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Local and systemic innate immune response to secondary human peritonitis. Influence of micro-organism
Critical Care 2013, 17:R201 doi:10.1186/cc12895

Florence Riché ( Etienne Gayat ( Corinne Collet ( Joaquim Mateo ( Marie-Josèphe Laisné ( Jean-Marie Launay ( Patrice Valleur ( Didier Payen ( Bernard P Cholley (

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1364-8535 Research 11 February 2013 2 July 2013 12 September 2013

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Local and systemic innate immune response to secondary human peritonitis. Influence of micro-organism Florence Riché1, Etienne Gayat 1-2-5, Corinne Collet 3-5, Joaquim Matéo 1, Marie-Josèphe Laisné 1, Jean-Marie Launay 3-5,, Patrice Valleur 4-5, Didier Payen 1-5, Bernard P Cholley 6-7


Departement d’Anesthésie-Réanimation, Hôpital Lariboisière, AP-HP, 2 rue Ambroise Paré 75010 Paris, France 2 U942, INSERM Hôpital Lariboisière 2 rue Ambroise Paré 75010 Paris, France

Service de Biochimie et de Biologie Moléculaire, Hôpital Lariboisière, AP-HP, 2 rue Ambroise Paré 75010 Paris, France Paris, France

Service de Chirurgie Digestive, Hôpital Lariboisière, AP-HP, 2 rue Ambroise Paré 75010 Paris, France Paris, France

Université Paris Diderot 5 rue Thomas Mann 75013 Paris, France

Service d’Anesthésie-Réanimation, Hôpital Européen Georges Pompidou, AP-HP, 20 rue Leblanc 75015 Paris, France

Université Paris Descartes - Sorbonne Paris Cité 12 rue de l’Ecole de Médecine 75005 Paris, France

Corresponding author: Florence Riche Mail:

01 and 0. occurrence of shock did not result in any difference in peritoneal cytokines. There was no correlation between plasma and peritoneal fluid concentration of any cytokine. Conclusions: Peritonitis triggers an acute systemic and peritoneal innate immune response with a simultaneous release of pro and anti-inflammatory cytokines.Abstract Introduction: Our aim was to describe inflammatory cytokines response in the peritoneum and plasma of patients with peritonitis. In the peritoneal compartment. We also tested the hypothesis that scenarios associated with worse outcome would result in different cytokine release patterns.04).02). IFNγ. Results: The concentration ratio between peritoneal fluid and plasma cytokines varied from 5 (2 – 21) (IFNγ) to 1310 (145 – 3888) (IL-1). In the plasma. Methods: Peritoneal and plasma cytokines (interleukin (IL) 1. tumor necrosis factor α (TNFα). Peritoneal IL10 was higher in patients who survived (1505 (450 to 3130) vs 102 (9 to 710) pg/ml. p=0. and IL-10 were higher in patients with shock versus no shock. Presence of anaerobes or Enterococcus specie in peritoneal fluid was associated with higher plasma TNFα: 50 (37-106) vs 38 (29-66) and 45 (36 – 87) vs 39 (27 – 67) pg/ml. TNFα. Therefore.03). p=0. There was no differential plasma release for any cytokine between communityacquired and postoperative peritonitis. type of peritonitis and peritoneal microbiology. Presence of anaerobes and Enterococcus specie was associated with higher peritoneal IFNγ: 2 (1-6) vs 10 (5-28) and 7 (2-39) vs 2 (1-6). IL-10. mortality. respectively (p=0. IL-6. IL-6. and in nonsurvivors versus survivors (p≤0.05 respectively). and interferon γ (IFNγ)) were measured in 66 patients with secondary peritonitis. we compared cytokine responses according to the occurrence of septic shock. Greater levels of all 2 .

non survivors). 3 .cytokines were observed in the plasma of patients with the most severe conditions (shock. but this difference was not reflected in their peritoneal fluid. There was always a large gradient in cytokine concentration between peritoneal and plasma compartments highlighting the importance of compartmentalization of innate immune response in peritonitis.

2) to evaluate the potential differences in mediator profiles between shocked and non-shocked patients. or Enterococcus specie were associated with worse prognosis.Introduction Secondary peritonitis is a severe compartmentalized infectious insult characterized by a rapid response of innate immunity leading to a major inflammatory process. Outcome of secondary peritonitis has been shown to be influenced by several clinical and bacteriological features of the disease. IFNγ . a finding that our own observations did not corroborate [12]. Other groups have suggested that postoperative peritonitis was also associated with worse outcome [9-11]. Therefore. The initial response is usually followed by a post-injury depression of innate immunity in various types of sepsis [1-4]. and 3) to look at a potential impact of peritoneal microbiological findings on mediator release. there is a paucity of data regarding systemic and local innate immune response during peritonitis in humans and on their relation to prognosis [5-8]. and anti-inflammatory: IL-10) in peritoneal and blood compartments of patients with secondary peritonitis . all patients with secondary peritonitis admitted in our unit were prospectively screened for peritoneal and plasma cytokine measurements. the aims of this study were : 1) to characterize the inflammatory mediator response (pro-inflammatory: IL-1. However. TNFα. IL-6. The study was approved by our Institutional Review Board (N° IRB00006477). intra-peritoneal anaerobes. Whether or not these features are associated with differential immune responses is unknown. Plasma cytokine measurements were performed on leftovers of blood from routine daily samples and patients 4 . yeasts. survivors and non survivors. and according to the type of peritonitis (community-acquired or post-operative). We recently reported that two or more microorganisms in peritoneal fluid culture. Methods Over a period of 2 years.

primary peritonitis (medical cause of intra-abdominal infection that did not require surgery). None of our patients underwent open-wound management and the abdomen was not irrigated after surgery. which was previously reported [12].0 × 109/l or less than 4. They were not included if they had secondary peritonitis as a result of penetrating trauma. tertiary peritonitis defined as recurrent postoperative peritonitis. Diagnosis and surgical management of GP: By definition. Patients were included if they were over 18 years and if the diagnosis of secondary generalized peritonitis (community-acquired and postoperative peritoneal infection) was confirmed surgically. After incision and confirmation de visu of intra-abdominal infection involving the whole peritoneal cavity. Particular 5 .were informed during follow-up. and patients were reoperated on-demand exclusively. abrupt alteration in mental status). but the need for written informed consent was waived. heart rate higher than 90/min.5°C or lower than 35°C. (b) evidence of a nidus of infection. and (c) systolic blood pressure less than 90 mmHg (for at least 1 h) despite adequate fluid replacement and infusion of vasopressor associated with at least two signs of perfusion abnormality (lactic acidosis. Abundant peritoneal lavage was then performed using sterile saline solution. peritoneal fluid was sampled for microbiology and cytokine measurements. respiratory rate higher than 20/min or PaCO2 less than 32 mmHg or need for mechanical ventilation. oliguria. white blood cell count higher than 12. Ostomies were systematically preferred to primary anastomosis.0 × 109/l or containing more than 10% immature forms. or if they received steroids as part of their treatment. all cases required laparotomy for abdominal sepsis. This cohort was a subgroup of a larger cohort of secondary peritonitis. We did not perform planned re-laparotomy. Septic shock definition: Septic shock was defined according to the criteria of the Critical Care Medicine Consensus Conference as: (a) systemic inflammatory response as defined by two or more of the following: temperature higher than 38.

and piperacillinetazobactam (4g every 6 hours) associated with gentamycine (3mg/kg daily) during 5 days. Antimicrobial therapy: Patients received antibiotics prior to anesthesia induction according to our institutional protocols. the first plasma samples were always obtained within 24 hours after the onset of septic shock. ICU length of stay. SAPS II. and origin of peritonitis. To evaluate the balance between pro and anti-inflammatory mediators. Microbiological and mycological results of all cultures (peritoneal fluid collected 6 .e.attention was paid to microbiological findings in the peritoneal fluid that were associated with worse outcome according to our previous study (i. followed by amoxicillin-clavulanic acid (1g-200mg every 6 hours) and gentamycine (3mg/kg daily) during 5 days. Enterococcus specie. and yeasts [12]. Data collection: We collected demographic and clinical data including age. IL-6. Antibiotic therapy was then adjusted to germ sensitivity. we used amoxicillin-clavulanic acid (2g-200mg) associated with gentamycin (3mg/kg) at the time of induction of anesthesia. If a patient was allergic. D2. gender.: ≥2 micro-organisms.e.: higher incidence of septic shock and/or death): the presence of polymicrobial cultures (i. anaerobes. and IFNγ) as well as one anti-inflammatory cytokine (IL-10) were measured using ELISA kits (R&D Systems) in plasma and peritoneal fluid. We also evaluated the impact of “microbial synergy” (i. Cytokines measurements: Peritoneal fluid was harvested for microbiological culture and cytokine measurement immediately after opening the peritoneal cavity. occurrence of septic shock. Plasma cytokines were measured daily during the first 3 postoperative days (D1. For postoperative peritonitis. ICU mortality. we used piperacilline-tazobactam (4g) with gentamycine 3mg/kg at induction. four proinflammatory cytokines (IL-1. For community-acquired peritonitis. 14]. D3).: association of different bacterial strains) on cytokine plasma levels [13. TNFα. In patients presenting septic shock. we used gentamycine (3mg/kg/day) associated with ornidazole (1g) during 5 days.e. bacteria or fungi). as soon as available.

The origin of peritonitis was colon (n=20). gastro-duodenal (n=13). and 8 of them died while in ICU (ICU mortality: 34%).1 statistical software (The R Foundation for Statistical Computing. yeasts). and yeasts: 14% (n=9). mono versus polymicrobial peritonitis) and according to the type of bacteria in the peritoneal fluid culture (anaerobes. Plasma and peritoneal fluid IL-1. Laparotomy was always performed within 24 hrs of septic shock onset.10. CA). or nosocomial infection were tested using two-way analysis of variance on the log-transformed values of cytokine serum concentrations. 48%. Plasma cytokine profiles during the first 3 days were analyzed using Friedman repeated-measures analysis of variance on ranks. Enterococcus specie: 20% (n=13). IL-6.during surgery and blood samples obtained within the first 24 hours) were recorded. IFNγ. post-duodenal small bowel (n=18). Results Sixty-six patients with secondary peritonitis were studied prospectively. TNFα. Patient’s characteristics are presented in table 1.08). and IL-10 at day 1 (day of surgical 7 . Statistical analysis: Results are expressed as median with interquartile range for continuous variable and as count and percentage for categorical variable. Differences in cytokine profiles according to presence or absence of shock. anaerobes: 18% (n=12). The proportion of patients with polymicrobial cultures (≥2 germs) was 51% (n=34 patients). Incidence of shock did not reach statistical difference between community-acquired and post-operative peritonitis (24% vs. ICU death. Twenty three patients (34%) had septic shock. Enterococcus specie. Vienna. Austria) and StatView (SAS Institute Inc. San Francisco. respectively. Mann-Whitney rank sum test was used to compare values at Day 1 between subgroups (community versus postoperative. appendix (n=10) and others (n=2). biliary tract (n=3). p=0. All analyses were performed using R 2.

03). or when anaerobes or Enterococcus were present in the peritoneal fluid. to more than 1300 for IL-1).e. IFNγ and IL-10 did not differ significantly (i. while IL-6. The presence of yeast did not result in 8 .: no significant interaction). Plasma cytokines levels according to bacteriological findings (mono.versus polymicrobial cultures of peritoneal fluid. There was no correlation between plasma and peritoneal fluid concentration of any cytokine. Comparing survivors vs non-survivors. p=0.04). and ratio of peritoneal to plasma concentrations are presented in table 2. Plasma TNFα was significantly higher in case of polymicrobial culture.008). Plasma IL-10 was significantly higher in case of polymicrobial culture or when anaerobes were present in the peritoneal fluid. no shock (5 (5-8) vs 5 (5-8) pg/ml. or yeast) are presented in table 3. TNFα plasma profiles had significant interaction (p<0. There was no difference in plasma cytokine concentrations between community-acquired and post-operative peritonitis.procedure). Anaerobes and Enterococcus specie were associated with higher IFNγ in peritoneal fluid. We did not find any difference in peritoneal cytokines with regard to the occurrence of shock. Only peritoneal levels of IL-10 were higher in survivors vs non-survivors (1505 pg/ml (450 to 3130) vs 102 pg/ml (9 to 710) respectively. plasma IL-1 did not differ among groups: shock vs. whereas profiles of TNFα. with great variability of the peritoneal fluid/plasma ratio among cytokines (from 5 for IFNγ. IFNγ. presence or not of anaerobes. and IL-10 exhibited only intergroup and overtime differences (Figure 2). Table 4 shows peritoneal cytokine levels in relation to bacteriological findings. In the plasma compartment. p=0. IL-6 profile over the first three days differed between shock and no-shock patients (p<0. Enterococcus.54) and survival vs non survival (5 (5-8) vs 5 (5-6) pg/ml. Regardless of the clinical situation. Concentrations of cytokines were always higher in peritoneum than in plasma.73). but inter-group and overtime differences were noted between the two groups (Figure 1). p=0.

but there was a greater IL-10 concentration in survivors. especially when bacteremia occurred. IL-10. However. Plasma cytokines did not differ between communityacquired and postoperative peritonitis. The presence of Anaerobes and Enterococcus specie was associated with higher peritoneal IFNγ. a direct intravascular stimulation of cytokine release by monocytes cannot be ruled out in some patients. There is very limited data on innate immune response assessed by plasma and peritoneal inflammatory mediators in patients with secondary peritonitis. IL-6. IFNγ. TNFα. Plasma TNFα. and decreased over the first three postoperative days in a parallel manner. there was no difference in cytokine concentration between shock and no shock patients.higher plasma or peritoneal cytokine level. In the peritoneal compartment. with no correlation between peritoneal and plasma levels. we observed a large gradient between peritoneal fluid and plasma concentrations of cytokines. Discussion In this cohort of 66 patients with secondary generalized peritonitis. Our results confirm that IL-1. IL-10 plasma levels were also higher when anaerobes or polymicrobial positive culture were found. and IFNγ are present at high concentrations in peritoneal fluid of patients with peritonitis. This observation fits well with the concept of the “tip of the iceberg”. only one study addressed this issue and reported a large concentration gradient for TNFα and IL-6 between peritoneal fluid and plasma in a small group (n=17) of patients with peritonitis [6]. IL-6. To our knowledge. Presence of peritoneal anaerobes or Enterococcus specie was associated with a higher plasma level of TNFα. but only a few patients from our cohort (n = 9) had yeast in their peritoneal fluid. and IL-10 were higher in patients with shock and in non survivors. since this condition is associated with higher plasma cytokines 9 . 16]. which suggests that plasma levels increase only after saturation of tissues within abdominal compartment [15.

According to some authors. In this cohort.and anti-inflammatory mediators are released simultaneously at the early phase of peritoneal sepsis confirms what was recently noted in animal models of sepsis [20] and septic patients [4. both. the proportion of positive blood culture within the first 48 hours of peritonitis was 11/66 (16%). low plasma IFNγ is associated with increased mortality [23. 6-8. 19]. The only data available regarding IFNγ and outcome during abdominal infection comes from experimental studies and results are conflicting. pro and anti-inflammatory mediators are produced simultaneously in the peritoneum of patients with peritonitis [28]. no human data was available on IL-10 during peritonitis. The fact that pro. our findings corroborate the fact that. Since IL-10 is considered an anti-inflammatory mediator. 22]. we found that polymicrobial cultures or anaerobes in the peritoneal fluid were associated with more frequent septic shock [12]. Controversy exists regarding a specific role of some pathogens on the pattern of immune response.and anti-inflammatory mediators were higher in patients with shock and in non-survivors. Some authors support the concept of a "generic septic response" in which 10 . Our values for plasma and peritoneal IFNγ measurements represent the first set of data in humans with generalized peritonitis. In a previous study. 18. which fits well with our observation that intra-peritoneal IL-10 concentration was greater in survivors. 26]. Experimental studies suggest that intra-peritoneal or subcutaneous IL-10 injections reduce mortality [27]. a finding that has been reported by several authors [1.[17]. 24] while others reported that prophylactic inhibition of IFNγ improves survival [25. in accordance with what has been observed in experimental models of peritonitis [4]. 21. Similarly. The role of the infecting pathogen on innate immune response of patients with peritonitis has been poorly investigated. We also observed that plasma levels of pro. Plasma concentration of IFNγ was very low compared to other cytokines.

A large gradient in cytokine concentration was noted between peritoneal cavity and plasma. 11 . This theory has been contradicted by others who suggested that different types of germs may elicit various immune responses. 30].an identical immune response is triggered by any type of bacteria [29. In the present study. For example. described that adjunction of Enterococcus faecalis is associated with increased mortality as well as higher levels of TNFα and IL-6 in peritoneal fluid [33. In humans with sepsis of various origins. 34]. some of the observations we made are consistent with previous experimental findings and therefore provide the first human data to support laboratory hypotheses. Conclusion Secondary peritonitis is responsible for an acute local and systemic innate immune response involving a simultaneous release of both pro-and anti-inflammatory mediators. preventing any definitive conclusion to be drawn from these results. we observed that patients in whom anaerobes or Enterococcus specie were isolated from peritoneal fluid cultures released more TNFα in their plasma than those who were infected with other strains. One of the limitations of our study is that the number of patients with specific characteristics or bacteriological findings in each subgroup is rather small. Gogos et al recently observed that HLA-DR expression and apoptosis rate of CD-4 and CD-8 within 24h of sepsis onset varied according to the underlying pathogen [32]. In rats with peritonitis. Montravers et al. highlighting the importance of compartmentalization of innate immune response during peritonitis. distinct host responses to Streptococcus pneumoniae or Pseudomonas aeruginosa have been reported in experimental models of pneumonia [31]. In addition. despite a common pathway of activation. The most severe patients had higher plasma levels of all cytokines but this difference was not observed with peritoneal fluid cytokines. small differences must be considered cautiously as multiple comparisons were performed to compare various subgroups. However.

INFγ : Interferon gamma. • Higher plasma levels of pro and anti-inflammatory cytokines are associated with shock and mortality. IL-10 : Interleukin-10. HLA-DR: Human Leucocyte Antigen-DR. CD: Cluster of differentiation 12 . Abbreviations: IL-1: Interleukin-1. IL-6: Interleukin-6. • Innate immune response was not different between patients with post-operative and community-acquired peritonitis. SAPS : Simplified Acute Physiologic Score. TNFα : Tumor Necrosis Factor alpha.Key messages • Compartmentalization of innate immune response during peritonitis is reflected by a large gradient in cytokine concentration between peritoneum and plasma. • The infecting pathogen might influence host immune response.

Authors contributions section FR conceived the study. BC analyzed data and drafted the manuscript. and drafted the manuscript. CC and JML carried out cytokine dosage. its design. All authors read and approved the final manuscript. MJL participated to enrollment and correct routing of blood samples. PV participated to study design and coordination. JM and DP helped interpreting data and participated to manuscript drafting. 13 . EG performed the statistical analysis.

Torey Medical.Hôpitaux de Paris 14 . Vitech Italy. and Meditor during in the past 5 years. Funding Assistance Publique .Acknowledgements This work was performed at Hôpital Lariboisière. except DP who acknowledges receiving lecturing fees from Eli-Lilly. Paris. France Competing Interests The authors declare that they have no competing interests. AP-HP.

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n = 23) and no septic shock (open bars. IFNγ and IL-10 in nonsurvivors (hatched bars. IL-6. Figure 2: Box plots representing the time course (Day 1 to Day 3) of plasma TNFα. and IL-10 in patients with septic shock (hatched bars. error bars indicate 10th and 90th percentiles. Upper and lower limits of the box represent 25th and 75th percentiles. n = 43). the bar within the box corresponds to median value. n = 8) and survivors (open bars. and open circles correspond to outliers. Upper and lower limits of the box represent 25th and 75th percentiles. the bar within the box corresponds to median value. IL-6. 19 .Figure legends Figure 1: Box plots representing the time course (Day 1 to Day3) of plasma TNFα. n = 58). IFNγ. and open circles correspond to outliers. error bars indicate 10th and 90th percentiles.

Table 1: Patient characteristics.5 (18 .72) 36 (55%) / 30 (45%) 23 (35 %) 20 ± 24 (1-109) Community-acquired/Post-operative 37 (56%) / 29 (44%) SAPS II Overall ICU mortality Mortality among septic shock Nosocomial infections 32. 20 .48) 8 (12%) 8 (34%) 31 (47%) Results are expressed as mean ± SD and/or (range). Patients Age (years) Sex ratio F/M Septic shock Average length of ICU stay (days) n = 66 59 (48 . or as n (%).

Plasma (pg/ml) IL-1 TNFα IL-6 IFN γ IL-10 5 (5 .75) Values are expressed as median (25th .9) 1135 (260 . and peritoneal fluid/plasma ratio at Day 1 of peritonitis.2945) Peritoneal/plasma ratio 1310 (145 .69) 907 (289 .3888) 158 (8 .8) 40 (29 . 21 .454) 25 (3 .75) 5 (2 .21) 25 (4 .136) Peritoneal fluid (pg/ml) 7190 (1180 .882) 164352 (22859 .3) 43 (21 .Table 2: Plasma and peritoneal fluid cytokines.328410) 3 (1 .75th percentiles).2389) 1 (1 .22670) 262 (90 .

2828) 50 (30 .114) 1 (1 .54 0.3) no Yeast (n=57) IL-1 TNFα IL-6 IL-10 IFNγ 5 (5 .19 0.79 0.67) 880 (283 .2282) 40 (20 .2580) 50 (39 .71 0.90) 1 (1 .02 0.03 0.3) 0. 22 .2) Polymicrobial (n=32) 5 (5 .5) Yeast (n=9) 5 (5 . Monomicrobial (n= 34) IL-1 TNFα IL-6 IL-10 IFNγ 5 (5 .Table 3: Plasma cytokines (pg/ml) at Day 1 according to peritoneal fluid culture.62 0.51 0.8) 39 (29 .52) 630 (243 .017 0.8) 38 (29 .7) 45 (31 . See text for details.02 0.9) 45 (36 .129) 1 (1 .8) 36 (26 .96 0.119) 2 (1 .4550) 197 (27 .13) Enterococcus sp.88) 1360 (1085 .63) 855 (283 .2618) 40 (20 .1846) 40 (17 .39 0.715) 1 (1 .67) 1 (1 .0005 0.12 p value 0.75th percentiles).21 0.93 0. (n=13) 5 (5 .106) 2755 (456 . (n=43) IL-1 TNFα IL-6 IL-10 IFNγ 5 (5 .1360) 27 (5 .7) 39 (27 .49 Results are presented as median (25th .5) 52 (40 .154) 1 (1 .210) 1 (1 .100) 1500 (510 .8) 50 (37 .66) 876 (300 .65 0.32 0.3) Anaerobes (n=12) 5 (5 .2325) 50 (30 .87) 1500 (630 .2) no Enterococcus sp.2) no Anaerobes (n=44) IL-1 TNFα IL-6 IL-10 IFNγ 5 (5 .17 0.

342800) 1755 (403 .27090) 285 (90 .383700) 1505 (320 .88 0.96 0.201600) 550 (243 .89 0.23) no Anaerobes (n=44) IL-1 TNFα IL-6 IL-10 IFNγ 4682 (1000 .4693) 120 (96 .16 0.75th percentiles).1592) 51400 (12800 .4) 0.7) Anaerobes (n=12) 26000 (7282 .9) Polymicrobial (n=32) 4400 (509 .6) no Yeast (n=57) IL-1 TNFα IL-6 IL-10 IFNγ 7859 (1417 .42 0.328400) 1252 (386 .4380) 10 (5 .05 0.01 0.31440) 290 (89 .4246) 3 (1 .Table 4: Peritoneal fluid cytokines (pg/ml) at Day 1.34 0.1009) 156800 (1536 .28) Enterococcus sp.38880) 185 (87 .348300) 1252 (358 .54 0.1185) 72390 (13760 .2292) 2 (1 .530) 196800 (98600 .54890) 805 (88 . See text for details 23 .270300) 370 (167 .04 0.953) 143300 (20630 .16730) 260 (93 .2610) 2 (1 .848) 195600 (25460 .78 0.25 0. (n=43) IL-1 TNFα IL-6 IL-10 IFNγ 4850 (1000 .12 0.3679) 2 (1 .480) 7 (2 .2902) 3 (2 .695) 236800 (86670 .215100) 465 (40 .33 0. (n=13) 8528 (1850 .02 0.6) no Enterococcus sp.2785) 2 (1 .19220) 252 (95 .37 0.39) Yeast (n=9) 3010 (840 .44 0.09 0.22580) 265 (96 .23 Results are presented as median (25th . according to peritoneal fluid culture Monomicrobial (n= 34) IL-1 TNFα IL-6 IL-10 IFNγ 8194 (3115 .851) 164400 (25380 .190000) 435 (167 .01 p value 0.

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