Cope 194 by Wallioms & Witkin Circulating interleukin-8 concentrations in patients with multiple organ failure of septic and nonseptic origin Cuarre Marry, MS; Bexorr M: Jean-Marc Cavattion, DSc Objectives: Interleukin (IL)-8, a pro-inflam- matory cytokine, is a potent chemoattractant, factor and an activator of neutrophils produced by many cell types after stimulation by IL-1, tumor necrosis factor (TNF), or microbial prod- ucts such as endotoxins. We investigated whether the presence of measurable IL-8 in plasma was associated with the clinical status of severely ill septic or nonseptic patients sus- ceptible to the development of multiple organ failure. Design: Cohort study. Setting: A collaborative study between an intensive care unit and a research laboratory. Subjects: Circulating IL-8 concentrations were measured in the plasma of 27 patients with sepsis syndrome and in 16 patients with noninfectious shock because these two condi- tions put patients at risk for the development of multiple organ failure. Sixteen of 27 patients with severe infection and 13 of 16 patients with noninfectious pathologies developed multiple organ failure. Measurements and Main Results: A specific enzyme-linked immunosorbent assay (ELISA) for IL-8 was set up with a monoclonal and a rabbit polyclonal antihuman IL-8 using a sand- wich technique. High concentrations of From the Immuno-Allergy Unit (Ms. Marty, Drs. Tamion, Fitting, and Cavallo), Pasteur Institute, Paris; the Intensive Care Unit (re Mist and Carey, Hopital Set Joseph, Pars, ‘This work was supported, in part, by a “Contrat normalise études pilotes en recherche elinigue” from INSERM. Fabienne amin was supported by a grant from the “Fondation pour Is Recherche Médicale." ‘Address requests for reprints to: Dr. Jean-Mare Cavaillon, Unité dImmuno-Allerge, Institut Pasteur, 28 rue Dr. Roux, 75724 Paris Cedex 15, France, 080 399'9472204.067309.000 MD; Fastenve Tamion, MD; Catuenine Firvine; Jean Cass 673 , MD; circulating IL-8 were found in the plasma of patients with sepsis syndrome. Among septic patients, a significant difference was observed between concentrations of IL-8 in survivors ( 16) and nonsurvivors (n = 11) (81 * 13 pg/mL vs. 3826 = 1219 pgimL, respectively; p = .001). A correlation was noticed between plasma IL-8 and IL-6 concentrations (r* = .42; p = .001), while no correlation was observed between IL-8 and TNF-« values, or between IL-8 and IL-1. Al- though the mortality rate of nonseptic, multiple organ failure patients was 92%, low plasma con- centrations of IL-8 were found (78 + 34 pg/mL), while high plasma concentrations were meas- ured in septic, multiple organ failure patients (mortality rate 69%) who were sampled at a similar stage. By contrast, increased IL-6 values were observed in both septic and nonsepti multiple organ failure patients. Conclusions: In septic patients, high amounts of cireulating IL-8 concentrations correlate with fatal outcome, whereas only low plasma con- centrations of IL-8 are present in patients with nonseptic, multiple organ failure. This finding suggests that the signals involved in the exacer- bation of IL-8 production are different, depend- ing on infectious or noninfectious etiology. (Crit Care Med 1994; 22:673-679) ‘Key Worps: cytokines; interleukin-8; inter- leukin-6; polymorphonuclear cells; intensive care unit; multiple organ failure; infection; sep- sis; patient outcome; critical illness Increased concentrations of circulating tumor ne- crosis factor (TNF), as well as interleukin (IL)6, are associated with fatal outcome in patients with sepsis syndrome (1-4). The detection of TNF and IL-6 in plasma, together with IL-1 and y-interferon (3, 4},67a Curent, Cate: Meiers reflects the stimulation of immune cells by bacteria and bacterial-derived products and the exacerbated production of cytokines by these cells. Sepsis syn- drome corresponds to a systemic inflammatory re- sponse syndrome that involves many mediators as well as a cascade of eytokines. IL-1 and TNF-« can induce the release, by various cell types, of many other cytokines, including IL-8 (5). In addition, bacte- rial-derived products, such as endotoxin (lipopolysac- charide), are potent inducers of IL-8 (6). In the baboon model, injection of IL-1, tipopolysaccharide, or whole 'scherichia coli bacteria led to the appearance of IL-8 plasma (7, 8). Similarly, in human volunteers, IL-8 could be detected after lipopolysaecharide or TNF-a. administration (9, 10). The self-administration of li- popolysaccharide, 3,750 times the dose given to healthy volunteers in experimental studies, resulted in shock and multiple organ dysfunction accompanied by tre- ‘mendous concentrations of circulating cytokines, in- cluding IL-8 (11). IL-8 has been detected in the urine of patients with urinary tract infections (12), and in cerebrospinal fluid of patients with meningococcal disease (13). Translocation of endotoxins and/or hypoxia may cause the development of multiple organ failure. Both. ‘mechanisms can generate the production of eytokines that can be responsible for tissue damage. IL-8 is a chemoattractant factor and a potent activator of poly- morphonuclear leukocytes, which lead to the release of granule content that may favor the inflammatory process (6, 14). TNF-o-priming of neutrophils enhanced IL-8-promoted degranulation (15). Although the ex- cessive production of cytokines has been proposed in the etiology of multipie organ failure, few data are available to support this claim, The aim of our study was to correlate plasma concentrations of IL-8 with the concomitant occurrence of multiple organ failure in a cohort of patients at high risk for developing the disease, either with an infectious or a noninfectious triggering mechanism. MATERIALS AND METHODS Patients, Plasma cytokine concentrations were measured in 43 patients hospitalized in an intensive care unit (ICU). Inclusion criteria were the presence ‘ofa sepsis syndrome as defined by Bone et al. (16) (n = 27) or a nonseptic shock (arterial blood pressure of <80 ‘mm Hg) of known origin (n = 16), because each condi- tion puts the patient at risk for the development of multiple organ failure (17). Twenty-nine patients had multiple organ failure (ie., at least two organ system failures as defined by Knaus ¢t al. (18]), 11 patients had sepsis syndrome, and three patients had nonseptic Avni, 1994 ‘Table 1. Diagnoses of the study patients Inclusion Criteria Diagnosis No ‘Multiple organ failure Peritonitie 7 ofseptic ongin Catheter-related septicemia 3 Bacterial sortitis 3 Pyelonephnits 1 Miliary tuberculosis + catheterelated septicemia 1 Bacterial meningitis 1 Multiple organ feilure Gut infarction without peritonitist 7 ‘ofnonseptic origin Supra coelige aortic clamping 3 Cardiogenie shock a Sepsis syndrome Bacterial pneumonia 4 Catheter-rvlated sepsis 2 Endocarditis 1 Pyolonephritis, 1 Cellulitis 1 Bacterial arthritis 1 Malaria 1 [Nonseptic conditions Acute panereatitis 1 Predisposing to. Ruptured aortic aneurism 1 multiple organ Cardiogenie shock 1 failure “AIL the patienta with gut infarction ultimately died absence of peritoneal infection was confirmed at autopsy for all of them, shock without multiple organ failure (Table 1). These patients were aged 65 = 3 yrs, their mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 20 * 1, and 53% of these patients ulti- mately died. Nonsurvivors numbered 11 of 27 in the gToup of septic patients and 12 of 16 in the nonseptic patient group. All samples were obtained within 48 hrs after admission, except samples from five patients (two patients with aortic infection and three patients with gut infarction) who developed multiple organ failure during their ICU stay and who were sampled at the initiation of the multiple organ failure. Study protocol was approved by the Ethics Committee from Saint-Joseph Hospital, which waived the need for informed consent. Blood Samples and Plasma. A total of 20 mL of blood was collected into EDTA-containing test tubes. Blood was immediately placed on ice and processed within 2 hrs. Two hundred microliters of aprotinin (a protease inhibitor; 0.67 TUU'mL of blood, Sigma Chemical, St. Louis, MO) was added to the sample, and sample tubes were centrifuged at 400g at 4°C for 10 mins. Plasma was transferred in Eppendorf tubes and further centrifuged at 10,000 g at 4°C for 5 mins, Plasma was then aliquoted and kept at -30°C in polypropylene tubes,Vol. 22, No.4 IL-8 Enzyme-Linked Immunosorbent Assay (ELISA). An ELISA specific for IL-8 was set up using ‘a monoclonal antibody (MAb#4, prepared by Dr. J.-C. Mazié, Hybridolab, Pasteur Institute, Paris) against recombinant human IL-8 (Immugenex, Los Angeles, CA). Rabbit polyclonal anti-IL-8 antiserum was pro- vided by Dr. N. Vita (Sanofi Elf Biorecherche, Labege, France). The plates were coated with 100 pL/well of mouse monoclonal antihuman IL-8 (5 ng/mL in carbonate buffer, 0.05 M, pH 9.6) in microtitration plates (96 wells, Maxisorp, Nunclon, Rockeville, Denmark) dur- ing 2 hrs at 37°C or overnight at 4°C. After three cycles of washing with phosphate buffer saline (PBS)- ‘Tween buffer, the reactive sites were saturated for 1 hr at 37°C with 100 pL/well of bovine serum albumin (2% in carbonate buffer). After washing, standards of| recombinant IL-8, kept in polypropylene tubes to avoid nonspecific sticking to polystyrene tubes (Immugenex), were added in triplicates (100 nL/well), either in PBS- ‘Tween (0.1%)-bovine serum albumin (1%) containing 1% RPMI-1640 medium, or in a pool of normal human plasma, Plasma samples were added undiluted and cell supernatants of activated cell cultures in RPMI medium were tested 1:100 in PBS-Tween-bovine se- rum albumin, Incubation was performed for 2 hrs at 87°C. After washing, 100 pL. of rabbit polyclonal anti human IL-8 (diluted 1/5000 in PBS-Tween-bovine se- rum albumin) was added to each well. After 1.5 hrs at 37°C, three cycles of washings were performed, and 100 Liwell of a peroxidase-labeled goat antirabbit immunoglobulins (Byosis, Compiegne, France; 1/1000 in PBS-Tween-bovine serum albumin) was added. Af- ter thr incubation at 37°C, plates were washed three times, enzymatic activity was shown by the addi- tion of 200 L/well ortho-phenylene-diamine substrate 03 log 0.0. (490 nm) 0.6 oo o.1 1 To IL-8 (ng/mL) Figure 1. Titration curve of the specific IL-8 enzyme-linked ‘immunosorbent assays (ELISA) (n = 16 in buffer open squares n= in plasma [closed circles}, Mean 2 Seu values Iremiennin8 Values iv Mutsaria: Onan: Pann 675 (Sigma Chemical; 1 mg/mL) that. was prepared just before use in citrate buffer 0.05 M, pH 5 containing 0.06% hydrogen peroxide. Plates were kept in the dark, and the reaction was stopped by the addition of 50 uL/vell HCI 3N. Optical density at 490 nm was measured on a microplate reader spectrophotometer (MR 5000, Dynatech, Saint-Cloud, France). Standard curves for IL-8 representing the compila- tion of 16 assays in buffer and four assays in plasma are shown in Figure 1. The lower limit of sensitivity of the assay (blank « 2 sp) was 7 pg in buffer and 15 pg in plasma. The coefficients of variation of intra-assay and inter-assay were 5.8 = 12% and 18.2 + 2.6% in buffer, and 7.1 = 3.3% and 144 = 2.1%, respectively, for samples ranging from 10 pg/mL. to 10 ng/mL. IL-8 coneentrations could be accurately determined in sam- ples, and titration curves of IL-8 containing activated cell supernatants or plasma led to the same parallel curves as curves obtained with the IL-8 standard, ‘The ELISA was specific for IL-8 and was negative for other cytokines, such as IL-1a, IL-1, TNF-, IL-6. The ELISA was also negative for members of the IL-8 superfamily, such as platelet factor-4, monocyte- chemoattractant protein-1, and Gro 8. IL-6 Assays. Plasma concentrations of IL-6 were measured, using the 7TD-L-specific cell line (19, 20) Statistical Analysis. ‘The Mann-Whitney test. was used to analyze the significance of comparisons be- tween the different patient groups. Results are given as mean = SEM, RESULTS IL-8 Concentrations in Sepsis and in Multiple Or gan Failure. A significant difference was observed between the concentration of circulating IL-8 in septic (n = 27; survival, 59%) and in nonseptic in = 16; survival, 25%) patients; 1407 + 576 vs. 133 + 64 pe! mL, respectively (p =.008). Similarly, a nonsignificant, difference (p = .13) was observed between circulating concentrations of IL-8 among patients with multiple organ failure (n = 29; survival, 21%) and patients without this condition (n = 14; survival, 100%); 132 = 539 vs, 1320 + 68 pg/mL. To further analyze the values of IL-8 in these patients, we compared the septic patients according to their outcome, and we compared the patients with multiple organ failure according to the presence or absence of an associated infection. IL-8 Concentrations in Surviving and Non- surviving Patients with Infection, Follow-up of cireu- lating and cell-associated IL-la, IL-18, and TNF-« has previously been reported for most of the patients with sepsis syndrome reported in this study, Serum676 Crumiecal, Cane Menicint concentrations of IL-6 correlated with clinical out- come (19). As shown in Table 2, a clear dissociation ‘was observed between circulating IL-8 concentrations on admission in survivors and in nonsurvivors. The amounts of circulating IL-8 among surviving septic patients (n = 16) were significantly lower than amounts ‘among nonsurviving septic patients (n = 11)(p =.001). Interestingly, a significant correlation was found be- tween IL-8 and IL-6 values (r? = 42, p <.001), where- ‘as no correlation existed between IL-8 and IL-16 or ‘TNF-a values (data not shown), A longitudinal survey of septic patients confirmed the association of high concentrations of IL-8 with fatal outcome, Maximal mean circulating concentrations of IL-8 in surviving and nonsurviving patients were 100 = 17 and 4452 = 1610 pg/mL, respectively. IL-8 Concentrations in Patients Who Developed Multiple Organ Failure, IL-8 concentrations in blood samples of 16 patients with multiple organ failure of septic origin (survival, 31%) were compared with IL-8 concentrations in patients who developed multiple organ failure of nonseptic origin (n = 13; survival 8%). ‘Table 2. Comparison between plasms concentrations of interleu- kin (L)-8 and IL-6 in surviving and nonsurviving septic patientet Septic Patients No. TL8ipgimk) 1-6 (Vim) Survivors 16 Bei 534s 13 280-189" (<80-1900) Nonsurvivors 11 9326 = 12197469 + 3060 (56-11,829" —¢<80-30,000" pvalue (Mann-Whitney? 0001 ou “Plasma samples were taken within 4B hrs of admission; "mean + st "range, Table 3. Comparison of plasma interleukin (TLS and IL-6 con trations in patients with septic and nonseptic, multiple organ failure Multiple Organ Ls Le Failure No. Survival OSF (pg/mL) (Wika 11 6320 = 2250 Septic 16S «SS O" (62-11,829" (<80-30,000" Nonseptic 18 1 «34203 78234 2965 = 1262, (<30-480" (€80-14,805 value (Mann Whitney) 9002 NS ‘OSF, organ system failure Samples wore obtained within 48 hrs after admission of the patients in the intensive eare unit, except for five patients who were Sampled at the time of initiation of multiple organ failure (ie, sampling: 66 + S6hrs after admission for septic patients and 75 = 24 hrs for nonseptic patients); ‘mean = st, ‘range. Aru, 1994 The detection of high concentrations of plasma IL-8 was strongly associated with the presence of infection (Table 3), while both groups had high concentrations of IL-6. In both patient groups (.e., in all patients who developed multiple organ failure), no correlation ex- isted between the amounts of IL-8 and of IL-6. DISCUSSION In addition to the other mediators detected in bio- logical fluids during infection (1-4), we found that IL- 8 is also a marker of the exacerbation of cytokine production. Furthermore, the IL-8 concentration in plasma correlates with severity and outcome of the infectious disease. Similar to the results of this study, high concentrations of IL-8 were found in the plasma of patients with Pseudomonas pseudomallei infection (21), and Hack et al. (22) established that high amounts of IL-8 observed in septic patients correlated with IL-6 concentrations and outcome from the infection. High concentrations of IL-8 were also reported in the bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome (23-26). IL-8 is an im- portant prognostic indicator for the development: of adult respiratory distress syndrome (26) and its con- centration correiates with survival (23). Furthermore, Miller et al. (23) reported a correlation between the concentration of IL-8 and the number of neutrophils recovered in bronchoalveolar lavage fluid. The pres- ence of IL-8 in tissues or in the blood compartment might lead to different pathophysiologic mechanisms, For example, intradermal injection of IL-8 induces plasma leakage and neutrophil accumulation in the skin (27, 28); whereas the intravenous injection of IL- 8 prevents neutrophil margination. Circulating cytokines represent the tip of the ice- berg (29), and detection of these cytokines in plasma reflects the excessive production of mediators whose accumulation may favor the observed deleterious ef- fects, as assessed by the beneficial action of the IL-1 receptor-antagonist (30), chimeric molecules contain- ing the extracellular domain of the TNF receptor (31), or anti-TNF antibodies (32) in different animal mod- els. One can postulate that, in addition to IL-1 and TNF-a, an excess of IL-8 might contribute to the pathology via the capacity of IL-8 to trigger the secre- tion of pro-inflammatory mediators by neutrophils (33, 34), In agreement with our observation that IL-8 ‘was found in higher amounts in septic patients, other reports indicate that neutrophils play a major role in fatal sepsis (35) and are involved in endotoxin-induced injury (36). Previous findings established that neu- trophil activation is higher in the presence of sepsis than in noninfectious diseases. While comparingVol. 22, No. 4 polymorphonuclear leukocyte elastase in patients with organ failures, Waydhas et al. (37) found higher con- centrations in patients with sepsis than in patients without sepsis. Similarly in the baboon, Redl and colleagues (38) showed that plasma concentrations of elastase were higher in animals with sepsis than in animals with multiple trauma, In addition, the presence of circulating IL-8 might be one ofthe agents responsible for the reported defect in neutrophil migration during septicemia and endotoxemia (39-42), Many reports (43, 44) have indi- cated that IL-8 inhibits neutrophil adhesion to cytokine-activated endothelial cells. This phenome- non might reflect the ability of IL-8 to decrease the expression of leukocyte adhesion molecule-1 on poly- morphonuclear leukocytes (45), although the amounts of CD11b/CD18 are increased on their surface (46, 47). IL-8 also promotes a rapid detachment of tightly ad- herent neutrophils from activated endothelial cells and abolishes neutrophil transendothelial migration (48). Furthermore, preincubation of neutrophils with IL-8 reduces their chemotactic transmigration response to an IL-8 gradient (49), It is possible that IL-8 might have a beneficial action, such as the protection of endothelial cells from neutrophil-mediated damage (43). However, Vogels et al. (50) reported that IL-8 was a harmful molecule under a number of experimental conditions. Low concentrations of IL-8 were found in patients with multiple organ failure, in the absence of concom- itant infections. The fact that low concentrations of IL-8 were found in patients with noninfectious multi- ple organ failure has not been reported. It is possible that mechanisms leading to IL-8 production and/or catabolism may differ between infectious and nonin- fectious multiple organ failure. Furthermore, the number of receptors available for IL-8 on target cells might also be an important variable to consider, since this number of receptors governs the trapping of cir- culating IL-8 (29). The up- and down-regulation of IL- 8 receptors remain to be fully understood, depending on the different, pathologies. In addition, the produc tion of IL-8 in multiple organ failure patients might be underestimated, since an important part of IL-8 might. be fixed on red cells (51). So far, litle is known about the measurements of circulating cytokines in multi- ple organ failure patients, and there is no satisfac- tory animal model. Translocated endotoxin has been Proposed as a factor involved in the etiology of multi- ple organ failure (52), and TNF-x has also been pro- posed as a causative agent leading to the occur- rence of organ failure. In dogs, TNF-a, but not IL-1, causes lethal injury and multiple organ dysfunction (53), Similarly in rats, TNF-a acutely mediates Ttnmnsoxin-8 Vetus iv Muzruoni: ORGAN Panui 6I7 disseminated intravascular inflammation, resulting in multiple organ edema and subsequent. hemody: namic instability (54). In humans, TNF. concentra- tions, particularly within the lungs, correlate with the ‘occurrence of adult respiratory distress syndrome (55). The causative agents of multiple organ failure re- main to be characterized. In addition to endotoxin translocation, hypoxia and organ ischemia may con: tribute to the production of eytokines. Although anox- ia-hyperoxia induces IL-8 production (56), the effect of hypoxia on IL-8 production has not yet been estab- lished but has been shown to trigger the production of 'TNF-« and IL-16 (57). The different concentrations of IL-8 between septic and nonseptic multiple organ failure patients might reflect a possible synergy be- tween various IL-8 inducers, including cytokines (i.e, 'TNF-« and IL-1) and microbial-derived products. In conclusion, IL-8 production during clinical con- ditions that predispose to multiple organ failure seems to depend on the infectious character of the triggering mechanism initiating the systemic inflammatory re- sponse. In addition, similar to IL-6, high concentra- tions of circulating IL-8 correlate with outcome in septic patients. ACKNOWLEDGMENTS ‘Theauthors thank Dr. Jean-Claude Mazié Hybridolab, Institut Pasteur) for his contribution to the preparation ‘of monoclonal antihuman IL-Santibodies, and Dr. Natalio Vita (Elf-Sanofi Biorecherche, Labége) for his generous gift of rabbit anti-IL-8 antiserum, REFERENCES 1 Wanye A, Halstensen A, Espevik 7! 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Ghezai P, Dinarello CA, Binachi M, et sl: Hypoxia increases production of interleukin-1 and tumor necrosis factor by hus ‘man mononuclear eels: Cytokine 1981; :189-194 282-6050. CRITICAL CARE CENTRAL Critical Care Central, SCCM’s official catalogue, contains detailed information regarding all of SCOMs products and services including membership information, continuing education programs, educational materials, involvement opportunities, and much more! This source of information is your one-stop shop for critical care, To request your copy of Critical Care Central, contact SCCM Executive Office at 8101 East Kaiser Boulevard, Anaheim, CA 92808-2259; phone (714) 282-6000 or fax (714)