Department of Infectious Diseases, S. Bortolo Hospital, via Rodolfi, 36100 Vicenza, Italy
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that specifically regulates survival, proliferation and differentiation of neutrophilic granulocyte precursors and stimulates the function of mature neutrophils.1 Studies on the administration of G-CSF before experimental infection of non-neutropenic animals have repeatedly shown significant treatment benefits of G-CSF alone or in combination with antibiotics.2,3 Furthermore, G-CSF appears to attenuate the proinflammatory cytokine response in lipopolysaccharide-stimulated blood from G-CSF-treated human volunteers.4 In experimental pneumococcal meningitis in the rabbit, G-CSF pretreatment attenuates neutrophil pleocytosis and cerebrospinal fluid (CSF) IL-8 levels, and delays significantly the occurrence of alterations in TNF-, IL-1ß, protein and glucose levels in the CSF.5 Anti-inflammatory properties have therefore been ascribed to this cytokine.6
Based on these observations, the present pilot study was performed with the aim of evaluating the value of G-CSF as an adjunctive agent in the standard treatment of non-neutropenic adult patients affected by S. pneumoniae meningitis.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
CSF specimens from all patients were examined at admission, during therapy and after 10 days of treatment (usually at the end of the antibiotic course). Leucocyte count, WBC differential count, lactates, glucose and proteins were determined on all CSF specimens. CSF samples were routinely cultured. In some cases, CSF specimens were immediately frozen and held at 80°C pending testing for IL-8 and IL-10. A set of blood cultures was performed at enrolment, and the Simplified Acute Physiology Score (SAPS II) was determined for all patients.7 Renal and liver function tests were performed on admission and on at least every alternate day thereafter; complete blood and WBC differential counts were determined every 12 h. On admission, all patients underwent chest X-ray. Audiometric testing and, when indicated, CT scanning were also performed before discharging the patient. Neurological examination, complete blood counts, renal and liver function tests, audiometric testing and, in the event of abnormal findings, CT scanning, were repeated for each patient within 2 months of discharge.
Intravenous cefotaxime (3 g tid for patients weighing <70 kg and 4 g tid for patients >70 kg) was administered to all patients; they also received both subcutaneous recombinant G-CSF 300 µg/day (450 µg for patients weighing >70 kg) for 6 days and iv dexamethasone 16 mg/day for 3 days. The first dose of dexamethasone was administered 1015 min before starting cefotaxime. G-CSF was administered at enrolment to the study, usually with the first dose of cefotaxime. If the neutrophil count exceeded 40 x 109 cells/L within 6 days of commencement of therapy, G-CSF treatment was temporarily discontinued and re-administered at the same dosage only when the count fell to <40 x 109 cells/L.
IL-8 and IL-10 levels in CSF samples were determined with an ELISA assay (Bender MedSystems, Vienna, Austria) run according to the manufacturer's instructions (lower detection limits: IL-8, 11 pg/mL; IL-10, 2 pg/mL).
All results are presented as means and ranges (SAS statistical package, SAS Institute, Cary, NC, USA)
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients displayed an uneventful course; coma resolved in 2472 h and fever subsided after 3.0 ± 1.5 days (range: 25 days). All CSF cultures performed 2448 h after the establishment of therapy were sterile. Recovery was achieved without evident neurological sequelae in all but one case (bilateral hearing deficit)
G-CSF was administered for 4.5 ± 1.2 days (range: 36 days). The neutrophil counts were as follows: at recruitment, neutrophils ranged from 10 x 109 to 25 x 109 cells/L (global mean 18.7 x 109 ± 8.8 x 109 cells/L); the highest count found in a single patient during G-CSF therapy ranged from 25 x 109 to 50 x 109 cells/L (global mean: 35.6 x 109 ± 7.8 x 109 cells/L).
The Table shows the progressive improvement of the indices of inflammation in the CSF during the course of treatment. The most rapid improvement was seen in glucose concentration, which generally attained values within the normal range within the first 2448 h of therapy. The high CSF levels of both IL-10 and IL-8 (>1100 pg/mL) found on admission declined progressively during treatment (Table).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is difficult to hypothesize the mechanism by which G-CSF acts in pneumococcal meningitis. According to some authors, however, a complex range of causes (including a decreased production of IL-8, an impaired mobility of neutrophils toward a chemotactic gradient, a significant reduction of bacterial concentration and an increase in bacterial killing) may explain the attenuation of the inflammatory response achieved by G-CSF administration in experimental pneumococcal meningitis.5
In conclusion, we think that the safety and efficacy displayed in this pilot study by G-CSF justifies further randomized controlled clinical trials aimed at defining precisely its therapeutic role in S. pneumoniae meningitis.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Daifuku, R., Andresen, J. & Morstyn, G. (1993). Recombinant methionyl human granulocyte colony-stimulating factor for the prevention and treatment of non-neutropenic infectious diseases. Journal of Antimicrobial Chemotherapy 32, Suppl. A, 917.[ISI][Medline]
3 . Nelson, S. (1994). Role of granulocyte colony-stimulating factor in the immune response to acute bacterial infection in the non-neutropenic host: an overview. Clinical Infectious Diseases 18, Suppl. 2, S197204.[ISI][Medline]
4
.
Hartung, T., Docke, W. D., Gantner, F., Krieger, G., Sauer, A., Stevens, P. et al. (1995). Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood 85, 24829.
5
.
Østergaard, C., Benfield, T., Gesser, B., Kharazmi, A., Frimodt-Møller, N., Espersen, F. et al. (1999). Pretreatment with granulocyte colony-stimulating factor attenuates the inflammatory response but not the bacterial load in cerebrospinal fluid during experimental pneumococcal meningitis in rabbits. Infection and Immunity 67, 34306.
6 . Hartung, T. (1998). Anti-inflammatory effects of granulocyte colony-stimulating factor. Current Opinion in Hematology 5, 2215.[Medline]
7 . Le Gall, J. R., Lemeshow, S. & Saulnier, F. (1993). A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. Journal of the American Medical Association 270, 295763.[Abstract]
8 . Schmidt, H., Stuertz, K., Bruck, W., Chen, V., Stringaris, A. K., Fischer, F. R. et al. (1999). Intravenous granulocyte colony-stimulating factor increases the release of tumour necrosis factor and interleukin-1beta into the cerebrospinal fluid, but does not inhibit the growth of Streptococcus pneumoniae in experimental meningitis. Scandinavian Journal of Immunology 49, 4816.[ISI][Medline]
Received 26 January 2000; returned 27 April 2000; revised 6 June 2000; accepted 24 July 2000