The prognostic value of sCD163 in patients with acute respiratory distress syndrome

WANG -, -, -, -, -, △, -

(1Department of Anaesthesia Intensive Care Unit,Shanghai Cancer Center-Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China; 2Department of Anaesthesia,Critical Care and Pain Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China)

Acute respiratory distress syndrome (ARDS) has continued to be the leading cause of life-threatening severe hypoxemia disease in intensive care units worldwide in the past three decades.ARDS is a serial disease,characterized by systematic inflammation,increased microvascular permeability,consequently pulmonary edema and refractory hypoxemia.Diagnosing ARDS requires exclusion of cardiogenic pulmonary edema (CPE) based on the clinical feature,echocardiography and pulmonary artery catheters.

Identifying biomarkers for prognosis or pathophysiology in ARDS is a highly challenged issue.And it has yet to be found a special diagnostic parameter for ARDS.Inflammation is tightly associated with macrophage phenotype and function during the acute inflammatory stage of ARDS[1].They mainly sustain homeostasis by mediating the release of proinflammatory and anti-inflammatory cytokines.CD163 is a scavenger receptor for haptoglobin-hemoglobin complexes[2],which is solely expressed on monocytes and macrophages[3-4].CD163 expression is strongly induced by anti-inflammatory mediators IL-10 and IL-6.Since IL-10 and IL-6 secretion are induced by IFN-γ and LPS,we assume that these cytokines mediate the high expression of CD163 on anti-inflammatory macrophage subsets[5].Soluble CD163,the shedding form of CD163,is a marker of activated macrophages.Following an inflammatory stimulus or oxidative stress,sCD163 is released from the cell surface by proteolytic cleavage of monocyte bound CD163 through the action of MMPs and after LPS stimulation[6].Convincing evidence has shown that elevated levels of sCD163 in plasma is associated with inflammatory disease[7],including cirrhosis[8],infection[9],disseminated intravascular coagulation[10],and sepsis[11-13].At present,few studies have specifically analyzed the expressing level of CD163 and sCD163 in ARDS.If any,they mainly focus on alveolar macrophage CD163[14-15].In consideration of the effect of plasma sCD163 and its convenience to obtain,we investigated the plasma levels of sCD163 and analyzed its value in patients with ARDS.

Materials and methods

StudydesignThis prospectively,observational trail was approved by the Ethics Committee of Zhongshan Hospital,Fudan University (Shanghai,China) following the principle of the Helsinki declaration.Written informed content was obtained from all subjects or their closest relative.One hundred and three consecutive patients with ARDS or CPE admission to the ICU of Zhongshan Hospital participated in the study between January 2013 and April 2014.Healthy controls (n=21,free from pulmonary or cardiac disease) were defined as normal individuals.Those who refused to give informed consent,under the age of 18,have acquired immunodeficiency syndrome or primary abnormality of coagulation,pregnant,terminate their treatment by themselves or their closest relative during the course of observation were excluded from the study.

Trained intensivists reevaluated the value of sCD163 and other clinical parameters combined with therapy responsiveness.They then made their final diagnosis of ARDS or CPE.Echocardiography or pulmonary artery catheters examination were performed for the inconsistent cases.Intensivists reviewed all the findings,then discussed and reached the consensus.ARDS patients were defined according to the recently established Berlin definition[16].In the new Berlin definition,diagnostic criteria for ARDS relies on four categories:(1) timing,within one week of a known clinical event (such as sepsis,pneumonia,aspiration,trauma,blood transfusion and acute pancreatitis) or new or worsening respiratory symptoms;(2) chest imaging,bilateral radiography opacities-not fully explained by effusions,lobar/lung collapse or nodule;(3) origin of lung edema,respiratory failure not fully explained by cardiac failure or fluid overload,and need objective assessment(echocardiography,pulmonary artery catheters);(4) oxygenation impairment,classified depending on oxygenation as mild,moderate,or severe.Patients with CPE were diagnosed by a combination of clinical signs (gallop,jugular venous distension,systolic hypertension).Intensivists used a wide range of diagnostic methods:radiography (cardiothoracic ratio of>0.53 and vascular pedicle width of>65 mm),electrocardiography (new ST-segment and T-wave changes),laboratory test (elevated troponin T of >0.1 ng/mL),and hemodynamic findings [PAOP of≥18 mmHg (1 mmHg=0.133 kPa),decreased ejection fraction of <45%,presence of severe left-sided valvular heart disease(aortic or mitral stenosis or regurgitation)];and the response to appropriate therapy (preload/afterload reduction,treatment of ischemia or inotropic agents[17]) was observed.

ARDS were classified into mild,moderate or severe if PO2/FiO2was,respectively,between 201 and 300 mmHg,101 and 200 mmHg,or 100 mmHg or less,using a minimal PEEP level of 5 cmH2O.Additionally,ARDS were divided into infection group and non-infection group (aspiration,trauma,blood transfusion,hemorrhage shock,cardiac arrest) according to the precipitation factor.

Blood sample for determinating sCD163 value were collected on D1,D3,D5,D7 and D10 in 5 mL EDTA tubes,then were centrifugated at 4 ℃ for 15 minutes at 3 000 r/min within the next 1.5 hours.Plasma samples were removed to Eppendorf tubes,and stored at -80 ℃ until analysis.The levels of sCD163 were measured at key laboratory of breast cancer (Shanghai Cancer Center,Fudan University) using commercial ELISA following the manufacturer’s instructions (R&D,Minneapolis,MN,USA product number:BAM-16072).In this study,duplicate wells were used to detect plasma sCD163 concentration.The plates were read at 492 nm an automatic ELISA reader.Notable evidence has verified sCD163 was a highly stable maker stored at -80 ℃ for at least 16 months,also resistant to repeating freezing and thawing[21].

StatisticalanalysesNormal disturbance data were presented as mean±standard deviation (SD) or median (interquartile range) and categorical data were summarized as numbers and proportion.For two-group analyses,the unpaired Student’st-test,Wilcoxon’s rank-sum test,or chi-square test were used.Multiple group was compared with One Way ANOVA or Kruskal-Wallis test.Receiver operating characteristic (ROC) curves were employed to evaluate the accuracy of sCD163 diagnose ARDS and prediction 28-day ICU outcome.Cumulative survival curve was carried out by Kaplan-Meier survival analysis.Logistic regression analysis was assessed by univariate and multivariate analysis to identify independent predictors of outcome controlling for reported risk factor of mortality.Linear regression models were evaluated for the outcomes of VFD (ventilator-free days) and OFD (non-pulmonary organ failure-free days) by log-transforming corresponding variables to achieve a normal distribution.Two tailedP<0.05 were considered statistically significant.The SPSS software package,version 16.0 (SPSS Inc.,Chicago,Illinois,USA),was used for all statistical analysis.

Results

CharacteristicsofthepatientsOf all the 124 subjects,83 patients with ARDS,20 patients with CPE,and 21 healthy controls,have enrolled in this study.Two cardiac arrest patients,whose treatment was terminated by their closest relative,were excluded.Two patients were also excluded because the researchers were unable to reach a consensus on diagnosis.Four patients died during the days from D1 to D10 in patients with ARDS,therefore the number of subjects who were included in data analysis was 103 on D1 and D3,102 on D5,101 on D7,and 99 on D10,respectively.

The patients’ demographic information,underlying disease,laboratory findings,hemodynamic data at admission into ICU were presented in Tab 1.CPE patients tended to easily have a history of atrial fibrillation,lower APACHEⅡscore,lower SOFA score,and higher PO2/FiO2ratio compared with ARDS patients.Echocardiography and hemodynamic parameters showed that CPE patients had lower left ventricular ejection fraction (LVEF) and higher pulmonary artery occlusion pressure (PAOP).ARDS patients were classified into survivors and non-survivors according to 28-days mortality.Their baseline data and suggested precipitation factor of ARDS was shown in Tab 2.The causes of ARDS were sepsis (33/83),pneumonia (30/83),hemorrhage shock (7/83),aspiration (6/83),post-surgery (3/83),blood transfusion (2/83),cardiac arrest (2/83).The cause of CPE included congestive heart failure (9/20),myocardial infraction/ischemia (6/20) and acute volume overload (5/20).

Tab 1 Baseline characteristics of patients with ARDS or CPE

ARDS:Acute respiratory distress syndrome;CPE:Cardiogenic pulmonary edema;BMI:Body mass index;APACHE II:Acute physiology and chronic health evaluation II;SOFA:Sequential organ failure assessment;PO2/FiO2:A ratio of arterial oxygen partial pressure and inspiratory oxygen fraction;LVEF:Left ventricular ejection fraction;PAOP:Pulmonary artery occlusion pressure;SvO2:Oxygen saturation of venous blood;APTT:Activated partial thromboplastin time;HBP:Heparin-binding protein.Data were presented as median (interquartile range) for continuous variables and number (%) for categorical variables.1 mmHg=0.133 kPa.

Tab 2 Baseline characteristics of patients with ARDS according to survival

ARDS:Acute respiratory distress syndrome;BMI:Body mass index;APACHE II:Acute physiology and chronic health evaluation II;SOFA:Sequential organ failure assessment;PO2/FiO2:A ratio of arterial oxygen partial pressure and inspiratory oxygen fraction;LVEF:Left ventricular ejection fraction;PAOP:Pulmonary artery occlusion pressure;SvO2:Oxygen saturation of venous blood;APTT:Activated partial thromboplastin time.Data were presented as median (interquartile range) for continuous variables and number (%) for categorical variables.1 mmHg=0.133 kPa.

PlasmasCD163concentrationforthediagnosisofARDSPlasma median levels of sCD163 were significantly higher in ARDS patients compared with CPE patients [496.7(421.8-577.5) ng/mLvs. 284.5(141.7-459.2) ng/mL,P<0.001] and with healthy controls [496.7(421.8-577.5) ng/mLvs.209.8(103.9-425.9) ng/mL,P<0.001] at enrollment.There was no significant difference between CPE patients and healthy subjects in terms of sCD163 value (P=0.144).The receiver operating characteristic (ROC) curve was employed to evaluate sCD163’s ability distinguishing ARDS from CPE.The area under curve (AUC) turned out to be 0.784±0.062 (95% CI:0.661-0.906,P<0.001) with a cut-off point>413.1 ng/mL.The sensitivity was 79.5% and specificity was 75.0% (Fig 1A).

There was significant difference between non-infected group and CPE group [487.3(369.2-582.3) ng/mLvs. 284.5(141.7-459.2) ng/mL,P=0.001].Median sCD163 value in infected group was significantly higher than that in CPE group [496.7(429.9-577.5) ng/mLvs. 284.5(141.7-459.2) ng/mL,P<0.001].However,there was no significant difference of sCD163 levels between non-infected group and infected group [487.3 (369.2-582.3) ng/mLvs.496.7 (429.9-577.5) ng/mL,P=0.431] (Fig 2A).

A:Receiver operating characteristic curves for soluble CD163 differentiate acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE).B:Predicting 28-day mortality in patents with ARDS.

Fig1DiagnosticvalueofsolubleCD163forpatientswithARDSandmortalityprediction

A:Plasma soluble CD163 in CPE patients,non-infected ARDS patients,and infected ARDS patients.B:Plasma sCD163 value in mild,moderate and severe group of ARDS.

Fig2PlasmasCD163levelsinCPEgroupandARDSgroup

PlasmasCD163valuesforseverityassessmentofARDSOn the basis of oxygenation impairment,ARDS patients were further divided into mild (21/83),moderate (42/83) and severe (20/83) group.There was a stepwise increase of sCD163 levels on D1 from mild to severe.Thereby,the sCD163 concentration was significantly higher in the moderate group compared with the mild group [498.8(443.4-566.7) ng/mLvs.426.4(335.1-487.9) ng/mL,P=0.004].Compared with moderate group,the value of sCD163 in the severe group was significant higher [587.5(456.0-674.0) ng/mLvs. 498.8(443.4-566.7) ng/mL,P=0.015] (Fig 2B).There was only modest correlation between sCD163 value and severity of ARDS on D1 (r=0.482,P<0.001) and on D10 (r=0.402,P=0.003).

PlasmalevelsofsCD163predictingoutcomeofARDSARDS patients were divided into survivors (60/83) and non-survivors (23/83) based on the 28-day mortality.There were significant differences in age,APACHE II score,SOFA score and PO2/FiO2between non-survivors and survivors (Tab 2).Dynamics of median sCD163 in ARDS patients from D1 to D10 were shown in Fig 3.Soluble CD163 levels remained significant difference between nonsurvivors and survivors on D1 [577.5(503.7-624.3) ng/mLvs.479.6(395.5-520.8) ng/mL,P<0.001],on D3 [636.9(602.7-698.9) ng/mLvs. 564.7(478.9-630.9) ng/mL,P<0.001],on D5 [646.3(605.7-705.2) ng/mLvs. 530.4(451.5-610.3)ng/mL,P<0.001],on D7 [652.7(618.0-712.3)ng/mLvs.464.8(417.2-522.2)ng/mL,P<0.001] and on D10 [642.3(602.9-708.8) ng/mLvs. 374.2(341.2-454.7) ng/mL,P<0.001].

The AUC,which was used to assess the performance of sCD163 predicting 28-day outcome of ARDS,was 0.780±0.057 (95% CI:0.668-0.893,P<0.001).The optimal cut-off value predicting mortality was >519.9 ng/mL with sensitivity of 73.9% and specificity of 75.0% (Fig 1B).The cumulative survival curve with the cut-off value 519.9 ng/mL described the death over 28 days of follow-up (Fig 4).There was statistically significant difference in the occurrence of death (P<0.001).

Dynamics of soluble CD163 levels in patients with ARDS from Day1 to Day10 classified into survivors and nonsurvivors.

Fig3DynamicsofsolubleCD163levelsinpatientswithARDS

Kaplan-Meier survival probability by the threshold of soluble CD163 value was 519.9 ng/mL.

Fig4PrognosisvalueofsCD163basedon28-daymortality

The univariate logistic analysis revealed that higher SOFA score,higher sCD163 concentration,and severity of ARDS were correlated with higher odds of hospital mortality from ARDS.Multivariate logistic regression indicated that SOFA score (OR=1.63,P=0.007),severity of ARDS (OR=2.78,P=0.022) and sCD163 level (OR=1.02,P=0.001) value were independently factors associated with prognosis of patients with ARDS (Tab 3).

Tab 3 Logistic regression analysis of fatal outcome for patients with ARDS

ARDS:Acute respiratory distress syndrome;OR:Odds ratio;APACHE Ⅱ:Acute physiology and chronic health evaluation Ⅱ;SOFA:Sequential organ failure assessment.a:log-transformed to achieve a normal distribution.

Liner regression analysis showed D1 plasma sCD163 levels were associated with VFD (β=-0.348,P=0.017) controlling for APACHE II score,SOFA score and severity of ARDS.Moreover,soluble CD163 value was associated with nonpulmonary organ failure-free days (β=-0.301,P=0.021) in patients (56/83) who had at least one nonpulmonary organ failure in ARDS patients (Tab 4).

Tab 4 Liner regression analysis of the outcomes ofVFD and OFD in patients with ALI/ARDS

VFD:Ventilator-free days;OFD:Non-pulmonary organ failure-free days;ARDS:Acute respiratory distress syndrome;APACHE Ⅱ:Acute physiology and chronic health evaluation Ⅱ;SOFA:Sequential organ failure assessment,a:log-transformed to achieve a normal distribution.

Discussion

In the course of ARDS,mediators released from resident cells,alveolar macrophages or alveolar epithelial type 2 (AT2) cells,may act as chemoattractants and stimulate local cells to build up a proinflammatory micromilieu[22].CD163 is restricted to the monocytic-macrophage linage with exclusively expression in,red pulp macrophages,bone marrow macrophages,liver macrophages,lung macrophages,and in macrophages of several other tissues.It has anti-inflammatory properties and an immunoregulatory role.It has been revealed that CD163 is a mediator against systemic inflammation and is taking part in the resolution of inflammation in the late down-regulatory phase of both acute and chronic inflammation[23].At present,few studies have specifically analyzed the expressing level of CD163 and sCD163 in ARDS.If any,they mainly focus on alveolar macrophage CD163.

Substantial evidence shows that the multifunctional protein CD163 has diverse and important activities including immunoregulatory function,wound repair,and hemoglobin clearance.First,CD163,expressed on cells or as an immobilized protein,supported the binding of both Gram-negative and Gram-positive species,and a previously identified cell-binding motif in the second scavenger domain of CD163 was sufficient to mediate this binding.Binding of bacteria to CD163 contributes to macrophage cytokine production,which indicated CD163,functions as a macrophage surface receptor for recognition of bacteria,may also be involved in host defenseinvitrostudy[24].Furthermore,the membrane bound antigen RM3/1,now known as CD163,expressed by alternatively activated macrophages stimulation with glucocorticoids displayed actively inhibition proliferation of CD4 positive T-cellsinvitrostudy[25-26].Second,the expression of CD163 is significantly upregulated by anti-inflammatory compounds or mediators such as natural and synthetic glucocorticoids or interleukin 10 (IL-10),in contrast,markedly downregulation of CD163 was observed after exposure to proinflammatory mediators,tumor necrosis factor-alpha or interferon-gamma,resulting in a distinct population of cells called the “alternatively activated macrophages” .Third,extracellular space hemoglobin (Hb) can be toxic to the environment during the process of hemolysis or tissue injury,and its cytotoxicity has been attributed to oxidative processes driven by the heme group[27].Hemoglobin/heme can only be cleared by phagocytes when combined with haptoglobin and through the medium of CD163.The haptoglobin dependent CD163 scavenging system for hemoglobin clearance prevents toxic effects of hemoglobin to kidney and other organs[28].The plasma level of soluble CD163 reflects the total pool of membrane-bound CD163,which may be increased in case of proliferation of cells of myelomonocytic origin or upregulation of CD163 expression by acute phase mediators[29].

The plasma level of sCD163,more significantly increased in patients with ARDS than in patients with CPE,associated with its role in innate host defense and wound repair.This observational study has shown that patients with ARDS had markedly increased median levels of plasma sCD163 compared with patients with CPE.This is supported by the following case report and rat models.A case report showed that the lung samples of a 20-year-old man who suffered from ARDS were obtained for histological examination.The results implied that much stronger CD163-immunopositivity was observed in small-sized cells morphologically similar to the monocytes or small macrophages,which were located especially inside interalveolar septa.Much higher CD163-positive cell concentration was found in alveolar space[14].In nitrogen mustard (NM)-induced rat models of ALI and fibrosis,they found that,following NM exposure,numbers of proinflammatory CD11b+CD43+and iNOS+M1 macrophages increased transiently,beginning within 1 day;However,persistent time-related increase in anti-inflammatory/profibrotic CD68+,CD163+,CD206+M2 macrophages was also observed in the lung after NM (middle panel),a response correlated with fibrosis[30].

To date,the prognostic performance of sCD163 continues to be a highly charged issue.Møller HJetal[31]has shown that high sCD163 levels were strongly associated with a lethal outcome and baseline sCD163 were higher innon-survivors than in survivors.Whereas another study showed that sCD163 level did not correlate with patient mortality[13]In our study,there was significant difference of soluble CD163 value between mild,moderate and severe group of ARDS.Meanwhile,higher baseline plasma sCD163 levels were strongly associated with fewer VFD and OFD.Moreover,sCD163 levels of non-survivors were significantly higher than that of survivors.Logistic regression analysis indicated that plasma sCD163 value upon admission was an independently predictor for 28-day mortality in ARDS patients.

This may support that the role of sCD163 could possibly be a marker reflecting the severity of ARDS,and CD163 may act as a potential therapeutic target.The therapeutic anti-inflammatory effects of glucocorticoids relied largely on the suppressed release of tumor-necrosis factor-α,and other cytokines by macrophages and a modulation of phenotype in the direction of the alternatively activated macrophages[32-33].Steroid treatment was suggested to facilitate CD163-mediated endocytosis of hemoglobin to monocytes/macrophages[34].CD163 targeted therapy specifically binding the antibody drug conjugate to the hemoglobin scavenger receptor CD163 in macrophages,which showed a 50-fold anti-inflammatory effect compared with non-conjugated dexamethasone and no major side effects[35].This data demonstrated that CD163 was an ideal macrophage target for anti-inflammatory drug delivery and clearance of hemoglobin.This may raise the question whether CD163 targeted therapy could improve the survival of ARDS patients with the strongly anti-inflammatory effect and enhanced clearance of hemoglobin.

It has yet to be found a special diagnostic parameter for ARDS.Considering the relatively low value of AUC,it may be helpful for ealy prediction of ARDS combing with the other clinical parameters,such as SP-A,anti-IL-8/IL-8.A large number of studies have shown that SP-A levels in bronchoalveolar lavage fluid (BALF) are significantly lower in patients with Bleomycin-induced ARDS compared with healthy volunteers.In contrast,the serum levels of SP-A were raised in patients with Bleomycin-induced ARDS.Thus,the serum levels of SP-A may be suggested as a sensitive and specific serum marker on the diagnosis of ARDS[36].Previous observations have found that the amount of complexed IL-8 was significantly decreased in survivors of ARDS over time.In contrast,the concentration of complexed IL-8 did not decline with time in those individuals who died.Several observations support the likelihood that anti-IL-8∶IL-8 complexes may contribute to the initiation,potentiation and ultimate severity of ARDS.The presence of increased concentrations of anti-IL-8∶IL-8 complexes in lung fluids is associated with progression to ARDS.Moreover,the absolute level of these complexes correlates with mortality[37].

The present study,however,has its own limitations.First,it was a single-center,small sample size trail,our findings need to be confirmed in larger studies.Second,we did not measure the levels of sCD163 in alveolar fluid.Finally,there was no “golden standard”,for diagnosis of ARDS remained a challenge inherent to all studies assessing the diagnostic value of this syndrome.

In summary,our findings suggested that plasma sCD163 has potential value on discriminating ARDS from CPE.Moreover,it was an independently predictor for 28-day mortality in patients with ARDS.However,further investigations are needed to confirm whether CD163 could act as a potential therapeutic target of patients with ARDS.

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