Digestive Diseases and Sciences, Vol. 36. No. 1 (January, 1991). pp. 123-125
LETTERS TO THE EDITOR
IL-6 AND TNFa IN ASCITIC FLUID DURING SPONTANEOUS BACTERIAL PERITONITIS
To the Editor: Spontaneous bacterial peritonitis (SBP) is one of the major complications of portal hypertension (1). Symptomatology is characterized by fever, abdominal pain, or simply unexplained clinical deterioration. In order to be effective, antibiotic therapy must be initiated prior to the bacterial diagnosis. The latter is frequently hampered by the low number of bacteria in ascitic fluid (2). Laboratory methods enabling early diagnosis are thus mandatory. Leukocyte and granulocyte counts (1, 3) or arterial ascitic fluid pH gradient measurement (1, 4) are currently among the most widely used. In the absence of infection, macrophages represent the predominant cell type in the ascitic fluid. These cells are an important source of proinflammatory mediators such as tumor necrosis factor e~ (TNFc0 or interleukin 6 (IL-6). These cytokines may be implicated in a variety of systemic manifestations (5-7). We have studied TNFo~ and IL-6 levels in the plasma and ascitic fluid of six patients with alcoholic liver cirrhosis (ALC) and ascites, considered as controls, and in four patients with ALC complicated by SBP caused by either E. coli (three cases) or Streptococousfaecalis (1 case). In each case, SBP was successfully treated with ampicillin and gentamycin intravenously, started immediately after the first sampling. For patients with SBP, ascitic fluid samples were taken daily during five days, conserved on ice, and immediately centrifuged. T N F ~ in plasma and ascitic fluid were measured by an immunoradiometric assay (Ire-Medgenix, Fleurus, Belgium) and IL-6 by a bioassay using the IL-6-dependent 7TD1 cell line (8). In control ALC subjects, monokine concentrations were low but slightly elevated in ascitic fluid compared to plasma (P < 0.05 for IL-6, NS for TNFa). In contrast, a tremendous increase of IL-6 and T N F a was initially present in ascitic fluid of patients with SBP (Figure 1). In plasma, IL-6 and TNFoL levels were only slightly and inconsistently elevated among these patients. Following successful treatment, the monokine levels returned to nor-
mal values within five days while the patients clinically recovered. As rapid new tests such as E L I S A will soon be available for their measurement, IL-6 and T N F a might become useful markers both for the diagnosis of SBP and for monitoring treatment. On the other hand, these inflammatory mediators have been implicated in the pathogenesis of septic shock and in the cytopathic effects associated with infections (5-7). Their marked overproduction in ascitic fluid might reflect an important pathogenic mechanism involved in the severity of such infection and the subsequent poor prognosis associated with the decompensation of the underlying liver disease (9, 10). J. DEVIERE, MD J. CONTENT, MD A. CRUSlAUX, MS E. DUPONT, MD Departments of Gastroenterology and Immunology Universitd Libre de Bruxelles HOpital Erasme Institut Pasteur du Brabant Brussels, Belgium REFERENCES 1. Conn HE, Atterbury CE: Cirrhosis. Spontaneous bacterial peritonitis and other infections. In: L Schiff, ER Schiff (eds). Diseases of the Liver. Philadelphia, Lippincott, 1987, pp 829-864 2. Runyon BA, Umland ET, Merlin T: Inoculation of blood culture bottles with ascitic fluid at the bedside markedly improves detection of spontaneous bacterial peritonitis. Arch Intern Med 147:73-75, 1987 3. Fong TL, Akrivadis EA, Runyon BC: Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial peritonitis. Hepatology 9:423-426, 1989 4. Attali P, Turner K, Pelletier, G, Ink O, Etienne JP: pH of ascitic fluid: Diagnostic and prognostic value in cirrhotic and non cirrhotic patients. Gastroenterology 90:12551260, 1986 5. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ: Shock and tissue injury induced by recombinant human cachectin. Science 234:470-474, 1986 6. Kishimoto T: The biology of interleukin 6. Blood 74:1-10, 1989 7. Balkwill FR, Burke F: The cytokine network. Immunol Today 10:299-304, 1989
Digestive Diseases and Sciences, Iiol. 36, No. 1 (January 1991) 0163-2116/91/0100-0123506.50/0 ~0 1991 Plenum Publishing Corporation
123
LETTERS TO THE EDITOR 9 TNF (wMmL)
IL-6 (U/ml) o
TABLE 1. PREVALENCE OF ANTI-HCV ANTIBODIES (%) BEFORE AND AFTER HEART TRANSPLANTATION (HT)
10000-
\ Hepatitis B (N = 15) NANB hepatitis (N = 30) Drug-induced hepatitis (N = 5) Normal liver tests (N = 25)
x\~x
1000-
100-
,
I
I
r p
A
CIRRHOSIS WITHOUT
P
AjO
, A jl
I
I
' = AJ5
,
i
,
Aj2
A~3
AJ4
SBP ( N ~ 4 )
S B P (N=S)
Fig 1. IL-6 (-9 and T N F a (-0-) levels in plasma (P) and ascitic fluid (A) of patients with ALC and with or without SBP. Aj0 represents ascitic fluid levels in SPB at the time of diagnosis, before antibiotic therapy. Ajl-Aj5 represent ascitic fluid levels after one to five days of antibiotic therapy. Values are shown as mean - SEM.
8. Van Snick J, Cayphas S, Vink A, Opdenakker G, Van Damme J, Billiau A: Purification and NH2 terminal aminoacid sequence of a new T cell-derived lymphokine with growth factor activity for B cell hydridomas. Proc Natl Acad Sci USA 83:9679-9783, 1986 9. Hoers JC, Canawati HN, Sapico FL, Hopkins RR, Weiner J. Montgomerie JZ: Spontaneous bacterial peritonitis. Hepatology 2: 399-407, 1982 10. Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, Dupont E: Excessive in vitro bacterial LPS induced production of monocytes in liver cirrhosis. Hepatology 11:628-634, 1990
ANTI-HEPATITIS C VIRUS (HCV) ANTIBODIES IN HEART TRANSPLANT RECIPIENTS WITH POSTTRANSPLANTATION CHRONIC VIRAL B AND NON-A, NON-B HEPATITIS To the Editor:
The prevalence of anti-HCV antibodies in posttransfusion (PT) chronic non-A, non-B (NANB)
124
A t time o f l i T
After HT
6% (1/15) 0% (0/30)
28.5% (4/14) 60% (18/30)
0% (0/5)
0% (0/5)
0% (0/25)
0% (0/25)
hepatitis varies from 70% to 90% (1). Recently, Van der Poel et al (2) reported a low rate (43%) of anti-HCV antibodies positivity in PT chronic NANB hepatitis following open-heart surgery. We have studied the prevalence of anti-HCV antibodies in a series of 75 consecutive heart transplant recipients. Between 1982 and 1985, 120 patients received cardiac transplantation at the the PitiS-SalpStriSre Hospital. At three months 75 patients were alive and were included in this study. Median age was 42 years (28-54); 68 patients were males. Median follow up was 65 months (33-96). All patients received at least 10 units (8-45) of blood products during the perioperative period. After transplantation, 50 (66%) patients had impaired liver tests (serum alanine aminotransferase activity (ALT) twice the upper limit of normal range during at least three months). The other 25 patients (33%) had no evidence of liver disease (ALT serum values < 1.5N during the follow-up period) and were considered as controls. Liver abnormalities were related to N A N B hepatitis in 30 patients, hepatitis B in 15 patients, and drug-induced hepatitis in 5 patients. Delay of the onset of hepatitis after heart transplantation was 16 weeks (8-36) in HBsAg-positive p~/tients and 10 weeks (4-32) in patients with NANB hepatitis. Mean duration of ALT elevation was 36 months (6-85). A liver biopsy was performed in 47 (94%) patients with impaired liver tests (NANB = 28, B = 14, druginduced hepatitis = 5). Anti-HCV antibodies (Ortho HCV ELISA, Diagnostic System) were assayed in - 2 0 ~ C frozen sera at the time of heart transplantation, and every three to six months in all patients including the controls. Results are shown in Table 1. 28.5% of hearttransplant patients with PT hepatitis B had antiHCV antibodies and thus a B-C coinfection; 60% of patients with posttransplantation N A N B hepaDigestive Diseases and Sciences, Vol. 36, No. 1 (January 1991)
LETTERS TO THE EDITOR
IL-6 AND TNFa IN ASCITIC FLUID DURING SPONTANEOUS BACTERIAL PERITONITIS
To the Editor: Spontaneous bacterial peritonitis (SBP) is one of the major complications of portal hypertension (1). Symptomatology is characterized by fever, abdominal pain, or simply unexplained clinical deterioration. In order to be effective, antibiotic therapy must be initiated prior to the bacterial diagnosis. The latter is frequently hampered by the low number of bacteria in ascitic fluid (2). Laboratory methods enabling early diagnosis are thus mandatory. Leukocyte and granulocyte counts (1, 3) or arterial ascitic fluid pH gradient measurement (1, 4) are currently among the most widely used. In the absence of infection, macrophages represent the predominant cell type in the ascitic fluid. These cells are an important source of proinflammatory mediators such as tumor necrosis factor e~ (TNFc0 or interleukin 6 (IL-6). These cytokines may be implicated in a variety of systemic manifestations (5-7). We have studied TNFo~ and IL-6 levels in the plasma and ascitic fluid of six patients with alcoholic liver cirrhosis (ALC) and ascites, considered as controls, and in four patients with ALC complicated by SBP caused by either E. coli (three cases) or Streptococousfaecalis (1 case). In each case, SBP was successfully treated with ampicillin and gentamycin intravenously, started immediately after the first sampling. For patients with SBP, ascitic fluid samples were taken daily during five days, conserved on ice, and immediately centrifuged. T N F ~ in plasma and ascitic fluid were measured by an immunoradiometric assay (Ire-Medgenix, Fleurus, Belgium) and IL-6 by a bioassay using the IL-6-dependent 7TD1 cell line (8). In control ALC subjects, monokine concentrations were low but slightly elevated in ascitic fluid compared to plasma (P < 0.05 for IL-6, NS for TNFa). In contrast, a tremendous increase of IL-6 and T N F a was initially present in ascitic fluid of patients with SBP (Figure 1). In plasma, IL-6 and TNFoL levels were only slightly and inconsistently elevated among these patients. Following successful treatment, the monokine levels returned to nor-
mal values within five days while the patients clinically recovered. As rapid new tests such as E L I S A will soon be available for their measurement, IL-6 and T N F a might become useful markers both for the diagnosis of SBP and for monitoring treatment. On the other hand, these inflammatory mediators have been implicated in the pathogenesis of septic shock and in the cytopathic effects associated with infections (5-7). Their marked overproduction in ascitic fluid might reflect an important pathogenic mechanism involved in the severity of such infection and the subsequent poor prognosis associated with the decompensation of the underlying liver disease (9, 10). J. DEVIERE, MD J. CONTENT, MD A. CRUSlAUX, MS E. DUPONT, MD Departments of Gastroenterology and Immunology Universitd Libre de Bruxelles HOpital Erasme Institut Pasteur du Brabant Brussels, Belgium REFERENCES 1. Conn HE, Atterbury CE: Cirrhosis. Spontaneous bacterial peritonitis and other infections. In: L Schiff, ER Schiff (eds). Diseases of the Liver. Philadelphia, Lippincott, 1987, pp 829-864 2. Runyon BA, Umland ET, Merlin T: Inoculation of blood culture bottles with ascitic fluid at the bedside markedly improves detection of spontaneous bacterial peritonitis. Arch Intern Med 147:73-75, 1987 3. Fong TL, Akrivadis EA, Runyon BC: Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial peritonitis. Hepatology 9:423-426, 1989 4. Attali P, Turner K, Pelletier, G, Ink O, Etienne JP: pH of ascitic fluid: Diagnostic and prognostic value in cirrhotic and non cirrhotic patients. Gastroenterology 90:12551260, 1986 5. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ: Shock and tissue injury induced by recombinant human cachectin. Science 234:470-474, 1986 6. Kishimoto T: The biology of interleukin 6. Blood 74:1-10, 1989 7. Balkwill FR, Burke F: The cytokine network. Immunol Today 10:299-304, 1989
Digestive Diseases and Sciences, Iiol. 36, No. 1 (January 1991) 0163-2116/91/0100-0123506.50/0 ~0 1991 Plenum Publishing Corporation
123
LETTERS TO THE EDITOR 9 TNF (wMmL)
IL-6 (U/ml) o
TABLE 1. PREVALENCE OF ANTI-HCV ANTIBODIES (%) BEFORE AND AFTER HEART TRANSPLANTATION (HT)
10000-
\ Hepatitis B (N = 15) NANB hepatitis (N = 30) Drug-induced hepatitis (N = 5) Normal liver tests (N = 25)
x\~x
1000-
100-
,
I
I
r p
A
CIRRHOSIS WITHOUT
P
AjO
, A jl
I
I
' = AJ5
,
i
,
Aj2
A~3
AJ4
SBP ( N ~ 4 )
S B P (N=S)
Fig 1. IL-6 (-9 and T N F a (-0-) levels in plasma (P) and ascitic fluid (A) of patients with ALC and with or without SBP. Aj0 represents ascitic fluid levels in SPB at the time of diagnosis, before antibiotic therapy. Ajl-Aj5 represent ascitic fluid levels after one to five days of antibiotic therapy. Values are shown as mean - SEM.
8. Van Snick J, Cayphas S, Vink A, Opdenakker G, Van Damme J, Billiau A: Purification and NH2 terminal aminoacid sequence of a new T cell-derived lymphokine with growth factor activity for B cell hydridomas. Proc Natl Acad Sci USA 83:9679-9783, 1986 9. Hoers JC, Canawati HN, Sapico FL, Hopkins RR, Weiner J. Montgomerie JZ: Spontaneous bacterial peritonitis. Hepatology 2: 399-407, 1982 10. Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, Dupont E: Excessive in vitro bacterial LPS induced production of monocytes in liver cirrhosis. Hepatology 11:628-634, 1990
ANTI-HEPATITIS C VIRUS (HCV) ANTIBODIES IN HEART TRANSPLANT RECIPIENTS WITH POSTTRANSPLANTATION CHRONIC VIRAL B AND NON-A, NON-B HEPATITIS To the Editor:
The prevalence of anti-HCV antibodies in posttransfusion (PT) chronic non-A, non-B (NANB)
124
A t time o f l i T
After HT
6% (1/15) 0% (0/30)
28.5% (4/14) 60% (18/30)
0% (0/5)
0% (0/5)
0% (0/25)
0% (0/25)
hepatitis varies from 70% to 90% (1). Recently, Van der Poel et al (2) reported a low rate (43%) of anti-HCV antibodies positivity in PT chronic NANB hepatitis following open-heart surgery. We have studied the prevalence of anti-HCV antibodies in a series of 75 consecutive heart transplant recipients. Between 1982 and 1985, 120 patients received cardiac transplantation at the the PitiS-SalpStriSre Hospital. At three months 75 patients were alive and were included in this study. Median age was 42 years (28-54); 68 patients were males. Median follow up was 65 months (33-96). All patients received at least 10 units (8-45) of blood products during the perioperative period. After transplantation, 50 (66%) patients had impaired liver tests (serum alanine aminotransferase activity (ALT) twice the upper limit of normal range during at least three months). The other 25 patients (33%) had no evidence of liver disease (ALT serum values < 1.5N during the follow-up period) and were considered as controls. Liver abnormalities were related to N A N B hepatitis in 30 patients, hepatitis B in 15 patients, and drug-induced hepatitis in 5 patients. Delay of the onset of hepatitis after heart transplantation was 16 weeks (8-36) in HBsAg-positive p~/tients and 10 weeks (4-32) in patients with NANB hepatitis. Mean duration of ALT elevation was 36 months (6-85). A liver biopsy was performed in 47 (94%) patients with impaired liver tests (NANB = 28, B = 14, druginduced hepatitis = 5). Anti-HCV antibodies (Ortho HCV ELISA, Diagnostic System) were assayed in - 2 0 ~ C frozen sera at the time of heart transplantation, and every three to six months in all patients including the controls. Results are shown in Table 1. 28.5% of hearttransplant patients with PT hepatitis B had antiHCV antibodies and thus a B-C coinfection; 60% of patients with posttransplantation N A N B hepaDigestive Diseases and Sciences, Vol. 36, No. 1 (January 1991)
