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

Prognostic Values of Tumor Necrosis Factor/Cachectin, Interleukin-l, Interferon-α, and Interferon-γ in the Serum of Patients with Septic Shock

Serum concentrations of immunoreactive tumor necrosis factor/cachectin (TNF), interleukin-1β (IL-1β), interferon-γ (IFNγ, and interferon-α (IFNα) were prospectively measured in 70 patients with septic shock to determine their evolution and prognostic values. In a univariate analysis, levels of TNF (P = .002) and IL-1β (P = .05) were associated with the patient's outcome, but not IFNα (P = .15) and IFNγ (P = .26). In contrast, in a stepwise logistic regression analysis, the severity of the underlying disease (P = .01), the age of the patient (P = .02), the documentation of infection (nonbacteremic infections vs. bacteremias, P = .03), the urine output (P = .04), and the arterial pH (P = .05) contributed more significantly to prediction of patient outcome than the serum levels of TNF (P = .07). After 10 days, the median concentration of TNF was undetectable <100 pg/ml) in the survivors, whereas it remained elevated (305 pg/ml, P = .002) in the nonsurvivors. Thus, in patients with septic shock due to various gram-negative bacteria, other parameters than the absolute serum concentration of immunoreactive TNF contributed significantly to the prediction of outcom

New Pertussis Vaccination Strategies beyond Infancy: Recommendations by the Global Pertussis Initiative

Background. The Global Pertussis Initiative, an expert scientific forum, was established to address the ongoing problems associated with pertussis disease worldwide. Methods. The group analyzed pertussis disease trends, developed recommendations to improve disease control through expanded vaccination strategies, and proposed solutions to barriers to implementation and support of research activities. Results. Bordetella pertussis infection is endemic and continues to be a serious problem among unvaccinated or incompletely vaccinated infants. In addition, the reported incidence of pertussis disease is increasing in adolescents and adults, who not only experience a considerable health burden themselves but also infect vulnerable infants. Conclusions. Current vaccination strategies need to be reinforced. Expanded vaccination should include adding booster doses to existing childhood schedules (preschool or adolescent) and booster doses for those specific adult subgroups that have the highest risk of transmitting B. pertussis infection to infants (i.e., new parents, other contacts of newborns, and health care workers). More epidemiological studies and studies of disease transmission and the cost-effectiveness of vaccination would be valuable, and surveillance, diagnostic improvements, and educational campaigns are needed for implementation. However, as a prelude to universal adult vaccination, immediate universal adolescent vaccination should be instituted in countries in which it is economically feasibl

A Large Outbreak of Legionnaires’ Disease at a Flower Show, the Netherlands, 1999

In 1999, an outbreak of Legionnaires’ disease affected many visitors to a flower show in the Netherlands. To identify the source of the outbreak, we performed an environmental investigation, as well as a case-control study among visitors and a serologic cohort study among exhibitors to measure exposure to possible sources. Of 77,061 visitors, 188 became ill (133 confirmed and 55 probable cases), for an attack rate of 0.23% for visitors and 0.61% for exhibitors. Two whirlpool spas in halls 3 and 4 of the exhibition and a sprinkler in hall 8 were culture positive for Legionella pneumophila. One of three genotypes found in both whirlpool spas was identical to the isolates from 28 of 29 culture-positive patients. Persons who paused at the whirlpool spa in hall 3 were at increased risk for becoming ill. This study illustrates that whirlpool spas may be an important health hazard if disinfection fails

Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs

The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator's Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug's mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (C max) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by C max. Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies

Cost-Effectiveness of Adolescent Pertussis Vaccination for The Netherlands: Using an Individual-Based Dynamic Model

BACKGROUND: Despite widespread immunization programs, a clear increase in pertussis incidence is apparent in many developed countries during the last decades. Consequently, additional immunization strategies are considered to reduce the burden of disease. The aim of this study is to design an individual-based stochastic dynamic framework to model pertussis transmission in the population in order to predict the epidemiologic and economic consequences of the implementation of universal booster vaccination programs. Using this framework, we estimate the cost-effectiveness of universal adolescent pertussis booster vaccination at the age of 12 years in the Netherlands. METHODS/PRINCIPAL FINDINGS: We designed a discrete event simulation (DES) model to predict the epidemiological and economic consequences of implementing universal adolescent booster vaccination. We used national age-specific notification data over the period 1996-2000--corrected for underreporting--to calibrate the model assuming a steady state situation. Subsequently, booster vaccination was introduced. Input parameters of the model were derived from literature, national data sources (e.g. costing data, incidence and hospitalization data) and expert opinions. As there is no consensus on the duration of immunity acquired by natural infection, we considered two scenarios for this duration of protection (i.e. 8 and 15 years). In both scenarios, total pertussis incidence decreased as a result of adolescent vaccination. From a societal perspective, the cost-effectiveness was estimated at €4418/QALY (range: 3205-6364 € per QALY) and €6371/QALY (range: 4139-9549 € per QALY) for the 8- and 15-year protection scenarios, respectively. Sensitivity analyses revealed that the outcomes are most sensitive to the quality of life weights used for pertussis disease. CONCLUSIONS/SIGNIFICANCE: To our knowledge we designed the first individual-based dynamic framework to model pertussis transmission in the population. This study indicates that adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands. The model is suited to investigate further pertussis booster vaccination strategies

Sensitivity of three serum antibody tests in a large outbreak of Legionnaires' disease in the Netherlands.

In 1999, an outbreak involving 188 patients with Legionnaires' disease (LD) occurred at a flower show in the Netherlands. This large outbreak provided the opportunity to evaluate serum antibody tests to assay anti-Legionella pneumophila, since limited data are available on the sensitivity of these tests. The sensitivities of an indirect serotype 1-6 immunofluorescence antibody test (IFAT), a rapid micro-agglutination test (RMAT) IgM serotype 1 antibody assay, and an ELISA to detect IgM and IgG serotype 1-7 antibodies, were evaluated using serum samples from LD patients related to the 1999 outbreak. Sensitivity was calculated using positive culture and/or a positive urinary antigen test as the gold standard in outbreak-related patients with radiographically confirmed pneumonia who fulfilled the epidemiological criteria. The IFAT, RMAT and ELISA showed sensitivities of 61, 44 and 64%, respectively. The sensitivity of the three tests combined was 67%. In epidemic situations, however, high standing titres may be included in the laboratory evidence of LD cases. In the study population, high standing titres were found in 16% of cases. If the presence of high standing antibody titres was added to the criteria of a positive test, the sensitivities of IFAT, RMAT and ELISA were 86, 48 and 75%, respectively. The sensitivity was 91% for all tests combined. The higher sensitivity for the combined use of tests is offset by a reduction in specificity to 97.6%. The results of this study indicate that using a combination of serologic tests in pneumonia patients suspected to have LD does not substantially improve sensitivity. The results suggest that in the microbiological diagnosis of LD, both IFAT and ELISA are reasonably sensitive assays. In an epidemic situation, both tests are highly sensitive, the IFAT more so than the ELISA

The incidence of Bordetella pertussis infections estimated in the population from a combination of serological surveys.

OBJECTIVES: Bordetella pertussis circulates even in highly vaccinated populations. There is a considerable amount of infection in adults. For designing more effective vaccination schedules it is important to quantify the age-dependent relation between the number of notified cases and the number of infections. METHODS: We used a statistical relationship between the time since infection and the IgG antibody titers against pertussis toxin, derived from a longitudinal data set, to estimate time since infection for all individuals in a cross-sectional population-based study (1995-1996) based on their titers. Age-specific incidence of infection with B. pertussis was calculated and compared with the age-distribution of notified cases of pertussis in 1994-1996. RESULTS: Estimated incidence of infection was 6.6% per year for 3-79-year olds, annual incidence of notified cases 0.01%. Estimated age-specific incidence of infection was lowest for 3-4-year olds (3.3%) and increased gradually up to the age of 20-24 years (10.8%). The number of notified cases was highest for 3-9-year olds. CONCLUSIONS: In the Dutch population B. pertussis infections occur more frequently and in elder age-categories then suggested by notifications. Mathematical modeling could explore what booster vaccination strategies are most effective in reducing severe disease among not (completely) vaccinated infants