Usefulness of Presepsin (Soluble CD14 Subtype) as a Diagnostic Marker for Sepsis

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1 Review Article Usefulness of Presepsin (Soluble CD14 Subtype) as a Diagnostic Marker for Sepsis Shigeatsu Endo, Gaku Takahashi, Tatsuyori Shozushima, Naoya Matsumoto Masahiro Kojika, Yasushi Suzuki, Yoshihiro Inoue ABSTRACT The treatment of sepsis continues to be a major problem in emergency and intensive care, and that is another reason why there has been a desire for the development of a simple diagnostic method that would yield results in the early stage. CD14 is present intracellularly and in the cell membrane of macrophages, monocytes, and granulocytes, and is recognized to be responsible for endotoxin-induced intracellular signaling. CD14 is also known to be present in the blood in the form of a soluble protein. We discovered a soluble CD14 molecule that differs from conventional CD14, i.e., a soluble CD14 subtype (scd14- ST, 13 kd), and named it Presepsin. We also developed a quantitative method of determining Presepsin by an enzyme-linked immunosorbent assay, and we concluded that measuring Presepsin values of sepsis patients by this method is currently the best way to diagnose sepsis from the standpoint of diagnostic power. We have also developed a rapid semiquantitative method of measurement by a simple point of care test. In addition, at present, results can be obtained in approximately 15 min by performing a chemiluminescence enzyme immunoassay on whole blood. In the future it is expected to be widely used as a rapid diagnostic method for sepsis in clinical settings. (JJAAM. 212; 23: 27-38) Keywords: endotoxin, infection, severity, ELISA, POC test I. Introduction The mortality rates of sepsis patients in the previous reports have varied considerably, from 21.6% to 5.8% 1-9). The mortaility rates from sepsis increased markedly in the 196s and 197s 1,3), but the mortlity rates seem to have decreased during the past 2 years 1-12). Unfortunately, however, the figure in a recent report seems to be the highest 13). Because the subjects who were eligible for inclusion in the surveys differed from institution to institution, and there were differences in severity, etc., generally speaking it would be problematic to make evaluations based on such numerical value alone, however, in any event, the fact remains that the value are high. The degree of severity of sepsis varies widely, and early diagnosis is important from the standpoint of specific Department of Critical Care Medicine, School of Medicine, Iwate Medical University, Morioka, Japan Correspondence to: Shigeatsu Endo, MD, 19-1 Uchimaru, Morioka, Iwate 2-855, Japan treatment in the early stage. Clinical and diagnostic test, signs of systemic inflammation occur in association with sepsis and severe sepsis, but sometimes similar signs and symptoms are manifested in cases of non-infectious inflammation, and it is difficult to diagnose infection on the basis of the clinical findings alone. Even though there may be definite, specific bacteriological evidence of sepsis, it is not easy to obtain. Moreover, it takes time to obtain the results, and they are not always manifested at the same time as the clinical symptoms of sepsis. Thus, it is important to identify a marker that would make it possible to diagnose sepsis and organ dysfunction early and enable early specific therapeutic interventions. The ideal diagnostic method or diagnostic marker would be inexpensive, easy to measure, highly sensitive, rapid, capable of diagnosing sepsis early, correlated with the severity of infection, and useful from the standpoint of treatment. The diseases of patients who come to the hospital as emergencies are diverse, and many of them are grave. In quite a few cases a severe infection, such as sepsis or septic shock develops as a complication of a secondary infection due to increased susceptibility to infection associated with the patient s primary disease or poor gener- JJAAM. 212; 23:

2 Shigeatsu Endo, et al al condition, and the patient s disease then deteriorates to multiple organ failure. Since organ failure associated with infection is one of the factors that prolongs treatment in the emergency care field, and it has also become an enormous burden on healthcare, it is necessary to monitor biological and immunological markers and to provide appropriate treatment. CD14 is a glycosylphosphatidylinositol anchor-type bone marrow glycoprotein and has a molecular weight of 55 kda. In 199, CD14 was identified as an important cell surface receptor that binds lipopolysaccharide (LPS)- lipopolysaccharide binding protein (LBP) complexes14). CD14 has been demonstrated to play an important role in modulating the immune response to endotoxin (ET) in both in vitro and in vivo studies 15-18). CD14 was later shown to react with several other conserved surface bacterial ligands, including gram-positive peptidoglycans, lipoteichoic acid, lipoproteins, and mycobacterial lipoarabinomannan, and to mediate cell activities by forming bonds with them 19). CD14 has been described as representing a classical example of a pattern recognition receptor 19). Soluble CD14 (scd14) is found in micromolar concentrations in the serum of mammals, including humans. Its role is to bind to LPS and to other bacterial ligands, and activate cells without CD14 such as endothelial cells and epidermal cells 2). scd14 is LPS and LBP complex receptor on the cell membrane, and it is said to be responsible intracellular signal transmission of low concentration ET. Moreover, the soluble fraction of CD14 is present in blood plasma, and Basil et al. have reported that it exists in two forms, a 49kD form and a 55kD form 21). We previously reported that the plasma concentration of the 55kD form of scd14 increases in multiple organ failure 22). The origin of the 13kD form of scd14, on the other hand, is thought to be cleavage of the CD14 on the membrane surface as a result of some stimulus, such as infection. Based on enzyme inhibitor experiments it is suspected that cathepsin and other lysosomal enzymes are involved in the mechanism by which it is produced. We named this scd14-st Presepsin. We devised a novel enzyme-linked immunosorbent assay (ELISA) kit to measure it specifically, and have reported that it is useful as a diagnostic method for sepsis 23-25). II. Comparison between soluble CD14 and Presepsin in sepsis In previous studies we investigated scd14 and Presepsin in sepsis patients and in patients with systemic inflammatory response syndrome (SIRS) 26) that was not associated with infection 27). The scd14 values did not rise much even in sepsis patients (Fig. 1) 27). Presepsin, on the other hand, increased significantly in sepsis patients in comparison with patients with SIRS unassociated with infection, suggesting that it might be useful for diagnosing sepsis and and enabling evaluation of its severity as well (Fig. 2) 27). Moreover, as in a previous study 22), only a tendency for the scd14 values to rise was seen in the septic multiple organ dysfunction syndrome (MODS) cases in which Presepsin values rose significantly (Fig. 3) 27). Thus, scd14 does not seem to be useful as a diagnostic marker for sepsis. The physiological role and mechanism of production of scd14 in sepsis are unknown. Bufler et al. have reported that there are two mechanisms of production of scd14 by human monocytes 28). In one of the mechanisms it is released, and in the other it is secreted via a pathway. Bazil et al. have also reported that it is released 29). Because Presepsin increases within 2-3 h when sepsis develops as a complication, it would seem reasonable to conclude that Presepsin is more likely to be released than secreted. III. Significance of Presepsin as a diagnostic marker of sepsis When Presepsin was investigated in healthy subjects, sepsis patients, and SIRS patients who did not have sepsis, Presepsin values of the sepsis patients were found to be significantly higher than in the heatlhy subjects or in the SIRS patients who did not have an infection 23,24). Also, correlations were observed between Presepsin values and the procalcitonin (PCT) values, endotoxin values, etc., and Presepsin values were shown to be capable of serving as a useful diagnostic tool for sepsis 23,24). The diagnostic power of Presepsin for sepsis has been shown to be superior to that of any other humoral factors 11,12), and Presepsin values closely reflect changes in patients pathophysiology. C-reactive protein (CRP) and interleukin 6 (IL-6), on the other hand, flucutate at high levels even after recovery from sepsis, and they seem to be inadequate as diagnostic markers for sepsis. PCT has recently come to be used as a diagnostic marker for sepsis in Japan as well as abroad 3,31), but Presepsin is superior to PCT, CRP, and IL-6 as a diagnostic 28 JJAAM. 212; 23: 27-38

3 Presepsin as a Diagnostic Marker for Sepsis shock sepsis 6 3 scd scd14 ( g/ml) 2 1 Presepsin Hospital day Fig. 1. A male in the 5th decade of life. Emergency surgery was performed for panperitonitis secondary to perforation of the large intestine. scd14 values fluctuated within the normal range of 2-3 µg/ml, but Presepsin values exceeded 6 ng/ml during septic shock, and they rapidly decreased as the symptoms improved. p=.137 p<.1 1 1,5 8 scd14 ( g/ml) 6 4 1, 5 2 SIRS (n=15) sepsis (n=15) SIRS (n=15) sepsis (n=15) Fig. 2. Comparison between the scd14 values and Presepsin values of SIRS patients without an infection and of sepsis patients. JJAAM. 212; 23:

4 Shigeatsu Endo, et al MODS sepsis 1,5 15 Presepsin 1, 5 scd14 ( g/ml) 1 5 scd Hospital day Fig. 3. A woman in the 8th decade of life. She developed sepsis and multiple organ dysfunction syndrome (MODS) as complications of pneumonia. Her Presepsin values increased to over 1, ng/ml during the MODS, but her scd14 values increased to only about 6 µg/ml. Sensitivity (1- ) ROC area: ROC area: ROC area: ROC area: False positive rate ( ) Fig. 4. Presepsin had the best diagnostic power for sepsis (sepsis vs. SIRS + normal volunteers). marker for sepsis (Fig. 4) 23). Because PCT values also increase as a reflection of the severity of the body s response to traumatic stimuli even in the initial stage of trauma, when there are no signs of infection, they do not necessarily increase specifically in infection. Presepsin values are low in patients with SIRS that is unassociated with an infection, and even patients who have sustained highly invasive trauma do not have high Presepsin values unless there is an associated infection. This characteristic can be described as highly diseasespecific in comparison with PCT, tumor necrosis factor (TNF), IL-6, interleukin 8 (IL-8), other pro-inflammatory cytokines, etc. 3 JJAAM. 212; 23: 27-38

5 Presepsin as a Diagnostic Marker for Sepsis 5 2 APACHE II score SOFA score , 2, 3, 4, 1, 2, 3, 4, Fig. 5. Significant correlations were found between Presepsin values and both the APACHE II scores (r=.7536, p<.1) and the SOFA scores (r=.7964, p<.1). IV. Significance of Presepsin measurements as a means of evaluating severity and judging the efficacy of treatment Presepsin is superior to other humoral factors in terms of its diagnostic power for sepsis 23,24), and Presepsin values closely reflect shifts in patients' condition. Significant correlations have been found between Presepsin values and both acute physiology and chronic health evaluation II scores (APACHE II scores) and sequential organ failure assessment scores (SOFA scores) (Fig. 5) 32). The fact that Presepsin has been suggested to be capable of serving as a marker of the body s response to the insult of sepsis also seems capable of being inferred by making sequential observations (Fig. 6 and Fig. 7) 33,34). CRP and IL-6 increase 1-2 days later, and a slight time lapse develops between their rises and the changes in APACHE II scores. This seems to suggest that Presepsin might serve as a marker of the body s response to the insult of sepsis. Measuring Presepsin is also useful for evaluating the efficacy of treatment (Fig. 8) 35-37). This means that it might also be possible to decide when to start or conclude the treatment of sepsis by measuring Presepsin. V. Development of a simple kit We developed an ELISA kit that specifically measures Presepsin, and we have previously stated that it is useful as a diagnostic method for sepsis 23-25). However, there was a problem in terms of rapidity, because it takes sev- eral hours to obtain the results with this method. We therefore developed a point of care (POC) test in the form of a semiquantitative simple kit that applies the immunochromatography method 38). The method is designed for use with plasma or serum. The results are obtained in about 2 minutes with this method, and it is very useful in clinical settings. When 1+ was used as the cut-off value for the diagnosis of sepsis by the POC test (point of care test), sensitivity was 1%, specificity 56%, and effectiveness 73%, whereas when 2+ was used as the cut-off value, sensitivity was 73%, specificity 84%, and effectiveness 8%, and when 3+ was used as the cut-off value, sensitivity was 47%, specificity 96%, and effectiveness 78%. These findings showed that 2+ is the most effective cut-off value of the POC test to use for the diagnosis of sepsis 38). The patients courses are shown in Fig. 9. The APACHE II scores and Presepsin values decreased almost in parallel 26). POC test scores are a good reflection of disease severity and of the effectiveness of treatment (Fig. 1 and Fig. 11) 36,39-43). Plasma or serum is used to make the evaluations for the current POC test, however, since being able to use whole blood would make it an even more useful tool for the diagnosis of sepsis at the bedside, a whole blood Presepsin POC test is currently in the process of being developed. JJAAM. 212; 23:

6 Shigeatsu Endo, et al 2, APACHE II score 4, IL-6 (pg/ml) 1,5 1, 5 SOFA score CRP Presepsin IL CRP (mg/ml), APACHE II score, SOFA score Hospital day Fig. 6. A male in the 9th decade of life. The patient had panperitonitis secondary to perforation of the large intestine. His condition progressed from septic shock to multiple organ dysfunction syndrome (MODS). During the course of his illness his Presepsin values almost perfectly paralleled his APACHE II scores and SOFA scores. PMX-DHP 33 3, APACHE II score 3 15 SOFA score 2, 2 1, 1 APACHE II score 1 5 SOFA score Presepsin Blood culture ( - ) ( - ) ( - ) ( - ) (+) (+) (+) (+) ( - ) ( - ) Hospital day Skin culture ( - ) ( - ) (+) (+) (+) (+) (+) (+) (+) (+) Fig. 7. A male in the 9th decade of life. The patient developed septic shock as a complication of trauma. His APACHE II score was 33. His course was favorable, and the inflammatory response rapidly decreased. The changes in APACHE II scores and Presepsin values almost perfectly paralleled each other. (PMX-DHP: polymyxin-b-immobilized fiber-direct hemoperfusion) 32 JJAAM. 212; 23: 27-38

7 Presepsin as a Diagnostic Marker for Sepsis p<.5 p<.5 p<.5 p>.5 p>.5 p<.5 p<.5 p<.5 p>.5 p<.5 1, 5 APACHE II score days days Fig. 8. When intravenous immunoglobulin (IVIG) was administered, Presepsin values decreased, and the APACHE II scores declined at almost the same time. (From reference no.35) 3, APACHE II score IL-6 4 2, 3 1, CRP 2 Presepsin Hospital day POC test / - + / - APACHE II score, CRP (mg/dl) IL-6 (pg/ml) Fig. 9. A male in the 9th decade of life. His condition progressed from panperitonitis to a state of septic shock, and he was admitted to the hospital. On arrival at the hospital his APACHE II score was 33. Presepsin value was high (24 ng/ml), and the POC test was 3+. His condition rapidly improved postoperatively. The course of the changes in POC test values was: (3+) (2+) (2+) (1+) (1+) (1+) ( ±). The changes in APACHE II scores and Presepsin values almost perfectly paralleled each other. The IL-6 and CRP values increased almost a day later than Presepsin values, and they subsequently declined. VI. Development of a rapid diagnostic Presepsin test for use on whole blood A more rapid, simple diagnostic test for the diagnosis of sepsis and early start of treatment in clinical settings is desired. We used the PATHFAST immunoanalyzer to develop a method of measuring Presepsin by a chemiluminescent enzyme immunoassay (CLEIA) 44,45). The most distinguishing feature of this method is that it does not require any pretreatment and has been designed to make automated measurements in whole blood. Comparison between Presepsin values obtained in whole blood and in blood plasma showed that they almost perfectly coincided (Fig. 12) 46). Moreover, it was possible to obtain results similar to those obtained by the conventional ELISA, and it became possible to diagnose sepsis more rapidly and simply by using PATHFAST immunoanalyzer. JJAAM. 212; 23:

8 Shigeatsu Endo, et al 3 2 POC test 1 normal volunteer (n=1) SIRS (not infectious) (n=14) sepsis (n=1) severe sepsis (n=12) septic shock (n=1) Fig. 1. The POC test values closely reflected the severity of the sepsis. (From reference no.41) AT-III (1,5mg/day) -globulin (5g/day) Gabexate Mesilate (2,mg/day) Sivelestat sodium hydrate (3mg/day) PIPC / TAZ (13.5g/day) 3 APACHE II score 37 CRP 3 APACHE II score, SOFA score TNF- 2 IL-6 1 SOFA score POC test TNF- (pg/ml) 1, IL-6(pg/ml) 12, CRP(mg/dl) Hospital day Fig. 11. A male in the 9th decade of life. Panperitonitis became complicated by septic shock. The APACHE II score was 37 on arrival at the hospital. As a result of performing a variety of treatments the course of changes in POC test scores was as follows: (3+) (2+) (2+) (1+) ( ±) ( ±) (-) (-), and they closely reflected the efficacy of treatment. (From reference no.43) 34 JJAAM. 212; 23: 27-38

9 Presepsin as a Diagnostic Marker for Sepsis 2, y =.993x r=.996, p<.1 n=24 15, Whool blood (pg/ml) 1, 5, 2, 4, 6, 8, 1, 12, Serum (pg/ml) 14, 16, 18, Fig. 12. After correction for the hematocrit, the whole blood and plasma Presepsin values were correlated. Sepsis can be diagnosed simply and in a short time (approximately 15 minutes) by measuring Presepsin in whole blood, and it should be a very useful tool in clinical settings (Fig. 13 and Fig. 14) 46). VII. Conclusion The severity of sepsis varies considerably, and early diagnosis is important from the point of performing specific treatment early. Sepsis and severe sepsis occur in association with clinical signs and diagnostic test of systemic inflammation, but patients with non-infectious inflammation sometimes exhibit similar signs and symptoms, and it is difficult to diagnose infection on the basis of the clinical findings alone. It takes time to obtain the results of bacterial cultures, and sometimes they do not emerge at the same time as the clinical signs of sepsis. Thus, it is important to identify a marker that enables early diagnosis of sepsis and organ dysfunction and that makes early specific therapeutic intervention possible. In the past sepsis biochemical markers or immunological markers were not effective in diagnosing sepsis. An ideal marker must have high sensitivity and specificity, be easy to handle, and inexpensive enough to use routinely on a daily basis. Plasma concentrations must be correlated not only with patient outcome but with the stage of sepsis as well. From this perspective, measuring Presepsin seems to be the most beneficial method in terms of diagnosis and treatment of sepsis. It seems that Presepsin will be placed on the market soon, and it is expected to be widely used in clinical settings near future. Acknowledgement This paper received the grants from the Mutual Aid Corporation for Private School of Japan, the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, and Marumo Critical Care Foundation. The authors wish to express their gratitude to Mr. Kamon Shirakawa of Discovery Research III, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd. and to Mr. Yoshikazu Okamura of the Research Division, Mitsubishi Chemical Medience Co., Ltd. for their technical advice in this research. JJAAM. 212; 23:

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