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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 43  |  Issue : 1  |  Page : 9-15

The diagnostic value of serum level of soluble hemoglobin scavenger receptor CD163 for sepsis in the ICU


1 Department of Anesthesia, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of General Surgery, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission23-Apr-2014
Date of Acceptance29-Nov-2014
Date of Web Publication6-Apr-2015

Correspondence Address:
Reda S Abdelrahman
Department of Anesthesia, Faculty of Medicine, Tanta University, Tanta
Egypt
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DOI: 10.4103/1110-1415.154558

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  Abstract 

Background
Sepsis is the most important cause of morbidity and mortality in the ICU; however, sepsis lacks specific clinical manifestations. Current common clinical and laboratory indicators of infection include pyrexia, white blood cell counts (WBC), C-reactive protein (CRP), and procalcitonin (PCT).
Aim
We investigated serum-soluble CD163 (sCD163) levels in Egyptian patients in the ICU and its use in the diagnosis and severity assessment of sepsis, and compared sCD163 with other infection-related variables such as leukocyte counts, CRP, and PCT.
Patients and methods
A total of 20 patients with systemic inflammatory response syndrome (SIRS) were enrolled and 20 patients with sepsis were admitted to the ICU during the 6-month period. Serum levels of soluble hemoglobin scavenger receptor CD163 (sCD163), CRP, WBC count, and PCT were determined. Sequential Organ Failure Assessment scores for severe sepsis were also evaluated.
Results
On the day of ICU admission, patients in the sepsis group exhibited higher levels of serum sCD163 (2.41 ± 0.69 ng/ml) compared with those in the SIRS group (0.83 ± 0.19 ng/ml, P < 0.001). There was a significant positive correlation between sCD163 and WBC count (r = 0.356, P = 0.006), erythrocyte sedimentation rate (r = 0.471, P = 0.005), and CRP (r = 0.526, P = 0.001). The receiver operating characteristic curve for CRP for the diagnosis of infection showed that the reading of greater than 3.0 serves as a cutoff point for diagnosis, with a sensitivity of 86.7% and specificity of 90.2% in the studied groups, whereas for PCT the reading of 3.36 serves as a cutoff point for diagnosis, with a sensitivity of 91.6% and a specificity of 88.7% in all studied groups. sCD163 showed a cutoff point greater than 5.36, with a sensitivity of 93.5% and a specificity of 90.2%; this indicated that sCD163 was better than PCT and CRP for the diagnosis of sepsis.
Conclusion
sCD163 appeared to be a new diagnostic parameter for differentiating between patients suffering from SIRS and those with sepsis.

Keywords: procalcitonin, sepsis, soluble hemoglobin scavenger receptor CD163, systemic inflammatory response syndrome


How to cite this article:
Abdelrahman RS, Wagih AA, Elbarbary AH. The diagnostic value of serum level of soluble hemoglobin scavenger receptor CD163 for sepsis in the ICU. Tanta Med J 2015;43:9-15

How to cite this URL:
Abdelrahman RS, Wagih AA, Elbarbary AH. The diagnostic value of serum level of soluble hemoglobin scavenger receptor CD163 for sepsis in the ICU. Tanta Med J [serial online] 2015 [cited 2019 Dec 9];43:9-15. Available from: http://www.tdj.eg.net/text.asp?2015/43/1/9/154558


  Introduction Top


Sepsis is the most important cause of morbidity and mortality in the ICU; however, sepsis lacks specific clinical manifestations [1] . Early diagnosis is important to avoid delay in instituting appropriate treatment. However, diagnosis can be delayed because of difficulty in interpreting clinical features. Sepsis biomarkers can aid early diagnosis. Although some variables, such as leukocyte counts, C-reactive protein (CRP), and procalcitonin (PCT), have been applied to the diagnosis of sepsis and to determine its severity, recent evidence has highlighted the need for variables with high sensitivity and specificity that can be used to evaluate sepsis severity and prognosis [2] . CD163 is a hemoglobin scavenger receptor that is solely expressed in the monocyte-macrophage system, and it is a mediator against systemic inflammation and may modulate the inflammatory response [3] . It has been reported that oxidative stress induced by H 2 O 2 or a nitric oxide donor, as well as 8-iso-prostaglandin F2α, induces significant shedding of CD163 [4] . Feng et al. [5] recently demonstrated that sCD163 is a sepsis diagnostic biomarker that can help in defining the severity of sepsis and the assessment of prognosis. Moestrup et al. [6] also reported high serum sCD163 expression in bacteremia patients and demonstrated its value in prognosis.


  Patients and methods Top


This cross-sectional study was carried out between April 2013 and October 2013 in the ICU in Tanta University Hospitals for a period of 6 months, after obtaining approval from the local hospital ethics committee. Written informed consent was obtained from all patients or their relatives before enrollment.

Inclusion criteria

A total of 40 systemic inflammatory response syndrome (SIRS) or sepsis patients staying for more than 24 h in the ICU were consecutively enrolled in this study. In accordance with the 1991 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (ACCP/SCCM) Sepsis Directory [7] , and the diagnostic criteria advanced by the 2001 International Sepsis Definition Conference [8] , SIRS was diagnosed according to the following criteria: core body temperature >38°C or <36°C, heart rate ≥90 beats/min, respirations ≥20/min (or PaCO 2 <32 mmHg), white blood cell (WBC) ≥12 000/μl or ≤4000/μl, or >10% immature forms. Sepsis is a systemic inflammatory response to infection, and it can be recognized by the presence of suspected or confirmed infection and the systemic inflammatory response. Severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion abnormalities, or sepsis-induced hypotension (lactic acidosis, systolic blood pressure <90, or systolic blood pressure drop ≥40 mmHg of normal). When perfusion abnormalities cannot be corrected by adequate fluid resuscitation, septic shock occurs. The Sequential Organ Failure Assessment (SOFA) [9] score was used to describe a sequence of complications and the severity of organ dysfunction in critically ill patients.

Patients were included if they had two or more of the above-mentioned SIRS and/or sepsis diagnostic criteria within 24 h after ICU admission. On the basis of the results of examination and three experienced doctors' opinions, patients were divided into an SIRS group (group 1) and a sepsis group (group 2).

  1. Group 1 (the SIRS group): This group comprised 20 patients, 12 men and eight women; their ages ranged from 22 to 53 years, with a mean of 41.6 years.
  2. Group 2 (the sepsis group): This group included 20 patients, 14 men and six women; their ages ranged from 30 to 58 years, with a mean of 49.6 years.
Exclusion criteria

Patients who had chronic organ failure, thyroid cancer, or pancreatitis; who had received massive blood transfusion; or whose anticipated ICU stay was under 24 h were excluded from the study.

Upon admission to the ICU, all patients were subjected to complete history taking, including prior use of antibiotics; complete clinical examination for signs and symptoms of infection at the time of blood sampling; and examination for vital signs including temperature, heart rate, respiratory rate, arterial blood pressure, and urine output (APACH II) [10] .

SOFA [9] scores were calculated for each patient. Laboratory investigations included the following: complete blood count, blood urea nitrogen, blood glucose, serum sodium, serum potassium, serum calcium, aspartate aminotransferase, alanine aminotransferase, prothrombin time, activated partial thromboplastin time, serum albumin, arterial blood gas analysis, results of blood, urine, stool, or wound cultures according to the site of infection, and serum levels of PCT, CRP, and sCD163. Venous blood samples were collected on days 1, 3, 5, 7, and 10. Chest radiographs and pelviabdominal ultrasound were also performed for all patients. Arterial duplex study of the lower limb was performed for patients suffering from diabetic foot infection causing sepsis.

  1. CRP was determined by nephelometry using CardioPhase hsCRP (Siemens Healthcare, Indianapolis, IN, USA).
  2. PCT level (normal range 0-0.5 ng/l) was determined by means of a specific and ultrasensitive immunoluminometric assay (LUMI test PCT; Brahms Ag, Hennigsdorf/Berlin, Germany).
  3. Serum sCD163 concentrations: samples were stored at −80°C until analysis. sCD163 level was determined by an enzyme-linked immunosorbent assay, as described [11] . Serum sCD163 was determined using an enzyme-linked immunosorbent assay kit (sCD163 kit; IQ, Dade Behring Holding GmbH, Liederbach, Germany).
Statistical analysis

Results for normally distributed variables are given as mean ± SD, and results for non-normally distributed variables are given as medians and interquartile ranges. Group comparisons used Student's t-test for normally distributed variables and nonparametric Mann - Whitney U-tests for non-normally distributed variables. Receiver operating characteristic (ROC) curves were used to assess different variables with regard to the diagnosis and prognosis of sepsis. Statistical analyses were conducted using SPSS V.16 (SPSS Inc., Chicago, Illinois, USA). P value less than 0.05 was considered statistically significant.


  Results Top


A total of 40 patients were included in this study: group 1 comprised 20 patients (the SIRS group), 12 men and eight women, with ages ranging from 22 to 53 years with a mean age of 41.6 years, and group 2 comprised 20 patients (sepsis group), 14 men and six women, with ages ranging from 30 to 58 years with a mean age of 49.6 years. Sepsis patients had SIRS plus clinical evidence of any infection that could lead to rapid and significant physiological deterioration. Infections involved pneumonia, urinary tract infections, neglected peritonitis, diabetic foot infections, and central catheter-related infection. Surgical exploration and wound debridement were performed for peritonitis and diabetic foot, when appropriate, by a single surgeon. Among the sepsis patients, concurrent chronic diseases included chronic kidney disease, immune suppression, hepatic insufficiency, and respiratory failure ([Table 1]). Group 2 (sepsis group) had significantly higher CRP (59.5 ± 14.2), serum PCT (1.90 ± 2.9), and serum sCD163 (2.41 ± 0.69) compared with group 1 (SIRS patients). SOFA score in the sepsis group was 8.2 ± 3.8. Erythrocyte sedimentation rate (ESR), CRP, WBC count, and sCD163 (P < 0.05) were significantly different in group 1 in comparison with group 2 ([Table 2]). However, no significant difference was observed for PCT levels between these two groups (serum PCT was 1.12 ± 0.36 in the SIRS group; P = 0.22).
Table 1: Clinical and laboratory data at admission in the ICU

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Table 2: Receiver operating characteristic curve analysis to compare serum procalcitonin, sCD163, and C-reactive protein among the studied groups

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sCD163 levels in sepsis patients (group 2) peaked on day 5 and then gradually declined, which may suggest that inflammation in the sepsis patients (group 2) had reached maximum levels on day 5. If the level of sCD163 does not decline, it indicates a worse prognosis for the patients. These dynamic changes indicated that serum sCD163 was a stable predictor of sepsis outcomes ([Figure 1]a-c).
Figure 1: Dynamic changes of the mean value of PCT, sCD163, and CRP in the SIRS and sepsis groups (a– c). (a) Dynamic changes of the mean value of PCT in the SIRS and sepsis groups. (b) Dynamic changes of the mean value of sCD163 in the SIRS and sepsis groups. (c) Dynamic changes of the mean value of CRP in the SIRS and sepsis groups. CRP, C-reactive protein; PCT, procalcitonin; sCD163, soluble CD163; SIRS, systemic infl ammatory response syndrome.

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On day 1, ROC curve analysis was applied to values of the several variables to assess their diagnostic performance. The ROC curve for CRP for the diagnosis of infection showed that the reading of greater than 3.0 serves as a cutoff point for diagnosis, with a sensitivity of 86.7% and a specificity of 90.2%, whereas for PCT the reading of 3.36 serves as cutoff point for diagnosis, with a sensitivity of 91.6% and a specificity of 88.7% in all studied groups. sCD163 showed a cutoff greater than 5.36 with a sensitivity of 93.5% and a specificity of 90.2%, which showed a more favorable performance for sCD163. Thus, sCD163 can be used for the early diagnosis of sepsis, and it was superior to others for early detection of infection ([Table 3] and [Figure 2]), along with significant positive correlations between sCD163 and each of the following: WBC count (r = 0.356, P = 0.006), ESR (r = 0.471, P = 0.005), and CRP (r = 0.526, P = 0.001).
Figure 2: Receiver operating characteristic (ROC) curve analysis to compare serum procalcitonin (PCT), soluble CD163 (sCD163), and C-reactive protein (CRP) among the studied groups.

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Table 3: Correlations between sCD163 and other laboratory parameters among the studied groups

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  Discussion Top


Sepsis and its complications are the most common cause of death in the ICU [1] . Parameters of systemic inflammatory response, such as body temperature, heart rate, respiratory rate, leukocytic count, and CRP concentration, which are used in clinical practice are nonspecific and nonsensitive, and they often provide information that is inadequate for the discrimination of bacterial and nonbacterial infections and for diagnosis. The lack of specific early markers of infection may be responsible in part for withholding treatment, delaying treatment, or for unnecessary antimicrobial treatment in critically ill patients. There is a clear need for a reliable diagnostic procedure that allows early discrimination between patients suffering from SIRS and those with sepsis. A relatively new marker that has been associated with inflammation and sepsis is sCD163, which is a unique receptor for free hemoglobin in the blood [5] .

In this study, we analyzed the plasma concentrations of various biochemical markers used in differentiating between patients suffering from SIRS and from sepsis. We found that sCD163 was superior to CRP and PCT for the differentiation of sepsis from SIRS, as there were significant positive correlations between sCD163 and WBC count, ESR, and CRP.

Larsen et al. [12] reported that an increase of free hemoglobin in the blood had an important role in the development of severe sepsis and that it can aggravate tissue injury. The upregulation of sCD163 at the occurrence of sepsis, caused by activating the waterfall effect from the secretion of anti-inflammatory cytokines, helps scavenge hemoglobin and reduce its oxidative impairment to the body. sCD163 also functions as an innate immune sensor for bacteria [6] . The plasma membrane glycoprotein receptor CD163 is a member of the scavenger receptor cystein-rich superfamily class B that is highly expressed on resident tissue macrophages in vivo and has innate immunity functions in vitro [13] . The expression of sCD163 is strongly induced by anti-inflammatory mediators such as glucocorticoids and interleukin-10, while being inhibited by proinflammatory mediators such as interferon-g. sCD163-expressing mononuclear phagocytes, as well as soluble CD163, may both take part in downregulating an inflammatory response. Therefore, sCD163 may be an interesting target for therapeutic modulation of the inflammatory response [14] .

On comparing the sensitivity and specificity of both sCD163and PCT as bacterial inflammatory markers in infected and noninfected patients, the result of the present study showed that the sensitivity of sCD163 was 93.5% with an accuracy of 92.4% at cutoff greater than 5.36 ng/l, whereas the sensitivity of PCT was 91.6% and accuracy was 89.3% at a cutoff greater than 3.36 ng/l.

For diagnostic and prognostic purposes in critical care, PCT is an advance on CRP and other traditional markers of sepsis, but it is not accurate enough for clinicians to dispense with clinical judgment [15] . In this study, we demonstrated that sCD163 is more helpful in monitoring infection; moreover, it helps guide the use of antibiotics in clinical practice. This indicates the potential value of serum sCD163 levels for the identification of sepsis and for early assessment of patients' prognosis. However, this needs to be more supported by a larger clinical sample size.


  Conclusion Top


sCD163 is a new diagnostic parameter for early sepsis diagnosis and severity assessment, and it constitutes a risk diagnostic parameter for differentiating between patients suffering from SIRS and those with sepsis. Routine determination of sCD163 may improve the management of patients - for example, by preventing the use of unnecessary antibiotics that are known to select resistant strains.

Recommendation

Further studies of the early phases of sepsis are necessary to define the role of sCD163 in possible therapeutic strategies, such as antimicrobial and immunological therapies, and cost implications.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther 2012; 10:701-706.  Back to cited text no. 1
    
2.
Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L Procalcitonin and C-reactive protein during systemic inflammatory response syndrome, sepsis and organ dysfunction. Crit Care 2004; 8:R234-R242.  Back to cited text no. 2
    
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Buechler C, Ritter M, Ors E, Langmann T, Klucken J, Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 2000; 67:97-103.  Back to cited text no. 3
    
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Timmermann M, Högger P. Oxidative stress and 8-iso-prostaglandin F(2alpha) induce ectodomain shedding of CD163 and release of tumor necrosis factor-alpha from human monocytes. Free Radic Biol Med 2005; 39:98-107.  Back to cited text no. 4
    
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Feng L, Zhou X, Su LX, Feng D, Jia YH, Xie LX. Clinical significance of soluble hemoglobin scavenger receptor CD163 (sCD163) in sepsis, a prospective study. PLoS One 2012; 7:e38400.  Back to cited text no. 5
    
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Moestrup SK, Møller HJ. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 2004; 36:347-354.  Back to cited text no. 6
    
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Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101:1644-1655.  Back to cited text no. 7
    
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Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256.  Back to cited text no. 8
    
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Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707-710.  Back to cited text no. 9
    
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Møller HJ, Hald K, Moestrup SK. Characterization of an enzyme-linked immunosorbent assay for soluble CD163. Scand J Clin Lab Invest 2002; 62:293-299.  Back to cited text no. 11
    
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Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2010; 2:51ra71.  Back to cited text no. 12
    
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Fabriek BO, van Bruggen R, Deng DM, Ligtenberg AJ, Nazmi K, Schornagel K, et al. The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood 2009; 113:887-892.  Back to cited text no. 13
    
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Kowal K, Silver R, S³awiñska E, Bielecki M, Chyczewski L, Kowal-Bielecka O. CD163 and its role in inflammation. Folia Histochem Cytobiol 2011; 49:365-374.  Back to cited text no. 14
    
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Giamarellos-Bourboulis EJ, Tsangaris I, Kanni T, Mouktaroudi M, Pantelidou I, Adamis G, et al. Procalcitonin as an early indicator of outcome in sepsis: a prospective observational study J Hosp Infect 2011; 77:58-63.  Back to cited text no. 15
    


    Figures

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    Tables

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