Macrophage Migration Inhibitory Factor: Gene Polymorphisms and Susceptibility to Inflammatory Diseases

The cytokine macrophage migration inhibitory factor (MIF) is a constitutive element of the host antimicrobial defenses and stress response that promotes proinflammatory function of the innate and acquired immune systems. MIF plays an important role in the pathogenesis of acute and chronic inflammatory or autoimmune disorders, such as sepsis, acute respiratory distress syndrome, asthma, rheumatoid arthritis, and inflammatory bowel diseases. Polymorphisms of the humanMIF gene (that is, guanine-to-cytosine transition at position -173 or CATT-tetranucleotide repeat at position -794) have been associated with increased susceptibility to or severity of juvenile idiopathic and adult rheumatoid arthritis, ulcerative colitis, atopy, or sarcoidosis. Whether theseMIF polymorphisms affect the susceptibility to and outcome of sepsis has not yet been examined. Analyses ofMIF genotypes in patients with sepsis may help to classify patients into risk categories and to identify those patients who may benefit from anti-MIF therapeutic strategie

Clinical Trials of Antifungal Prophylaxis among Patients Undergoing Surgery

Invasive mycoses have emerged as a major cause of morbidity and mortality. Epidemiological studies have shown that surgery services have the highest rate of Candida infections in the hospital. In addition to classical risk factors, heavy Candida colonization, recurrent gastrointestinal perforations, and acute pancreatitis are frequently associated with invasive candidiasis. Because prompt initiation of antifungal therapy is critical for cure but difficult to accomplish, prevention of fungal infections may play an important role in this clinical setting; however, few prophylactic or preemptive studies have been done to date. The choice, route of administration, and dose of the antifungal and comparator regimens and the use of clinically relevant and robust study end points are critical for the trial design. Various criteria have been used to identify patients at risk of candidiasis: surgical condition, presence of multiple risk factors, colonization indexes, or expected length of stay in the intensive care unit. Some are not selective enough, and others are time consuming and expensive. Rigorous selection of high-risk patients is crucial to optimize the risk-benefit ratio of preventive antifungal strategies. The aim is to maximize chances of reducing morbidity and mortality while minimizing treatment costs, exposure of low-risk patients to adverse events, and emergence of resistant fungal strain

Macrophage Migration Inhibitory Factor and Host Innate Immune Defenses against Bacterial Sepsis

Macrophages are essential effector cells of innate immunity that play a pivotal role in the recognition and elimination of invasive microorganisms. Mediators released by activated macrophages orchestrate innate and adaptive immune host responses. The cytokine macrophage migration inhibitory factor (MIF) is an integral mediator of the innate immune system. Monocytes and macrophages constitutively express large amounts of MIF, which is rapidly released after exposure to bacterial toxins and cytokines. MIF exerts potent proinflammatory activities and is an important cytokine of septic shock. Recent investigations of the mechanisms by which MIF regulates innate immune responses to endotoxin and gram-negative bacteria indicate that MIF acts by modulating the expression of Toll-like receptor 4, the signal-transducing molecule of the lipopolysaccharide receptor complex. Given its role in innate immune responses to bacterial infections, MIF is a novel target for therapeutic intervention in patients with septic shoc

A European Organization for Research and Treatment of Cancer-International Antimicrobial Therapy Group Study of Secondary Infections in Febrile, Neutropenic Patients with Cancer

Background. Neutropenic patients with cancer may develop several episodes of fever and infection during chemotherapy-induced myeloaplasia. Methods. To identify risk factors for secondary infectious episodes among patients who responded to initial antibiotic therapy, we retrospectively analyzed 2 consecutive, prospective, randomized clinical trials performed by the International Antimicrobial Therapy Group of the European Organization for Research and Treatment of Cancer during 1991-1994. Results. Of 1720 patients with their first episode of febrile neutropenia, 836 responded to the initial antibiotic regimen and were therefore suitable for our analysis. A secondary infection was observed in 129 (15%) of 836 patients that occurred at a median of 10 days (range, 1-28 days) after the onset of the primary febrile episode. Factors at both baseline and day 4 were analyzed. Age of >16 years (odds ratio [OR], 3.46; P < .001), acute leukemia in first induction (OR, 3.17; P < .001), presence of intravenous line (OR, 1.88; P = .04), severe neutropenia (defined as an absolute granulocyte count of <100 cells/mm3) on day 4 (OR, 2.72; P < .001), and type of documentation of the primary episode (i.e., microbiologically documented cause or unexplained fever; OR, 2.56; P = .001) were found to be risk factors for secondary infection. The risk of death was higher among patients who developed a secondary infectious episode than among those who did not (5.4% vs. 1.4%; P < .01). Conclusions. The clinical parameters described above may help to identify neutropenic patients at risk of developing secondary infectio

Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes

Background. Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. Methods. This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. Results. A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from ⩽1 mg/L (the minimum inhibitory concentration at which, for most fungal pathogens, 90% of isolates are susceptible) in 25% of cases to >5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels ⩽1 mg/L (6 [46%] of 13 patients, including 5 patients with aspergillosis, 4 of whom were treated orally with a median dosage of 6 mg/kg per day) than in those with voriconazole levels >1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels ⩽5.5 mg/L presented with neurological toxicity (P=.002). Comedication with omeprazole possibly contributed to voriconazole accumulation in 4 patients. In all cases, discontinuation of therapy resulted in prompt and complete neurological recovery. Conclusions. Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycose

Treatment of Gram-Negative Septic Shock with Human IgG Antibody to Escherichia coli J5: A Prospective, Double-Blind, Randomized Trial

In a randomized, double-blind, multicenter trial we compared the efficacy of a preparation of human IgG antibody to Escherichia coli 15 (J5-IVIG) with that of a standard IgG preparation (IVIG) for the treatment of gram-negative septic shock. At study entry, patients received a single intravenous dose of 200 mg/kg of body weight (maximal dose, 12 g) of either J5-IVIG or IVIG. Of the 100 patients randomized, 71 (30 receiving J5-IVIG and 41 receiving IVIG) had a documented gram-negative infection. Mortality from gram-negative septic shock was 50% (15 of 30) in J5-IVIG recipients and 49% (20 of 41) in IVIG recipients. In addition, treatment with J5-IVIG did not reduce the number of systemic complications of shock and did not delay the occurrence of death due to septic shock. Thus we conclude that 15-IVIG was not superior to IVIG in reducing mortality or in reversing gram-negative septic shoc