Scand J Infect Dis 24: 787-791, 1992
Cerebrospinal Fluid Levels of IL-6 in Patients with Acute Infections of the Central Nervous System DONATO TORRE, CLAUDIA ZEROLI, GIORGIO FERRARO. FICIPPO SPERANZA, ROBERTO TAMBINI, ROBERTO MARTEGANI dnd GIOVANNI PAOLO FIORI From the Division of Infectious Diseases. Regional lioypitd and E wid 3 M i i c ( h 1
Scand J Infect Dis Downloaded from informahealthcare.com by RMIT University on 02/28/13 For personal use only.
Foundarton, Varese, Italy Interleukin-6 (IG6) activity was measured in the cerebrospinal fluid (CSF) of patients with acute bacterial or viral meningitis and in AIDS patients with various cerebral disorders. Increased levels of IL-6 were detected in the CSF of patients with bacterial meningitis. On the contrary, most of the samples from patients with viral meningitis (predominantly caused by mumps virus) had no detectable IC6 activity in CSF. A moderate increase of I G 6 levels was detected in the CSF of AIDS patients with AIDS dementia cornpkx (ADC), progressive multifocal leukoencephalopathy and cerebral toxoplasmosis. Moreover, higher levels of I L 6 were detected in the CSF of patients with cryptococcal meningitis. We conclude that the initial events of CSF inflammation in patients with acute viral meningitis are different from those in patients with acute bacterial meningitis, and the role of I L 6 is less critical to the process. D . Torre, MD, Division of Infectious Diseases, Regional HospitaI, Viale Born' 57,21IOO Varese, Italy
INTRODUCTION IL-6 is a multi-functional cytokine that is produced by a variety of cells regulating immune response, acute phase reactions and hematopoiesis, and may play a central role in host defense mechanisms (1, 2 ) . I L 6 has been linked specifically to stimulation of acute phase plasma protein synthesis by hepatocytes ( 3 , 4 ) . In particular, IL-6 induces the broadest range of acute phase proteins such as C-reactive protein, serum arnyloid A, haptoglobin, fibrinogen, a,-antitrypsin, a,-acid glycoprotein and ceruloplasmin. Furthermore, IL-6 is a cytokine that promotes differentiation of B-cells to antibody-secreting cells ( 5 ) . It has been shown that high levels of IL-6 can occur in the cerebrospinal fluid (CSF) of patients with acute infections of the central nervous system (CNS; 6, 7) as well as in those with multiple sclerosis (8), but the possible pathogenetic role of the interleukin in diseases of the CNS is not elucidated. Contrasting data are reported by some investigators on the participation of TNF alpha, IL-1 and IL-6 in aseptic or viral meningitis (6. 9). Since the initial events of CSF inflammation in patients with viral meningitis are different from those in patients with bacterial meningitis, the participation of these 3 cytokines is less critical to the process. A moderate increase of TNF alpha and IL-1 has been observed in the CSF of patients with HIV infection (10). The present study was undertaken to investigate the CSF levels of IL-6 in patients with acute bacterial or viral meningitis and in HIV-infected patients with cerebral disorders. MATERIALS AND METHODS The patient population consisted of 39 patients with various infections of the CNS followed at the Division of Infectious Diseases. 20 patients had acute bacterial or viral meningitis. Nine patients had acute bacterial meningitis caused by the following organisms: Streptococcus pneumoniae (n = 4). Streptococcus faecalis ( n = 2).
SI Scand J Infect Dis
788 D. Torre et al.
Scand J Infect Dis 24
I1 6 (pg/ml)
^T Scand J Infect Dis Downloaded from informahealthcare.com by RMIT University on 02/28/13 For personal use only.
1500
Bacterial Meningitis
Viral Meningitis
Fig. 1. IL-6 levels in the CSF of patients with acute bacterial or viral meningitis.
Haemophilus influenzae ( n = l), Staphylococcus epidermidis ( n = l), Staphylococcus warneri ( n = I). (This coagulase-negative staphylococcus may be responsible for ventriculo-peritoneal shunt infection; (11, 12.) 11 patients had acute viral meningitis caused by the following organisms: mumps virus (n = 7). Epstein-Barr virus ( n = 2), none detected ( n = 2). The age range was 3-57 years. 19 AIDS patients with various cerebral disorders were also included in this study. Eight patients had AIDS dementia complex (ADC), 3 had progressive multifocal leukoencephalopathy. 4 had cerebral toxoplasmosis and 4 had cryptococcal meningitis. The age range was 21-42 years. The diagnosis of cerebral disorders in AIDS patients was mainly based on neurologic examination, neuropsychologic assessment, computed tomography scan, magnetic resonance imaging and evaluation of CSF. Diagnosis of cryptococcal meningitis was made by using India ink staining and a latex agglutination test on CSF. Within the first 72 h of admission to the hospital, CSF samples were collected from all patients. and stored at -70°C until they were assayed for IL-6 activity. The IL-6 levels in undiluted CSF were detected using a commercially available ELISA kit for human IL-6 (R and D Systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. Standards and samples were tested in duplicate. The concentration of IL-6 in the test samples was calculated using a standard curve and expressed in picograms (pg)/ml. The detection limit was 10 pg/ml. All data are expressed as mean and standard deviation. Statistical analysis was performed using Student’s t test and correlations between I L 6 and other CSF parameters in the different group of patients wcre investigated by Spearman rank-order correlation coefficient.
RESULTS
Fig. 1 shows IL-6 levels in the CSF of patients with bacterial or viral meningitis. A marked Table I. CSFfindings and IL-6 levels in patients with bacterial and viral meningitis All data indicate mean and standard deviation ~~
CSF findings
Viral meningitis (n= 11)
Bacterial meningitis (n=9)
p value
IL-6 (pg/ml) WBC ( x 10%) Glucose (g/l) Protein (g/l)
5.8f 8.5 415.4k864.7 0.5f 0.1 1 . O f 0.6
975.5f 617.8 2 133.5k 1367.1 0.2+ 0.2 2.22 1.3
Cerebrospinal Fluid Levels of IL-6 in Patients with Acute Infections of the Central Nervous System DONATO TORRE, CLAUDIA ZEROLI, GIORGIO FERRARO. FICIPPO SPERANZA, ROBERTO TAMBINI, ROBERTO MARTEGANI dnd GIOVANNI PAOLO FIORI From the Division of Infectious Diseases. Regional lioypitd and E wid 3 M i i c ( h 1
Scand J Infect Dis Downloaded from informahealthcare.com by RMIT University on 02/28/13 For personal use only.
Foundarton, Varese, Italy Interleukin-6 (IG6) activity was measured in the cerebrospinal fluid (CSF) of patients with acute bacterial or viral meningitis and in AIDS patients with various cerebral disorders. Increased levels of IL-6 were detected in the CSF of patients with bacterial meningitis. On the contrary, most of the samples from patients with viral meningitis (predominantly caused by mumps virus) had no detectable IC6 activity in CSF. A moderate increase of I G 6 levels was detected in the CSF of AIDS patients with AIDS dementia cornpkx (ADC), progressive multifocal leukoencephalopathy and cerebral toxoplasmosis. Moreover, higher levels of I L 6 were detected in the CSF of patients with cryptococcal meningitis. We conclude that the initial events of CSF inflammation in patients with acute viral meningitis are different from those in patients with acute bacterial meningitis, and the role of I L 6 is less critical to the process. D . Torre, MD, Division of Infectious Diseases, Regional HospitaI, Viale Born' 57,21IOO Varese, Italy
INTRODUCTION IL-6 is a multi-functional cytokine that is produced by a variety of cells regulating immune response, acute phase reactions and hematopoiesis, and may play a central role in host defense mechanisms (1, 2 ) . I L 6 has been linked specifically to stimulation of acute phase plasma protein synthesis by hepatocytes ( 3 , 4 ) . In particular, IL-6 induces the broadest range of acute phase proteins such as C-reactive protein, serum arnyloid A, haptoglobin, fibrinogen, a,-antitrypsin, a,-acid glycoprotein and ceruloplasmin. Furthermore, IL-6 is a cytokine that promotes differentiation of B-cells to antibody-secreting cells ( 5 ) . It has been shown that high levels of IL-6 can occur in the cerebrospinal fluid (CSF) of patients with acute infections of the central nervous system (CNS; 6, 7) as well as in those with multiple sclerosis (8), but the possible pathogenetic role of the interleukin in diseases of the CNS is not elucidated. Contrasting data are reported by some investigators on the participation of TNF alpha, IL-1 and IL-6 in aseptic or viral meningitis (6. 9). Since the initial events of CSF inflammation in patients with viral meningitis are different from those in patients with bacterial meningitis, the participation of these 3 cytokines is less critical to the process. A moderate increase of TNF alpha and IL-1 has been observed in the CSF of patients with HIV infection (10). The present study was undertaken to investigate the CSF levels of IL-6 in patients with acute bacterial or viral meningitis and in HIV-infected patients with cerebral disorders. MATERIALS AND METHODS The patient population consisted of 39 patients with various infections of the CNS followed at the Division of Infectious Diseases. 20 patients had acute bacterial or viral meningitis. Nine patients had acute bacterial meningitis caused by the following organisms: Streptococcus pneumoniae (n = 4). Streptococcus faecalis ( n = 2).
SI Scand J Infect Dis
788 D. Torre et al.
Scand J Infect Dis 24
I1 6 (pg/ml)
^T Scand J Infect Dis Downloaded from informahealthcare.com by RMIT University on 02/28/13 For personal use only.
1500
Bacterial Meningitis
Viral Meningitis
Fig. 1. IL-6 levels in the CSF of patients with acute bacterial or viral meningitis.
Haemophilus influenzae ( n = l), Staphylococcus epidermidis ( n = l), Staphylococcus warneri ( n = I). (This coagulase-negative staphylococcus may be responsible for ventriculo-peritoneal shunt infection; (11, 12.) 11 patients had acute viral meningitis caused by the following organisms: mumps virus (n = 7). Epstein-Barr virus ( n = 2), none detected ( n = 2). The age range was 3-57 years. 19 AIDS patients with various cerebral disorders were also included in this study. Eight patients had AIDS dementia complex (ADC), 3 had progressive multifocal leukoencephalopathy. 4 had cerebral toxoplasmosis and 4 had cryptococcal meningitis. The age range was 21-42 years. The diagnosis of cerebral disorders in AIDS patients was mainly based on neurologic examination, neuropsychologic assessment, computed tomography scan, magnetic resonance imaging and evaluation of CSF. Diagnosis of cryptococcal meningitis was made by using India ink staining and a latex agglutination test on CSF. Within the first 72 h of admission to the hospital, CSF samples were collected from all patients. and stored at -70°C until they were assayed for IL-6 activity. The IL-6 levels in undiluted CSF were detected using a commercially available ELISA kit for human IL-6 (R and D Systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. Standards and samples were tested in duplicate. The concentration of IL-6 in the test samples was calculated using a standard curve and expressed in picograms (pg)/ml. The detection limit was 10 pg/ml. All data are expressed as mean and standard deviation. Statistical analysis was performed using Student’s t test and correlations between I L 6 and other CSF parameters in the different group of patients wcre investigated by Spearman rank-order correlation coefficient.
RESULTS
Fig. 1 shows IL-6 levels in the CSF of patients with bacterial or viral meningitis. A marked Table I. CSFfindings and IL-6 levels in patients with bacterial and viral meningitis All data indicate mean and standard deviation ~~
CSF findings
Viral meningitis (n= 11)
Bacterial meningitis (n=9)
p value
IL-6 (pg/ml) WBC ( x 10%) Glucose (g/l) Protein (g/l)
5.8f 8.5 415.4k864.7 0.5f 0.1 1 . O f 0.6
975.5f 617.8 2 133.5k 1367.1 0.2+ 0.2 2.22 1.3
