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Department of Anaesthesia, Helsinki University Central Hospital, Anestesiaosasto, PO Box 260, FIN-00029 HYKS, ... 1999 The Biochemical Society and the Medical Research Society ..... arium Research Foundation, Helsinki, the Paulo Foun-.
Clinical Science (1999) 96, 287–295 (Printed in Great Britain)

Systemic inflammatory response syndrome without systemic inflammation in acutely ill patients admitted to hospital in a medical emergency Annika TAKALA, Irma JOUSELA, Klaus T. OLKKOLA, Sten-Erik JANSSON*, Marjatta LEIRISALO-REPO†‡, Olli TAKKUNEN and Heikki REPO†‡ Department of Anaesthesia, Helsinki University Central Hospital, Anestesiaosasto, PO Box 260, FIN-00029 HYKS, Finland, *Department of Clinical Chemistry, PO Box 360, Helsinki University Central Hospital, Finland, †Department of Medicine, PO Box 340, Helsinki University Central Hospital, Finland, and ‡The Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland

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Criteria of the systemic inflammatory response syndrome (SIRS) are known to include patients without systemic inflammation. Our aim was to explore additional markers of inflammation that would distinguish SIRS patients with systemic inflammation from patients without inflammation. The study included 100 acutely ill patients with SIRS. Peripheral blood neutrophil and monocyte CD11b expression, serum interleukin-6, interleukin-1β, tumour necrosis factor-α and C-reactive protein were determined, and severity of inflammation was evaluated by systemic inflammation composite score based on CD11b expression, C-reactive protein and cytokine levels. Levels of CD11b expression, C-reactive protein and interleukin-6 were higher in sepsis patients than in SIRS patients who met two criteria (SIRS2 group) or three criteria of SIRS (SIRS3 group). The systemic inflammation composite score of SIRS2 patients (median 1.5 ; range 0–8, n l 56) was lower than that of SIRS3 patients (3.5 ; range 0–9, n l 14, P l 0.013) and that of sepsis patients (5.0 ; range 3–10, n l 19, P 0.001). The systemic inflammation composite score was 0 in 13/94 patients. In 81 patients in whom systemic inflammation composite scores exceeded 1, interleukin6 was increased in 64 (79.0 %), C-reactive protein in 59 (72.8 %) and CD11b in 50 (61.7 %). None of these markers, when used alone, identified all patients but at least one marker was positive in each patient. Quantifying phagocyte CD11b expression and serum interleukin-6 and C-reactive protein concurrently provides a means to discriminate SIRS patients with systemic inflammation from patients without systemic inflammation.

INTRODUCTION The systemic inflammatory response syndrome (SIRS) denotes the host’s reaction to inflammatory stimuli of a diverse nature such as infection, trauma, burns, haem-

orrhagic pancreatitis and immune-mediated tissue injury [1]. According to the nomenclature, SIRS associated with a documented infection is sepsis. To date, most studies of the aetiology and outcome of SIRS have focused on severely ill patients treated at intensive care units [2–8].

Key words : acute illness, CD11b, C-reactive protein, cytokine, interleukin, monocyte, neutrophil, systemic inflammatory response syndrome, tumour necrosis factor. Abbreviations : CRP, C-reactive protein ; IL, interleukin ; RFU, relative fluorescence units ; SICS, systemic inflammation composite score ; SIRS, systemic inflammatory response syndrome ; TNF-α, tumour necrosis factor. Correspondence : Dr A. Takala.

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The SIRS criteria were developed, among other reasons, to improve the detection of sepsis in individual patients in general [1]. However, as initially pointed out [1] and later on repeatedly emphasized [9–11], the criteria are so sensitive that when used alone they will include patients who virtually lack systemic inflammation. This poor specificity hampers the use of the SIRS criteria in the evaluation of an acutely ill patient. The purpose of the present study was to explore additional markers of inflammation that would distinguish SIRS patients with systemic inflammation from SIRS patients with little or no systemic inflammation. As markers of systemic inflammation, we measured serum levels of pro-inflammatory cytokines including tumour necrosis factor-α (TNF) [12], interleukin (IL)-1β [13] and IL-6 [14], C-reactive protein (CRP), an acute phase reactant [15], and cell surface expression of an adhesion molecule, CD11b, on peripheral blood neutrophils and monocytes, which increases upon phagocyte activation [16–21]. On the basis of these markers, we calculated the systemic inflammation composite score (SICS) to evaluate the severity of inflammation in individual patients with SIRS.

observation of the patients who will be either discharged from the hospital or transferred to other wards or units within 48 h. Surgical and unconscious patients were excluded. Parallel blood samples were collected from the SIRS patients and from a healthy adult volunteer (control) representing 36 different volunteers from the hospital staff without medication and with no signs of infection. A total of 50 of such experiments was carried out. The main reason for hospitalization, medication and survival was assessed from the medical records. Pneumonia was verified by radiological examination of the chest, urinary tract infection by clinical symptoms with compatible findings in urinalysis, and erysipelas by clinical picture. In one patient, blood culture was positive for Enterobacter cloacae. Without regard to the reason for hospitalization, the patient with proven infectious focus was allocated to the sepsis group. Finally, the patients who met 2, 3 or 4 criteria of SIRS, but did not meet the criteria of sepsis, severe sepsis or septic shock, were allocated into groups named SIRS2, SIRS3 and SIRS4 respectively.

Blood samples

PATIENTS AND METHODS Patient selection and classification The protocol was approved by the institutional review board. All subjects gave their informed consent to participation. The criteria of SIRS, sepsis, severe sepsis and septic shock were according to the recommendations of the ACCP\SCCM Consensus Conference Committee [1]. The clinical manifestation of SIRS included two or more of the following criteria : a body temperature  38 mC or 36 mC ; a heart rate  90 beats\min ; tachypnoea with a respiratory rate  20 breaths\min, or hyperventilation, as indicated by a PaCO 32 mmHg ; # and an alteration in the leucocyte count, such as  12i10*\l or 4i10*\l, or the presence of more than 10 % immature band forms. Sepsis is SIRS associated with a documented infection. Severe sepsis is sepsis associated with hypotension (a systolic blood pressure 90 mmHg or a reduction of  40 mmHg from baseline in the absence of other causes of hypotension), hypoperfusion or organ dysfunction. Septic shock is hypotension despite adequate fluid resuscitation with the presence of organ perfusion abnormalities. One hundred patients who met two or more criteria of SIRS were enrolled in the study within 24 h of admission to Helsinki University Central Hospital during a 6month period. The patients were recruited by one of the investigators from among all those admitted to the medical emergency unit and subsequently hospitalized in an adjoining observation ward. The ward is for temporary # 1999 The Biochemical Society and the Medical Research Society

Two blood samples were collected from each subject by venepuncture. One sample was taken into a pre-chilled polystyrene tube (Falcon No. 2058, Becton Dickinson Labware, Lincoln Park, N.J., U.S.A.) supplemented with 500 µlofpyrogen-freecitrate(113 mmol\l ;BaxterHealthcare Ltd, Norfolk, U.K.) and 300 µl of dextran (70 kDa, 60 g in 1 litre of physiological saline ; Kabi Pharmacia, Sweden), and the other into a glass tube (Venoject VT100PZX, Terumo Europe N.V., Leuven, Belgium). Immediately after sampling, the tubes were pressed into thawing ice (0 mC) to minimize leucocyte activation ex vivo [18]. Serum was separated by centrifugation at 4 mC, and stored in aliquots at k20 mC until use. The polystyrene tube was incubated for 60 min at 0 mC, the leucocyte-rich plasma layer was collected into a prechilled polystyrene tube and again kept at 0 mC until labelling of the cells with monoclonal antibodies (see below).

Flow cytometry The method of cell labelling for flow cytometry was as described earlier [20,22]. Briefly, aliquots of leucocyterich plasma were double-labelled by the addition of saturating amounts of CD14-FITC (mouse anti-CD14 IgG2b) and CD11b-PE (mouse anti-CD11b IgG2a) or a corresponding control (mouse anti-keyhole limpet haemocyanin IgG2a-PE) antibody (Becton Dickinson, San Jose, CA, U.S.A.). Contaminating erythrocytes were lysed by the addition of 1 : 10 diluted ice-cold FACS lysing solution (Becton Dickinson). The leucocytes were collected by centrifugation at 4 mC, washed once in ice-

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cold PBS and resuspended in 300 µl of saline supplemented with formaldehyde (final concentration 0.5 %). Finally, the cells were stained with LDS-751 (Exciton, Dayton, OH, U.S.A.), a nucleic acid dye [18]. The FACScan flow cytometer (Becton Dickinson) and LYSYS II software were used for the acquisition and analysis of the data. Two separate data sets, one for neutrophils (5i10$ LDS-751-positive events) and the other for monocytes (1i10$ CD14-positive events), were acquired for each specimen, as described previously [20,22]. During the analysis, multiple electronic gates were used to identify intact neutrophil and monocyte populations. In a forward\side light-scatter dot plot, LDS-751-positive neutrophils were first separated from contaminating mononuclear cells by creating a region, R1. Next, in an LDS-751 fluorescence\side scatter dot plot, a second region, R2, was created to separate neutrophils from cell aggregates and from damaged cells with markedly increased LDS-751 permeability and fluorescence intensity. Finally, the CD11b expression on intact neutrophils (i.e. on cells co-located in the regions R1 and R2) was evaluated by creating a CD11b histogram. CD14-positive monocytes collected in live mode were similarly analysed. CD11b expression is reported in relative fluorescence units (RFU), i.e. as the median channel of the positively fluorescent cell population. In all experiments,  95 % of neutrophils and monocytes were CD11b positive.

Cytokine and CRP determinations The ELISA kit for human IL-6 (lowest standard 10 pg\ml, sensitivity 10–15 pg\ml) was purchased from the Central Laboratory of the Netherlands Red Cross, Amsterdam, The Netherlands, and the Predicta2 ELISA kits for human IL-1β (lowest standard 4 pg\ml, sensitivity 3 pg\ml) and TNF (lowest standard 15 pg\ml, sensitivity 10 pg\ml) were from Genzyme Diagnostics, Cambridge, MA, U.S.A. The serum concentration of CRP was measured immunoturbidimetrically (detection limit 2 µg\ml). The reagents were from Orion Diagnostica, Espoo, Finland.

Evaluation of systemic inflammation To evaluate the severity of systemic inflammation, we used the SICS. To obtain the SICS value for each patient, a subscore between 0 and 4 points was assigned to each marker of systemic inflammation as follows. The subscores for IL-1β, IL-6 and TNF concentrations were as used by Rixen et al. [6], with some modifications based on the cytokine levels detected in previous studies of patients with sepsis [23–25] : 0 point if non-detectable, 1 point if detectable but 250 pg\ml (IL-6) and 100 pg\ml (IL-1β and TNF), 2 points if between 250 and 500 pg\ml (IL-6) and between 100 and 200 pg\ml (IL-1β and TNF), 3 points if between 500 and 1000 pg\ml

(IL-6) and between 200 and 300 pg\ml (IL-1β and TNF), and 4 points if  1000 pg\ml (IL-6) and  300 pg\ml (IL-1β and TNF). The respective subscore limits for CRP were  10 µg\ml, 11 to 50 µg\ml, 51 to 100 µg\ml, 101 to 200 µg\ml, and  200 µg\ml [26–28]. The limits for phagocyte CD11b expression were set as follows : 0 point if fluorescence intensity  77 RFU (the mean value j2 S.D. of neutrophil CD11b expression in samples from healthy subjects) or  66 RFU (the mean value j2 S.D. of monocyte CD11b expression in control samples), 1 point if  77 RFU but  100 RFU (neutrophils) or  66 RFU but  100 RFU (monocytes), 2 points if between 101 RFU and 150 RFU, 3 points if between 151 RFU and 200 RFU, and 4 points if  200 RFU [26]. In the calculation of the SICS for a given patient, only the higher phagocyte CD11b subscore (that of the neutrophils or that of the monocytes) was used. The maximum SICS was 20 (IL-6 level  1000 pg\ml, IL-1β and TNF levels both  300 pg\ml, CRP level  200 µg\ml, and CD11b fluorescence intensity value  200 RFU in either neutrophils or monocytes).

Data analysis Statistical comparisons between SIRS2 patients, SIRS3 patients, patients with sepsis and healthy subjects were performed using the Kruskal–Wallis analysis of variance and the Mann–Whitney U-test. The significance of the difference in mortality between the groups was evaluated by Fisher’s exact test. Probabilities were regarded as statistically significant at the 0.05 level. Results are reported as median values (range).

RESULTS Patients The characteristics of the patients are shown in Table 1. The spectrum of the diagnoses was markedly broad (Table 2). Out of a total of 100 patients, 61 met two criteria of SIRS (the SIRS2 group), 14 met three criteria (the SIRS3 group) and two met four criteria (the SIRS4 group). There were 17 patients with drug intoxication, Table 1

Characteristics of patients

Age is given as the mean and range. Sex (M/F) Age (years) Underlying diseases Malignancy Diabetes Chronic medication Acetylsalicylic acid Corticosteroid

51/49 60 (16–89) n 8 9 19 12

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Table 2

Diagnoses

*SIRS2, SIRS3 and SIRS4 denote patients who met 2, 3 and 4 SIRS criteria respectively. †No infectious focus present on admission. SIRS2 group (n l 61)

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SIRS3 group (n l 14)

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SIRS4 group (n l 2)

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Acute myocardial infarction Drug intoxication Congestive heart failure Atrial fibrillation or flutter Chronic obstructive pulmonary disease or emphysema Dilating cardiomyopathy Convulsions Confusion Musculoskeletal pain Exacerbation of asthma or obliterating bronchiolitis Breast cancer with deep vein thrombosis or malignant pleuritis Ventricular fibrillation Stable angina Postpericardiotomy syndrome Collapse Cerebral infarction Rupture of abdominal aortic aneurysm Exacerbation of Crohn’s disease Gastrointestinal bleeding Gastroenteritis Hyponatraemia Rhabdomyolysis Alcohol abuse Leucopenia Psychosis Electric shock Bladder cancer with malignant pericarditis

12 9 6 3 3

Drug intoxication Congestive heart failure Malignant pericarditis Acute myocardial infarction Atrioventricular dissociation Rectal cancer Breast cancer Acute bronchitis Epidemic nephropathy† Postoperative pelvic haematoma

3 2 2 1 1 1 1 1 1 1

Acute myocardial infarction Alcohol abuse

1 1

Sepsis group (n l 20)

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Severe sepsis (n l 2)

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Septic shock (n l 1)

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Suspected urinary tract infection, blood culture positive for E. cloacae Burn injury of lower limbs

1

Agranulocytosis after exposure to β-lactams

1

Pneumonia Urinary tract infection Drug intoxication and pneumonia Erysipelas Acute myocardial infarction and pneumonia

2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

6 6 5 2 1

five of whom had concurrent pneumonia and were allocated into the sepsis group. There were 15 patients with acute myocardial infarction (12 in the SIRS2 group and one each in the SIRS3, SIRS4 and sepsis groups). A total of 23 patients met the criteria of sepsis ; two met the criteria of severe sepsis and one of septic shock. A total of 9 patients died ; five in the SIRS2 group (two with cardiogenic shock due to acute myocardial infarction, one with dilating cardiomyopathy, one with abdominal aortic aneurysm and one with breast cancer), two in the SIRS3 group (one with lung cancer and the other with rectal cancer), one in the sepsis group (pneumonia) and # 1999 The Biochemical Society and the Medical Research Society

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one in the septic shock group (adult respiratory distress syndrome and acute renal failure). Twenty-six patients were discharged from the hospital after a surveillance period of less than 48 h. Sixty-nine patients were transferred to medical wards, four patients to an intensive care unit, and one patient died in the observation ward.

CD11b expression on neutrophils and monocytes The median levels of phagocyte CD11b expression increased with the severity of SIRS and sepsis (Figure 1).

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Figure 1

CD11b expression on neutrophils and monocytes

Horizontal bars indicate median relative fluorescence units (RFU). Comparison between SIRS2, SIRS3, sepsis and healthy subjects was made by the Kruskal–Wallis ANOVA, and P values indicate significance of difference in post-hoc analysis (Mann–Whitney U-test). Figure 2

The fluorescence intensity value of control neutrophils [51 (31–76) RFU] was significantly lower than those of neutrophils from the SIRS2 [57 (32–112) RFU], SIRS3 [58 (40–167) RFU] and sepsis groups [85 (43–235) RFU]. The fluorescence intensity value of control monocytes [45 (23–74) RFU] was significantly lower than the corresponding values of the SIRS2 [50 (26–163) RFU], SIRS3 [64 (35–311) RFU] and sepsis groups [74 (45–199) RFU].

Serum concentrations of IL-6, CRP, IL-1β and TNF The median serum levels of IL-6 increased in the order of SIRS2 l SIRS3 sepsis (Figure 2). The concentrations in the sepsis patients [65 (0–775) pg\ml] were significantly higher than those in the SIRS2 [10 (0–280) pg\ml] and SIRS3 patients [26 (0–210) pg\ml]. The CRP levels increased in the order of SIRS2 SIRS3 sepsis (Figure 2). The levels in the SIRS2 patients

Serum concentrations of IL-6, CRP and IL-1β

Horizontal bar indicates median, and dotted line the assay detection limit. See legend to Figure 1 for comparison of groups. [8 (0–216) µg\ml] were significantly lower than those in the SIRS3 [85 (0–160) µg\ml] and sepsis patients [151 (6–238) µg\ml]. In the sepsis group, one patient had pneumonia and a history of aspiration 12 h before hospitalization, and another patient had urinary tract infection and onset of fever 6 h before hospitalization. The CRP levels were 6 µg\ml and 22 µg\ml respectively, suggesting an absence of systemic inflammation. However, neutrophil CD11b expression levels were 235 RFU and 99 RFU respectively, and serum IL-6 levels 95 pg\ml and 270 pg\ml respectively, indicating an ongoing systemic reaction. By the next day, the CRP levels had increased to 133 µg\ml and 151 µg\ml respectively. The serum levels of IL-1β were detectable in 21 patients only, and increased in the order of SIRS2 l SIRS3 sepsis (Figure 2). TNF was found in the sera of two # 1999 The Biochemical Society and the Medical Research Society

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SICS 3. The median SICS of the patients who died was 5 (range 2–8, n l 8 ; in one case SICS could not be calculated due to missing data). In 13 patients (13.8 %, 11 patients in the SIRS2 group and two in the SIRS3 group) SICS was 0, indicating an absence of systemic inflammation. Out of 70 SIRS2 and SIRS3 patients, 24 (34.3 %) had a SICS between 3 and 9, suggesting that the degree of systemic inflammation was similar to that of the sepsis patients. Five of the 24 patients with a SICS  3 died, whereas only one of the 46 patients with SICS 3 died (P l 0.016, Fisher exact test). In the SIRS2 group, the highest SICS values, 7 and 8 respectively, were seen in two patients, one with large, acute myocardial infarction complicated by alveolar oedema, and the other with exacerbation of Crohn’s disease. In the SIRS3 group, two patients had a SICS of 7, one with drug intoxication and the other with malignant pericardial effusion. The patient with the SICS value of 9 in the SIRS3 group later on proved to be suffering from nephropathia epidemica, a European form of haemorrhagic fever with renal syndrome caused by Puumala hantavirus [29]. Of the two patients in the SIRS4 group, one (SICS l 5) had acute myocardial infarction and the other suffered from alcohol intoxication.

Markers that identify patients with systemic inflammation

Figure 3 Systemic inflammation composite score (SICS) values of 94/100 patients

Six patients were excluded due to incomplete data. SICS was calculated as described in the Methods section. SIRS2 (median SICS 1.5, range 0–8) versus SIRS3 [3.5 (0–9)], P l 0.013 ; SIRS3 versus sepsis [5.0 (3–10)], P l 0.018 ; SIRS2 versus sepsis, P 0.001 (Mann–Whitney U-test).

patients, one with postoperative haematoma (15 pg\ml) and the other with malignant pericarditis (25 pg\ml).

Severity of systemic inflammation Complete data for calculating SICS were available from 94 patients. SICS increased in the order of SIRS2 SIRS3 sepsis, and the differences between the groups were statistically significant (Figure 3). SICS was 3 in 36 patients (38.3 %). Out of these, 34 patients (94.4 %) belonged to the SIRS2 group and the remaining patients to the SIRS3 group. Thus, none of the sepsis patients had # 1999 The Biochemical Society and the Medical Research Society

A total of 81 patients had a SICS  1. IL-6 was increased in 64 (79.0 %), CRP in 59 (72.8 %), CD11b expression in 50 (61.7 %), IL-1β in 21 (25.9 %) and TNF in 2 (2.5 %). Thus, none of the markers, if used alone, identified all patients. Of the 81 patients, 92.6 % had increased levels of either CRP or IL-6, or both, 86.4 % had increased levels of either CRP or CD11b expression, or both, and 92.6 % had increased levels of either IL-6 or CD11b expression, or both. At least one marker (IL-6, CRP or CD11b expression) was increased in each of the 81 patients.

DISCUSSION The clinical criteria of SIRS are commonly considered to be so sensitive that they are probably able to include all patients with ongoing systemic inflammation. However, the criteria are not very specific [1,9–11], and therefore, when used alone, may not facilitate recognition of an acutely ill individual patient with systemic inflammation. The results in the present study show that 13.8 % of acutely ill patients had a SICS of 0. They belonged to the SIRS2 or SIRS3 group. In other words, despite the fact that these patients met two or three SIRS criteria, there was no evidence of ongoing systemic inflammation, as determined by the levels of circulating IL-6, CRP, IL-1β and TNF, and by the CD11b expression on peripheral blood neutrophils and\or monocytes. On the other hand,

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34.3 % of the patients in the same SIRS groups had a SICS as high as that of the patients with sepsis. The present results agree with recent findings demonstrating a lack of correlation between the severity of SIRS and plasma proinflammatory cytokine levels in patients with acute respiratory distress syndrome [7], and confirm that the clinical criteria of SIRS do not reliably discriminate between patients with and without systemic inflammation. However, because inflammation is a dynamic process involving sequential activation of humoral and cellular host-defence mechanisms, a crucial question is whether the markers of inflammation used in the present study are sensitive enough to detect systemic inflammation at its different stages. Several lines of evidence suggest that this is the case. First, the increase in CD11b\CD18 expression may serve as an extremely early and sensitive cell-associated marker of phagocyte activation because it does not require time-consuming de novo protein synthesis [30], can be verified in a small subpopulation of cells [31] and occurs in vivo within minutes in response to the stimulus [32]. It also occurs in several SIRS-triggering disorders like sepsis [18,19,33], haemodialysis [21], whole-body trauma [34], burn injury [35] and cardiac surgery [20,32,36]. Secondly, the induction of TNF, IL-1β, and IL-6 production occurs sequentially within hours in response to the insult [37]. Together, these pro-inflammatory cytokines and phagocyte CD11b expression should provide early humoral and cell-associated markers of systemic inflammation. However, the present study design should also cover later stages of systemic inflammation. The CRP concentration peaks 24 to 48 h after the onset of the fever [38]. This, and the finding that an increase in the IL-6 level precedes increases in the CRP level in patients with infection [39], indicates that circulating CRP serves as a delayed marker of systemic inflammation. In keeping with this assumption, we recorded in two patients an increase in IL-6 and CD11b expression levels before a CRP elevation. In concert, the present findings strongly suggest that circulating IL-6 and CRP levels and surface expression of CD11b, quantified concurrently, provide reasonably reliable means to identify acutely ill patients who present with systemic inflammation at its different stages. TNF was found in only two patients in the present study. TNF has a median elimination half-life as short as 17 min [40] and its concentrations can change substantially within hours [41]. Therefore, in clinical studies transient elevations of circulating TNF are easily missed. This can explain at least partially the wide variation in results of 15 studies indicating that immunoreactive TNF occurs in 16–100 % of patients (for references, see [42]). The detectable levels of IL-1β in patients with severe infections are also variable [42]. Casey et al. [24] found IL-1β in 37 % of patients (n l 97) with sepsis syndrome. In the present study, IL-1β was found in 21 % of the

patients. Together, these findings suggest that TNF and IL-1β are not particularly sensitive markers of systemic inflammation in the patients with SIRS. To characterize the systemic inflammation status of an individual patient, we calculated for each patient a SICS, i.e. the sum of the subscore values determined by the levels of cytokines, CRP and CD11b expression. The limits for maximum subscore value (equal to 4) and minimum subscore value (equal to 0) for cytokines and CRP were set according to the results of previous studies carried out by us [26] and others [23–25,27,28]. Respective limits for CD11b expression were set with regard to our previous studies of patients with sepsis\ septic shock [26] and to the current study of healthy subjects (Figure 1). Next, the limits for the subscores 1–3 were set arbitrarily. Because the cut-off points were selected by exploiting the results of sepsis studies, but in the present study only a minority of the patients had sepsis, we also tested other cut-off points, especially for IL-6 and CRP, but did not achieve any better separation between SIRS groups and the sepsis group. Our results show that each patient in the sepsis group had a SICS  3. However, the high SICS values were not exclusively associated with sepsis. Furthermore, it was difficult to exclude with certainty the presence of an infectious focus in some patients with a high SICS. This is exemplified in our patient with myocardial infarction complicated by alveolar oedema in whom the signs of systemic inflammatory response may have derived from either heart tissue injury [43] or concurrent pneumonia, or from both. Taken together, the results suggest that if the SICS is low, an acutely ill patient who meets the SIRS criteria most probably does not have sepsis whereas if the SICS is high, the patient should be carefully examined for the presence of infection, among other disorders able to elicit the systemic inflammatory reaction. In conclusion, the results show that it is possible to distinguish SIRS patients with and without systemic inflammation by quantifying concurrently phagocyte CD11b expression and circulating IL-6 and CRP levels. These additional markers make it possible to take advantage of the great sensitivity of the SIRS criteria when evaluating acutely ill individual patients in general.

ACKNOWLEDGMENTS This study was supported by grants from the Instrumentarium Research Foundation, Helsinki, the Paulo Foundation, Helsinki, the Clinical Research Institute of the Helsinki University Central Hospital, Helsinki, and the Research Foundation of Orion Corp., Espoo, Finland. We are grateful to Eine Virolainen for her skilful assistance. # 1999 The Biochemical Society and the Medical Research Society

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Received 14 August 1998/8 October 1998; accepted 23 October 1998

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