A randomized, placebo-controlled study of the use of filgrastim in non neutropenic patients with nosocomial pneumonia.

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.

Hypercortisolism caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid therapy. 2 case reports and a review of the literature.

Recent in vitro and in vivo studies have shown a potent inhibition of cytochrome P450 CYP3A4 through human immune deficiency virus (HIV) protease inhibitors (PIs). The PI ritonavir is described as the most potent compound within these CYP3A4 inhibitors. We present 2 cases who developed the sequelae of glucocorticoid excess following ritonavir therapy and inhalative glucocorticoid treatment: A 60-year-old HIV positive man developed the typical symptoms of Cushing's syndrome and a 52-year-old HIV positive man developed severe osteoporosis.

Increase of anti-inflammatory cytokines in patients with esophageal cancer after perioperative treatment with G-CSF.

Granulocyte colony-stimulating factor (G-CSF) has been shown to effectively stimulate granulopoiesis, in both neutropenic and in non-neutropenic patients. Recently, other effects of G-CSF on the immune system have attracted interest in treating non-neutropenic patients with a high risk of severe infection. In this phase II trial, we measured the effects of G-CSF on the serum cytokine levels in patients with esophageal cancer undergoing esophagectomy. Twenty subsequent patients (study group, 19 evaluable) received G-CSF (rhG-CSF, Filgrastim) at standard doses (300 microg or 480 microg) subcutaneously 2 days before and up to 7 days after surgery. G-CSF was well tolerated. Leukocytes increased from 7600/microl at study entry (day -2) to a maximum of 45 100/microl (day 6). In the study patients, we found a highly significant (P<0.001) postoperative increase of G-CSF, IL-1ra, sTNFRp55 and sTNFRp75 as compared with the baseline level. In contrast, IL-8 levels were decreased by a factor of 6.8; there were no changes in the very low TNF-alpha levels. The comparison of the study group with a control group of 21 cancer patients undergoing major surgery who were not treated with G-CSF showed significant differences in the serum levels of G-CSF, sTNFRp55, sTNFRp75, and IL-1ra, respectively. There was no infection in the study group up to 10 days after surgery as compared with 29.9% in a historical control group (P=0.008). Thus, the induction of anti-inflammatory cytokines and the downregulation of pro-inflammatory cytokines by G-CSF might be a promising adjuvant treatment of infectious complications in patients undergoing esophagectomy.

Suppressed neutrophil function as a risk factor for severe infection after cytotoxic chemotherapy in patients with acute nonlymphocytic leukemia.

Severe infections are a major problem in patients suffering from acute nonlymphocytic leukemia (ANLL) undergoing myeloablative chemotherapy. Possible factors leading to infectious complications in these patients are suppressed immune defense mechanisms existing prior to therapy, including those involving the neutrophil granulocyte department. In this study we investigated whether neutrophil function as measured by oxidative burst and phagocytosis before the start of treatment correlates with the severity of infection after therapy. Forty-four patients were included, 27 men and 17 women. Their median age was 46 years (range 20-70 years). According to the development of infectious complications the patients were assigned retrospectively to group 1 (no or only mild infections, n = 29) or to group 2 (severe infection or death due to infection, n = 15). The phagocytic activity was significantly reduced in group 2 as compared with group 1 [113.7+/-13.7 (SEM) vs 170.0+/-19.2, mean channel fluorescence; p =0.04]. In contrast, the oxidative burst as measured by FMLP stimulation was pronounced but not significantly enhanced in group 2 (24.8+/-6.1 vs 14.5+/-3.4, mean channel fluorescence). In conclusion, patients with severe infections after chemotherapy might already have preactivated neutrophils with suppressed function prior to treatment. Thus, evaluating function parameters could help to estimate the individual risk of infection for a patient with ANLL.

The short synacthen test in the evaluation of adrenal masses in patients with malignancies.

Adrenal computed tomography with determination of Hounsfield units has proved to be sensitive and specific in the differential diagnosis of benign vs. malign adrenal lesions. On the other hand, computed tomography may fail in patients with small adrenal masses of less than 1.0 cm. However, especially in patients with diagnosed malignancies and small adrenal masses which were discovered during the diagnostic staging procedure it is important to determine the origin of the adrenal lesion. An augmented increase in 17alpha-hydroxyprogesterone (17-OHP) levels following corticotropin (1-24) stimulation has been noted in incidentally discovered adrenal masses by several groups. Therefore, we tested the hypothesis that elevated ACTH-stimulated 17-OHP (delta > 2.6 ng/mL) can predict primary adrenal lesions. We evaluated the use of the ACTH test in 85 patients with adrenocortical tumors and in 16 patients who underwent abdominal imaging for staging of a carcinoma other than of adrenal origin. We found an augmented 17-OHP response in 70 (>82%) of patients with known adrenocortical tumors and in 10 (>62%) of patients with adrenal masses and diagnosed malignancies. Results in the latter group have been confirmed in histological studies after operation or puncture. In the group of patients who suffered from a solid malignant tumor and had an adrenal mass, it was thus possible to separate primary from secondary adrenal lesions in 100%. In the group of patients with known adrenocortical tumors, it failed to differentiate between benign and malignant adrenocortical lesion in one case. We therefore think that the ACTH test is a valuable biochemical tool to distinguish primary adrenal tumors from adrenal metastasis derived from other malignancies.

Perioperative treatment with filgrastim stimulates granulocyte function and reduces infectious complications after esophagectomy.

We investigated the effects of recombinant G-CSF (Filgrastim) on the function of neutrophils and the rate of infectious complications in an open-label, nonrandomized study of patients with esophageal cancer undergoing esophagectomy. In this single-center phase-II trial 20 sequential patients (19 evaluable) received Filgrastim at standard doses (300 microg or 480 microg) subcutaneously for 2 days prior to and up to 7 days after surgery. The phagocytotic activity of neutrophils and the oxidative burst in the study group and in an experimental control group (n=27) were measured on days -2, 2, and 10. Neutrophil function was enhanced in the Filgrastim-treated group by factor 1.2 for phagocytosis (p=0.016) and 1.4 for oxidative burst (p)=0.154). Leukocyte counts increased from 7.6 x 10(9)/l (day -2) to a maximum of 45 x 10(9)/l on day 6. No infection was reported in the study group (mean age 59.7 years; 13 men, seven women) up to 10 days after surgery. In contrast, 23 patients (29.9%) in a historical control group (mean age 56 years; 67 men, ten women) treated at the same center developed infections within the first 10 days (p = 0.008). In addition, no postoperative deaths occurred in the study group, compared with 9.1% in the group of historical controls. Thus, in this study, administration of Filgrastim stimulated neutrophil function in patients undergoing esophagectomy, and it might be effective in reducing infectious complications related to the surgical procedure.