 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 dif- ferentiate between the two groups, the CRP level on the 4th day of admission was signicantly 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 a, and IL-1b 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 admis- sion to have 93% sensitivity and 80% specicity 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 specicity of 75% [42]. Liu et al, [17] found a value of 60 mg/L with a sen- sitivity of 80.7% and specicity of 96.0% for diagnosing bac- terial 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% specic for sepsis [43] however Miller and his colleagues reported a higher value of 170 mg/L for CRP with 100% specicity [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 46 h of stimulus and doubles every 8 h to reach a peak at 3650 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 signicance of ser- um Leptin between both groups in our study on admission and on day 4 but the only signicance was on day 2. Despite the detection of an early serum CRP on admission of 51 mg/L to have 80% specicity for the diagnosis of sepsis, the later serum Leptin on day 2 of 38.05 lg/L was found to have 100% specicity. The late yet more specic 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 Figure 6 ROC curve for cut-off value of serum CRP of day 4. 116 N.A. Farag et al. day of admission the use of elevated serum Leptin level may be more specic 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 sam- ples 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 pa- tients included in the study; further studies are needed to con- rm 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 appropri- ately assigned. Conict of interest None declared. References [1] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):130310. [2] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348(2):13850. 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