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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

OBJECTIVE: To evaluate the efficacy of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the treatment of early-onset neonatal sepsis among premature infants.MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled trial was performed among forty-four preterm neonates who had "clinical diagnosis" of early-onset sepsis. The treatment group (n=22) received 10 micro g/kg/d of rhG-CSF, IV once daily for three consecutive days, and the placebo group (n=22) received the same volume of a visually-indistinguishable vehicle. Prior to the first dose, and prior to the second and third doses, and again 10 days after the first dose, we measured tumor necrosis factor-a, interleukin-6, granulocyte-macrophagocyte colony-stimulating factor, G-CSF, leukocyte count, absolute neutrophil count, immature/total neutrophil ratio, platelet count, and hemoglobin concentration. A bone marrow aspiration was performed seven days after the first dose, and both the neutrophil storage pool (NSP) percent and the NSP/NPP (neutrophil proliferative pool) ratios were tabulated.RESULTS: The treatment and placebo groups were of similar gestational age (29-/+ 3 vs 31-/+ 3 weeks) and birth weight (1376 -/+ 491 vs 1404 -/+ 508 grams). They had similar Apgar scores and 24 hour SNAP scores. No deaths occurred during the first week of life among the treatment group while three deaths occurred in the placebo group. RhG-CSF treatment did not alter the serum concentrations of the cytokines measured (except for G-CSF). Serum G-CSF levels, blood leukocyte counts, absolute neutrophil counts, NSP percentages, and NSP/NPP ratios were higher in the treatment group 24 hours and 72 hours after dosing. The occurrence of a subsequent infection over the two week period following dosing was significantly lower in the treatment group (n=2) than in the placebo group (n=9; p<0.02, RR 0.19 [0.05-0.78]). The overall mortality rate during the entire hospitalization was not different between treatment and placebo groups.CONCLUSIONS: Administration of rhG-CSF to premature neonates with the clinical diagnosis of early-onset sepsis was associated with lower incidence of nosocomial infection over the ensuing three weeks period, but it did not change the overall mortality rate.
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PMID:[Assessing the efficacy of the recombinant human granulocyte colony-stimulating factor "rhG-CSF" in the treatment of early neonatal sepsis in premature neonates] 1464 69

Microvascular endothelial cells (mECs) circulate at higher numbers in patients with severe sepsis and hemophagocytic syndromes. Although these blood mECs might stem from damaged microvasculature, they are perfectly viable and lead to the establishment of cell lines. Such mECs were cultured in low-dose human serum pools (0.5%) and MEM-alpha medium. Antigenic profiling revealed the expression of CD36, factor VIIIa, CD95-ligand, and CD44, but also CD146. We studied the antioxidative effect of the hematopoietic growth factor G-CSF(1) after in vitro stimulation with LPS from E. coli 0111:B4; the growth factor appeared to exhibit a protective effect on organ function in patients with SIRS. mECs were stimulated with 1 micro g/mL of LPS for 24 h and 48 h with and without G-CSF (3x10(3) U/mL) preincubation. After 24 h, supernatants of the stimulated mEC were tested for IL-8 by ELISA, and cells were tested for hemoxygenase-1 (HO-1, Hsp32) by immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene). Stimulation with LPS upregulated IL-8 by a factor of 2 to 10 in mEC. Preincubation with G-CSF markedly downregulated the LPS-induced IL-8 secretion (20-50%), but IL-6 production was not affected. Upon 48 h of LPS stimulation, mECs developed massive signs of apoptosis and concomitant caspase 3 activation. Caspase 3 activity induced by LPS (24 h) or by staurosporin (6 h) was found to be dramatically downregulated by the G-CSF preincubation protocol.
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PMID:G-CSF modulates LPS-induced apoptosis and IL-8 in human microvascular endothelial cells: involvement of calcium signaling. 1503 98

In addition to the ability of G-CSF to stimulate the maturation and function of granulocytes, experimental and clinical evidence suggests that induction of leukemia cell differentiation may also be possible. This critical effect has received little attention with respect to its potential therapeutic application in myeloid malignancies. We describe the clinical course of a 62-year-old patient with atypical AML1/ETO-positive AML-M2 who repeatedly displayed a marked, dose-dependent response to G-CSF. He was originally investigated for neutropenia, but declined chemotherapy at diagnosis of AML (40% bone marrow blasts) and commenced G-CSF therapy when a life-threatening chest infection occurred. The bone marrow infiltration regressed and his blood counts normalized after 20 days. A slow relapse occurred over the next 3 months but a second hematological remission was achieved upon reintroduction of G-CSF. He remained well and free of transfusions for 2.5 years, receiving only maintenance G-CSF. Despite the presence of the AML1/ETO transcript, his leukemic blasts always failed to demonstrate the typical morphological, immunological and cytogenetic characteristics of AML1/ETO-AML of M2 subtype. He eventually developed resistance to G-CSF and died from sepsis after cytotoxic therapy. In selected AML cases differentiation therapy with growth factors may emerge as a useful antileukemic strategy, either alone or as an adjunct to established treatment modalities.
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PMID:Dose dependent long-term in vivo remission of AML1/ETO positive acute myeloid leukemia with G-CSF. 1520 65

Bacterial factors stimulate the release of tissue factor as well as proinflammatory and antiinflammatory cytokines. TNF augments inflammation, TNF and IFN-gamma induce coagulation, and IL-1beta induces coagulation and fibrinolysis. IL-8 augments synergistic inflammation and coagulation. IL-6 augments coagulation and inhibits fibrinolysis. IL-10 inhibits inflammatory process and inhibits fibrinolysis. IL-4, IL-13, and TGF-beta act for anticoagulation. Administration of IL-2, G-CSF or IFN-gamma has been reported to have side effect of induction of coagulation. IL-12 induces coagulation first and fibrinolysis later. On the other, tissue factor induces proinflammatory (except TNF) and antiinflammatory cytokines, and thrombin enhances inflammation. Patients who died of SIRS/sepsis have been complicated with hypercoagulopathy and impaired fibrinolysis correlated with increased IL-10 production. Inhibition of IL-10 production or administration of fiblynolitic agents may be useful. Recently, activated protein C (APC) which has antiinflammatory effect has been paid attention in the treatment of SIRS/sepsis.
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PMID:[Correlation between intravascular coagulation/fibrinolysis system and cytokines]. 1559 92

Pneumonia remains the number one cause of death from infectious diseases in Western Europe and the United States despite the introduction of potent broad-spectrum antibiotics. Granulocyte colony-stimulating factor is considered to improve host defense during infection and may be an effective adjunctive in the treatment of severe infections. We examined the efficacy of granulocyte colony-stimulating factor (r-metHUG-CSF, filgrastim) with regard to clinical response in non-neutropenic ICU patients with nosocomial pneumonia in a prospective, randomized, placebo-controlled trial. 28 patients with newly diagnosed nosocomial pneumonia were randomly assigned to receive 300-480 microg filgrastim or placebo subcutaneously for up to seven days. Study endpoints were death within 15 days, duration of antibiotic therapy and occurrence of serious adverse events (SAE). No significant differences were observed in respect of 15-day (filgrastim1/12 vs. placebo 2/16) or 30-day mortality (1/12 vs.4/16, p=0.355), and length of antibiotic treatment (13.5 vs.11.5 days, p=0.985). Sepsis developed in 1/12 patients in the filgrastim and 6/16 patients in the placebo group (p=0.184). None of the patients developed ARDS or any other SAE related to the study medication. Filgrastim is safe in non-neutropenic ICU patients with nosocomial pneumonia. A benefit of filgrastim with regard to clinical endpoints could not be observed, while there was a trend toward reduced sepsis rate.
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PMID:A randomized, placebo-controlled study of the use of filgrastim in non neutropenic patients with nosocomial pneumonia. 1573 51

The objective of this study was to examine the incidence and characteristics of Ara-C-related fever and the frequency and severity of infections after single-drug, high-dose Ara-C treatment (HDAC) in children treated for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). A retrospective review was performed of 169 courses of HDAC administered to 57 patients (age 1.8-17.8 years). Procalcitonin values (PCT) were analyzed in a subgroup of 16 patients. Fever during HDAC occurred in 113 of 169 (67%) cases. C-reactive protein (CRP) was elevated in the febrile patients (median 38 mg/L [range 3-150]). PCT was elevated (>0.5 ng/mL) during HDAC in 4 of the 16 evaluated patients. Corticosteroids could inhibit fever (P < 0.001). Myelosuppression after HDAC was prominent: 99% developed neutropenia (<0.5 x 10/L) and 92% thrombocytopenia (<25 x 10/L). An early lymphopenia (median 0.1 x 10/L [range 0.01-0.68]) was seen during the first week. G-CSF was used after 12 of the 169 HDAC courses. A febrile episode occurred after 93 of the 169 (55%) HDAC courses, with no need for intensive care and no deaths. The incidence of viridans streptococcal septicemia was 2 of the 169 cases. Ara-C fever is common, and evaluation with inflammation markers is complicated by the fact that HDAC can induce a moderate release of both CRP and PCT. Profound neutropenia and lymphopenia are causative factors for the high incidence of infections, but the risk of life-threatening complications after HDAC in children in remission of lymphoid malignancies is low, even without prophylactic use of colony-stimulating factors.
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PMID:Ara-C fever and infections after high-dose ara-C treatment in pediatric lymphoid malignancies. 1601 25

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection over the last decade but may have exacerbated the problem of post-transplant infections. Causes of early mortality include graft dysfunction and sepsis. Late mortality occurs mainly due to sepsis. An excessive inflammatory response followed with a dramatic paralysis of cell-mediated immunity has been documented in septic patients. In transplanted individuals the pathophysiological changes of the immune response are further complicated by immunosuppressive agents. This article will focus on the effect of immunosuppressive agents and sepsis on cell-mediated immune responses. Moreover, potentially promising immunomodulatory approaches, i.e. human activated protein C, immunomodulatory diets containing L-arginine and fish oil, selective cytokine blockade, platelet-activating factor receptor antagonist, LPS receptor CD14 blockade and G-CSF, for the treatment of immunodysfunction in septic patients will be outlined in this review article. Most of them, however, have not been tested in the clinical arena in transplanted patients. Thus, the main part of the article, immunomodulation during sepsis in organ transplanted children is quite speculative and based on immunomodulatory strategies in other non-transplanted septic patients.
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PMID:Immunomodulation during sepsis in organ transplanted children. 1620 9

The inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II associated with increased in vitro sensitivity of tumors to etoposide. Maximal synergy has been observed for the sequence of topotecan followed by etoposide. Carboplatin has clinical activity when combined with either of these two agents. These interactions were the pharmacologic rationale for topotecan p.o. days 1-5, carboplatin i.v. day 6, and etoposide p.o. days 6-10. Three successive dose levels were explored: (1) topotecan 2mg/day, carboplatin AUC 5, etoposide 150 mg/day; (2) topotecan 3mg/day, carboplatin AUC 5, etoposide 150 mg/day; and (3) topotecan 3mg/day, carboplatin AUC 5, etoposide 200mg/day. Filgrastim 5 microg/kg/day was injected s.c. days 11-18. Up to 6 cycles were administered every 21 days. Eligible patients had measurable or evaluable, extensive disease, small lung cell lung cancer, no prior chemotherapy, ECOG performance status 0-2, and adequate hematologic, renal, and hepatic function. Follow-up was weekly for CBC. Tumor response was assessed after 2 and 6 cycles. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: grade 3 or 4 non-hematologic toxicity other than nausea and vomiting, grade 4 neutropenia lasting more than 3 days, neutropenic fever or sepsis, grade 4 thrombocytopenia, or failure to recover neutrophils >or=1500/microl or platelets >or=100,000/microl by day 28. Ten patients were enrolled: median age 62 (range, 50-79); female/male 4/6; and performance status 0/1/2 in 2/7/1. Three patients each were treated on dose levels 1 and 2 without DLT. The first 2 patients entered on dose level 3 had no DLT. The third patient on dose level 3 developed grade 4 neutropenia lasting more than 3 days, neutropenic fever, and grade 4 thrombocytopenia on day 15 of cycle 1. The fourth patient on dose level 3 developed grade 4 thrombocytopenia on day 18 of cycle 1. One patient received only 1 cycle and was not evaluable for response. Seven patients completed 6 cycles: 1 had a complete response and 6 achieved a partial response. The third patient on dose level 3 received 2 cycles and had stable disease, but had to be removed from protocol treatment because of grade 4 neutropenia despite dose reduction in cycle 2. The fourth patient on dose level 3 achieved a partial response, but had to be removed from protocol therapy after cycle 5 because of recurrent grade 4 thrombocytopenia. In conclusion, neutropenia and thrombocytopenia were dose-limiting. The maximum tolerated dose (MTD) is topotecan 3mg/day p.o. days 1-5, carboplatin AUC 5i.v. day 6, and etoposide 150 mg/day p.o. days 6-10 with filgrastim.
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PMID:Phase I and pharmacologic study of sequential topotecan-carboplatin-etoposide in patients with extensive stage small cell lung cancer. 1704 3

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.
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PMID:Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. 1706 11

The five-part "Pointers in Practical Pharmacology" immunomodulation series has presented some of the agents researchers are investigating in hopes of finding the means to effectively prevent and treat infectious processes in neonates. The phosphodiesterase inhibitor pentoxifylline appears promising, but large, randomized, clinical trials are still lacking. So far, there is no clear evidence to support the use of G-CSF for either the prevention or the treatment of sepsis. The results of a large, randomized, clinical trial of G-CSF in the United Kingdom are pending. Although intravenous immunoglobulin (IVIG) therapy does not appear to be useful in the prevention of sepsis, its effectiveness in the treatment of sepsis is uncertain. It is hoped that the results of the International Neonatal Immunotherapy Study will provide definitive answers regarding treatment of sepsis with IVIG. The "conditionally essential" amino acid glutamine administered either enterally or parenterally does not make a difference in the rate of systemic infection or NEC in very low birth weight infants. Finally, probiotics appear promising as documented by at least two of the three randomized, clinical trials described here. As the search continues for agents to enhance the neonate's immune system and prevent and treat infectious diseases, remember that our best prevention tool is excellent and consistent hand hygiene.
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PMID:Immunomodulation, Part V: probiotics. 1728 88


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