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A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).

The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study. To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF. After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar. AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).

•FHbp expression is not restricted to serogroup B strains of N. meningitidis.•Protection against non-MenB strains by antibodies elicited by the MenB-FHbp vaccine was studied.•hSBA response rate after dose 3 was ≥83% for MenC/W/Y/X and 28% for MenA strains.•MenB-FHbp may protect against meningococcal disease regardless of serogroup. MenB-FHbp (Trumenba®; bivalent rLP2086) is a meningococcal serogroup B vaccine containing 2 variants of the recombinant lipidated factor H binding protein (FHbp) antigen. The expression of FHbp, an outer membrane protein, is not restricted to serogroup B strains of Neisseria meningitidis (MenB). This study investigated whether antibodies elicited by MenB-FHbp vaccination also protect against non-MenB strains. Immunological responses were assessed in serum bactericidal assays using human complement (hSBAs) with non-MenB disease-causing test strains from Europe, Africa, and the United States. Importantly, FHbp variant distribution varies among meningococcal serogroups; therefore, strains that code for serogroup-specific prevalent variants (ie, representative of the 2 antigenically distinct FHbp subfamilies, designated subfamily A and subfamily B) and with moderate levels of FHbp surface expression were selected for testing by hSBA. After 2 or 3 doses of MenB-FHbp, 53% to 100% of individuals had bactericidal responses (hSBA titers ≥ 1:8) against meningococcal serogroup C, W, Y, and X strains, and 20% to 28% had bactericidal responses against serogroup A strains; in fact, these bactericidal responses elicited by MenB-FHbp antibodies against non-MenB strains, including strains associated with emerging disease, were greater than the serological correlate of protection for meningococcal disease (ie, hSBA titers ≥ 1:4). This is in comparison to a quadrivalent polysaccharide conjugate vaccine, MCV4 (Menactra®, targeting meningococcal serogroups A, C, W, and Y), which elicited bactericidal responses of 90% to 97% against the serogroup A, C, W, and Y strains and had no activity against serogroup X. Together, these results provide clinical evidence that MenB-FHbp may protect against meningococcal disease regardless of serogroup.

Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to Neisseria meningitidis infections. The two mainstays to reduce the risk of infection are vaccination and antibiotic prophylaxis. In this retrospective study, serologic response was analyzed after vaccination with a meningococcal vaccine in 23 PNH patients (median age 36 years; range 25 - 88 years; 15 males, 8 females) by measuring serum bactericidal assay (SBA) using rabbit complement (rSBA) titers against meningococcal serogroups A, C, W, and Y. Serologic protection was defined by an rSBA titer ≥1:8. Forty-three percent (10/23) were vaccinated more than once due to chronic eculizumab treatment. Overall serologic response for the meningococcal serogroups was A: 78% (18/23), C: 87% (20/23), W: 48% (11/23), and Y: 70% (16/23). No meningococcal infections have been observed. As immunological response to vaccines varies, the use of serologic response analyses is warranted. Re-vaccination with a tetravalent conjugate vaccine under eculizumab therapy every 3 years is essential or should be based on response rates. If meningococcal infection is suspected, standby therapy with ciprofloxacin and immediate medical evaluation are recommended. The novel vaccines covering serogroup B may even further reduce the risk for infection.

Group W135 polysaccharide vaccines were licensed without efficacy trials using the serum bactericidal antibody (SBA) assay as a surrogate of protection. Standardization of group A and C SBA assays has been largely achieved. However, no such efforts have been focussed on W135. Although W135 strains have been recommended by WHO for polysaccharide production, no such recommendation are in place for use in immunoassays. Strain characterization is of importance as W135 strains may possess either an O-acetylated or de- O-acetylated polysaccharide capsule and the human immune response can vary according to the O-acetylation of the target antigen. Following conjugate or polysaccharide vaccination, few data are published with respect to complement source comparisons although both human and baby rabbit sera have been utilized with similar end points. In studies of natural immunity subcapsular antigens are primarily the target antigens and thus strain choice for use in the SBA assay is important. International standardization of assays is necessary to allow for comparisons of data over time and place.

The immunogenicity and safety of a meningococcal trivalent A/C/W135 polysaccharide vaccine was compared with that of a tetravalent A/C/Y/W135 polysaccharide vaccine in a randomised, double blind trial. The study included 360 adults, who received either a trivalent or tetravalent polysaccharide meningococcal vaccine. Antibody responses were determined by serum bactericidal antibody (rSBA) assays prior to vaccination and on day 28 and month 11 after vaccination. The percentage of participants in the trivalent vaccine group who had rSBA titres ≥8 on day 28 post-vaccination against serogroups A, C and W135 meningococci were 99, 98 and 91%, respectively. The corresponding figures in the tetravalent vaccine group were 99, 99 and 90%. The percentage of participants with various cut off levels of rSBA against serogroups A, W135 and C meningococci on day 28 and 11-month post-vaccination and the incidence of adverse events did not differ significantly between the two groups.

Brucellosis is a zoonotic disease caused by Brucella spp. and is still a serious problem of public health for some regions around the world such as the Mediterranean Sea, Middle East, Latin America, and Asia. Citation: Libyan J Med 2013, 8: 20417 - http://dx.doi.org/10.3402/ljm.v8i0.20417

Although pooled human serum diluent is advocated in the serum dilution test, its use may compensate for protein binding defects in patients and yield nonrepresentative titers. To test this hypothesis, comparison was made of serum ultrafiltrate (molecular weight cutoff ⩽30,000) serially diluted into either pooled serum ultrafiltrate or Mueller-Hinton broth with patient serum samples diluted into pooled human serum in 111 assays from 55 patients and 6 volunteers. Of 111 bactericidal titers in ultrafiltrate and/or Mueller-Hinton broth, 101 were within a single twofold dilution of titers in pooled human serum. Nine of 10 discordant titers involved highly bound drugs and were usually higher in ultrafiltrate than in pooled human serum. In seven additional volunteers with renal failure, titers in ultrafiltrate and in each volunteer's serum were higher than those diluted in pooled human serum (P = .002). Recommended methods using pooled serum diluent may not accurately predict actual bactericidal titers in patients with abnormal protein binding.

•All MenB disease isolates from England and Wales, 2007–2008, were analyzed in MATS.•Stratified proportional sampling identified a representative subset for hSBA testing.•hSBA was performed with sera from 4CMenB-vaccinated infants and adolescents.•MATS predicted hSBA results with good accuracy and positive predictive power.•MATS underestimates 4CMenB vaccine coverage for a strain panel representative of IMD. 4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency. Assessment of 4CMenB strain coverage in specific epidemiologic settings is of primary importance to predict vaccination impact on the burden of disease. The Meningococcal Antigen Typing System (MATS) was developed to predict 4CMenB strain coverage, using serum bactericidal antibody assay with human complement (hSBA) data from a diverse panel of strains not representative of any specific epidemiology. To experimentally validate the accuracy of MATS-based predictions against strains representative of a specific epidemiologic setting. We used a stratified sampling method to identify a representative sample from all MenB disease isolates collected from England and Wales in 2007–2008, tested the strains in the hSBA assay with pooled sera from infant and adolescent vaccinees, and compared these results with MATS. MATS predictions and hSBA results were significantly associated (P=0.022). MATS predicted coverage of 70% (95% CI, 55–85%) was largely confirmed by 88% killing in the hSBA (95% CI, 72–95%). MATS had 78% accuracy and 96% positive predictive value against hSBA. MATS is a conservative predictor of strain coverage by the 4CMenB vaccine in infants and adolescents.