Diabetes mellitus and the progression of non-alcoholic fatty liver disease to decompensated cirrhosis: a retrospective cohort study.

OBJECTIVE: To determine the incidence of decompensated cirrhosis and associated risk factors in people hospitalised with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with or without cirrhosis. DESIGN: Retrospective cohort study; analysis of linked Queensland Hospital Admitted Patient Data Collection, Queensland Registry of Births, Deaths and Marriages, and Queensland Cancer Register data. SETTING, PARTICIPANTS: Queensland residents aged 20 years or older admitted to Queensland hospitals with NAFLD/NASH during 1 July 2009 - 31 December 2018. MAIN OUTCOME MEASURES: Progression to decompensated cirrhosis (ascites, hepatic encephalopathy, or oesophageal variceal bleeding). RESULTS: We included data for 8006 patients in our analysis (10 082 admissions), including 4632 women (58%) and 2514 people with diabetes mellitus (31%); median follow-up time was 4.6 years (interquartile range, 2.7-7.2 years). Three hundred and fifty-one people (4.4%) experienced decompensated cirrhosis during the follow-up period. Of the 6900 people without cirrhosis, 4.5% (95% confidence interval [CI], 3.6-5.7%) experienced decompensated cirrhosis within ten years (mean, 0.5% per year; 95% CI, 0.4-0.6% per year); risk of progression was greater for people aged 70 years or older (v 20-39 years: adjusted hazard ratio [aHR], 4.7; 95% CI, 2.0-11.0) and those who had extrahepatic cancers (aHR, 5.0; 95% CI, 3.0-8.2), history of major cardiovascular events (aHR, 1.9; 95% CI, 1.2-3.1), or diabetes mellitus (aHR, 2.8; 95% CI, 2.0-3.9). Of the 1106 people with cirrhosis, 32.4% (95% CI, 27.2-38.3%) experienced decompensated cirrhosis within ten years (mean, 5.5% per year; 95% CI, 4.8-6.3% per year); risk of progression was greater for those with portal hypertension (aHR, 1.8; 95% CI, 1.3-2.7), extrahepatic cancer (aHR, 1.8; 95% CI, 1.1-2.9), or diabetes mellitus (aHR, 1.5; 95% CI, 1.1-2.0). Compared with people who had neither cirrhosis nor diabetes mellitus, the risk of decompensation was greater for people with cirrhosis (aHR, 10.7; 95% CI, 7.6-15.0) or cirrhosis and diabetes mellitus (aHR, 14.4; 95% CI, 10.1-20.6). CONCLUSIONS: Given the greater risk of progression to cirrhosis decompensation in people with diabetes mellitus, a disorder common in people with NAFLD/NASH, identifying advanced fibrosis and providing appropriate treatment for averting disease progression is vital.

Utility of Serum Biomarker Indices for Staging of Hepatic Fibrosis Before and After Venesection in Patients With Hemochromatosis Caused by Variants in HFE.

BACKGROUND & AIMS: Hemochromatosis that is associated with variants in the homeostatic iron regulator gene (HFE) is characterized by intestinal absorption of iron and excessive body and hepatic iron stores; it can lead to hepatic fibrosis and cirrhosis. Fibrosis has been staged by analysis of liver biopsies, but non-invasive staging methods are available. We evaluated the ability of aspartate aminotransferase:platelet ratio index (APRI), the fibrosis-4 (FIB-4) index, and gamma-glutamyl transferase:platelet ratio (GPR) to assess hepatic fibrosis staging in subjects with HFE-associated hemochromatosis, using liver biopsy-staged fibrosis as the reference standard. METHODS: We performed a retrospective, cross-sectional analysis of 181 subjects with HFE-associated hemochromatosis and hepatic fibrosis staged by biopsy analysis and available serum samples. We calculated APRI, FIB-4, and GPR at diagnosis for all 181 subjects and following venesection therapy in 64 of these subjects (7 subjects had follow-up biopsy analysis). We used area under the receiver operating characteristic curve (AUROC) analysis to assess the relationships between APRI score, FIB-4 score, and GPR and advanced (F3-F4) fibrosis and to select cut-off values. RESULTS: Hepatic fibrosis stage correlated with APRI score (r = 0.54; P < .0001), FIB-4 score (r = 0.35; P < .0001), and GPR (r = 0.36, P < .0001). An APRI score above 0.44 identified patients with advanced fibrosis with an AUROC of 0.88, 79.4% sensitivity, 79.4% specificity, and 81% accuracy. A FIB-4 score above 1.1 identified patients with advanced fibrosis with an AUROC of 0.86, 80% sensitivity, 80.3% specificity, and 81% accuracy. A GPR above 0.27 identified patients with advanced fibrosis with an AUROC of 0.76, 67.7% sensitivity, 70.3% specificity, and 69% accuracy. APRI score was significantly more accurate than GPR (P = .05) in detecting advanced fibrosis; there was no difference between APRI and FIB-4. Venesection treatment was associated with significant reductions in APRI (P < .0001) and GPR (P < .001), paralleling fibrosis regression observed in available liver biopsies. Post-venesection APRI identified 87% of subjects with advanced fibrosis that decreased to levels that indicate stage F1-F2 fibrosis. CONCLUSIONS: In a retrospective study of 181 subjects with HFE-associated hemochromatosis, we found that APRI and FIB-4 scores identified patients with advanced hepatic fibrosis with 81% accuracy. APRI scores might also be used to monitor fibrosis regression following venesection.

CpG Island Methylation in Sessile Serrated Adenomas Increases With Age, Indicating Lower Risk of Malignancy in Young Patients.

Among sessile serrated adenomas (SSAs) with identical histologic features, some never progress, whereas others become dysplastic and develop into invasive cancers. Development of the CpG island methylator phenotype is a feature of SSA progression; we examined the CIMP status of 448 SSAs and examined the association with patient clinical data. Overall, 190 SSAs were CpG island methylator phenotype-positive. CpG island methylator phenotype positivity was associated with older patient age (P < .001) and proximal polyp site (P < .001), but not with patient sex (P = .94) or polyp size (P = .34). These results might be used to improve SSA surveillance guidelines.

Accuracy of Transient Elastography Data Combined With APRI in Detection and Staging of Liver Disease in Pediatric Patients With Cystic Fibrosis.

BACKGROUND & AIMS: Liver disease develops in 15%-72% of patients with cystic fibrosis, and 5%-10% develop cirrhosis or portal hypertension, usually during childhood. Transient elastography (TE) is a noninvasive method to measure liver stiffness. We aimed to validate its accuracy in detection of liver disease and assessment of fibrosis in children with cystic fibrosis. METHODS: We performed a cross-sectional study to evaluate the accuracy of TE in analysis of liver disease in 160 consecutive children who presented with cystic fibrosis (9.0 ± 0.4 years old, 53% male) at a tertiary referral pediatric center in Australia, from 2011 through 2016. Patients were classified as having cystic fibrosis-associated liver disease (CFLD) or cystic fibrosis without liver disease (CFnoLD) based on clinical, biochemical, and imaging features. Fibrosis severity was determined from histologic analysis of dual-pass liver biopsies from children with CFLD, as the reference standard. Data from healthy children without cystic fibrosis (n = 64, controls) were obtained from a separate study. Liver stiffness measurements (LSMs) were made by Fibroscan analysis, using the inter-quartile range/median ≤30% of 10 valid measurements. Children with macronodularity or portal hypertension with heterogeneous changes on ultrasound without available biopsy were assigned to the category of stage F3-F4 fibrosis. RESULTS: LSM was made reliably in 86% of children; accuracy increased with age. LSMs were significantly higher in children with CFLD (10.7 ± 2.4 kPa, n = 33) than with CFnoLD (4.6 ± 0.1 kPa, n = 105) (P < .0001) or controls (4.1 ± 0.1kPa) (P < .0001); LSMs were higher in children with CFnoLD than controls (P < .05). At a cut-off value of 5.55kPa, LSM identified children with CFLD with an area under the receiver operating characteristic (AUROC) curve of 0.82, 70% sensitivity, and 82% specificity (P < .0001). Classification and regression tree models that combined LSM and aspartate aminotransferase to platelet ratio index (APRI) identified children with CFLD with an AUROC curve of 0.89, 87% sensitivity, and 74% specificity (odds ratio, 18.6). LSMs correlated with fibrosis stage in patients with CFLD (r = 0.67, P = .0001). A cut-off value of 8.7kPa differentiated patients with stage F3-F4 fibrosis from patients with stage F1-F2 fibrosis (AUROC, 0.87; 75% sensitivity; 100% specificity, P=.0002). The combination of LSMs and APRI improved the differentiation of patients with F3-F4 fibrosis vs F1-F2 fibrosis (AUROC, 0.92; 83% sensitivity; and 100% specificity (P < .01). CONCLUSIONS: LSMs made by TE accurately detect liver disease in children with cystic fibrosis; diagnostic accuracy increases when LSMs are combined with APRI. LSMs also differentiate between children with cystic fibrosis with mild-moderate fibrosis vs advanced fibrosis.

Response to a monovalent 2009 influenza A (H1N1) vaccine.

BACKGROUND: A novel 2009 influenza A (H1N1) virus is responsible for the first influenza pandemic in 41 years. A safe and effective vaccine is needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, split-virus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia. METHODS: We evaluated the immunogenicity and safety of the vaccine after each of two scheduled doses, administered 21 days apart. A total of 240 subjects, equally divided into two age groups (<50 years and >or=50 years), were enrolled and underwent randomization to receive either 15 microg or 30 microg of hemagglutinin antigen by intramuscular injection. We measured antibody titers using hemagglutination-inhibition and microneutralization assays at baseline and 21 days after vaccination. The coprimary immunogenicity end points were the proportion of subjects with antibody titers of 1:40 or more on hemagglutination-inhibition assay, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in the geometric mean titer. RESULTS: By day 21 after the first dose, antibody titers of 1:40 or more were observed in 114 of 120 subjects (95.0%) who received the 15-microg dose and in 106 of 119 subjects (89.1%) who received the 30-microg dose. A similar result was observed after the second dose of vaccine. No deaths, serious adverse events, or adverse events of special interest were reported. Local discomfort (e.g., injection-site tenderness or pain) was reported by 56.3% of subjects, and systemic symptoms (e.g., headache) by 53.8% of subjects after each dose. Nearly all events were mild to moderate in intensity. CONCLUSIONS: A single 15-microg dose of 2009 H1N1 vaccine was immunogenic in adults, with mild-to-moderate vaccine-associated reactions. (ClinicalTrials.gov number, NCT00938639).

Advanced but not mild liver disease is a predictor of decreased survival in children with cystic fibrosis, with far greater impact in females: A 27-year real-life cohort study.

BACKGROUND: Improved survival of children with CF has increased our need to understand the relevance of cystic fibrosis-associated liver disease (CFLD). We assessed the impact of liver disease and disease severity on the survival of children with cystic fibrosis. METHODS: A real life, single center cohort study with 27 years follow up was conducted. Mild CFLD was diagnosed as children with abnormal serum liver function tests and abnormal ultrasound. Advanced CFLD was established by detection of cirrhosis or portal hypertension. A directed acyclic graph, Kaplan-Meier (KM) and Cox regression analysis were used to model survival. RESULTS: 290 patients were enrolled, 48 (16.5%) had mild CFLD and 55 (19%) had advanced CFLD. Ten children with advanced CFLD and 1 with mild CFLD died. Based on the KM analysis, the mean (SE) overall survival age of all CF children was 29.1 years (0.50). The mean (SE) survival among females with advanced CFLD was 24.7 years (1.58) compared to 30.4 years (0.66) for females without advanced CFLD (p = 0.0027). Advanced CFLD was a predictor of decreased survival when adjusted for sex and diabetes (HR 2.54, 95%CI 1.05-6.15, p = 0.039). Mild CFLD was not associated with decreased survival. The effect of advanced CFLD on survival was mainly borne by females (HR = 6.37, 95%CI 1.62-25.06 vs. males, HR = 1.00, 95%CI 0.25-4.01). CONCLUSION: Advanced but not mild CFLD was associated with an increased risk of death when adjusted for sex and diabetes, and resulted in premature death in females with cystic fibrosis by approximately 6 years.

Gamma-glutamyl transpeptidase-to-platelet ratio as a biomarker of liver disease and hepatic fibrosis severity in paediatric Cystic Fibrosis.

BACKGROUND: Cystic fibrosis (CF)-associated liver disease (CFLD) causes significant morbidity and mortality in children with CF. Diagnosis of liver disease prior to development of cirrhosis or portal hypertension (PHT) is challenging. While imaging modalities using Elastography show great promise they are still not widely available to all clinicians. This study investigated gamma-glutamyl transpeptidase-to-platelet ratio (GPR) as a non-invasive biomarker to detect liver disease and stage fibrosis severity in children with CF. METHODS: 237 children were enroled including 76 with CFLD and 161 with CF and no detectable liver disease (CFnoLD). CFLD was diagnosed using standard clinical, biochemical and imaging practice guidelines. Hepatic fibrosis was staged on liver biopsies available from 54 children with CFLD. Serum liver biochemistry was used to calculate GPR (median, [IQR]) and receiver operating characteristics (ROC) analysis assessed utility to detect liver disease and stage fibrosis severity. RESULTS: GPR was significantly increased in CFLD versus CFnoLD (0.33 [0.19-0.96] vs. 0.15 [0.11-0.21], P<0.0001). GPR demonstrated good diagnostic utility for detecting CFLD with an area under the curve (AUC) of 0.81 (95% confidence Interval [CI] [0.75-0.87]; P<0.0001), with sensitivity of 74% and specificity of 73%, using a cut-off of 0.20. GPR increased with increasing hepatic fibrosis stage. GPR discriminated both moderate-advanced (F2-F4) fibrosis vs. F0-F1 (AUC=0.82; 95%CI [0.71-0.94]; P<0.0001) and advanced (F3-F4) fibrosis vs. F0-F2 (AUC=0.77; 95%CI [0.64-0.90]; P = 0.004), with a cut-off 0.32 and 0.61, respectively. An elevated GPR of >0.84 was predictive of PHT at diagnosis of CFLD (AUC=0.81; 95%CI [0.67-0.95]; P = 0.0003). CONCLUSIONS: GPR demonstrates good diagnostic utility for assessing the presence of liver disease, PHT and hepatic fibrosis severity in children with CF. These findings will aid in better identification of patients at risk for CF-related liver involvement and the potential for more targeted and timely follow-up and treatment.

A single dose of unadjuvanted novel 2009 H1N1 vaccine is immunogenic and well tolerated in young and elderly adults.

BACKGROUND: When the novel H1N1 influenza A strain appeared in April of 2009, development of novel H1N1 vaccines became a public health priority. METHODS: We conducted a phase­2, multicenter, randomized, placebo­controlled, observer­blind clinical trial of a 2009 H1N1 vaccine in 1313 young (age, 18-64 years) and older (age, >or=65 years) adults. Participants were randomized 1:4:4:4 to receive 2 doses of placebo or 7.5, 15, or 30 µg of H1N1 hemagglutinin administered 21 days apart. In post hoc analyses, hemagglutination inhibition (HI) titers measured at baseline and after vaccination were analyzed for young adults (age, 18-64 years), "younger elderly" adults (age, 65-74 years), and "very elderly" adults (age, >or=75 years). RESULTS: At baseline, 28.8% of young adults, 43.9% of younger elderly adults, and 62.9% of very elderly adults had HI titers to A/2009 H1N1 of >or=1:40. A single 7.5­µg dose induced HI titers >or=1:40 in 94.5% (95% confidence interval [CI], 91.8%-96.3%) of all adults. After one 7.5­µg dose, the geometric mean titers achieved were 326.4 (95% CI, 275.9-386.0) in young adults, 155.4 (95% CI, 123.4-195.8) in "younger elderly" adults, and 243.9 (95% CI, 167.1-356.0) in "very elderly" adults. CONCLUSIONS: This large phase-2 trial demonstrated that a single 7.5­µg dose of a monovalent unadjuvanted H1N1 vaccine induced protective HI antibody levels in adults of all ages, including very elderly adults. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00958126.

The presence of knockdown resistance mutations reduces male mating competitiveness in the major arbovirus vector, Aedes aegypti.

BACKGROUND: The development of insecticide resistance in mosquitoes can have pleiotropic effects on key behaviours such as mating competition and host-location. Documenting these effects is crucial for understanding the dynamics and costs of insecticide resistance and may give researchers an evidence base for promoting vector control programs that aim to restore or conserve insecticide susceptibility. METHODS AND FINDINGS: We evaluated changes in behaviour in a backcrossed strain of Aedes aegypti, homozygous for two knockdown resistance (kdr) mutations (V1016G and S989P) isolated in an otherwise fully susceptible genetic background. We compared biting activity, host location behaviours, wing beat frequency (WBF) and mating competition between the backcrossed strain, and the fully susceptible and resistant parental strains from which it was derived. The presence of the homozygous kdr mutations did not have significant effects on blood avidity, the time to locate a host, or WBF in females. There was, however, a significant reduction in mean WBF in males and a significant reduction in estimated male mating success (17.3%), associated with the isolated kdr genotype. CONCLUSIONS: Our results demonstrate a cost of insecticide resistance associated with an isolated kdr genotype and manifest as a reduction in male mating success. While there was no recorded difference in WBF between the females of our strains, the significant reduction in male WBF recorded in our backcrossed strain might contribute to mate-recognition and mating disruption. These consequences of resistance evolution, especially when combined with other pleiotropic fitness costs that have been previously described, may encourage reversion to susceptibility in the absence of insecticide selection pressures. This offers justification for the implementation of insecticide resistance management strategies based on the rotation or alternation of different insecticide classes in space and time.

A randomised study of comfort during bronchoscopy comparing conscious sedation and anaesthetist-controlled general anaesthesia, including the utility of bispectral index monitoring.

BACKGROUND: The difference in patient comfort with conscious sedation versus general anaesthesia for bronchoscopy has not been adequately assessed in a randomised trial. This study aimed to assess if patient comfort during bronchoscopy with conscious sedation is noninferior to general anaesthesia. METHODS: 96 subjects were randomised to receive conscious sedation or general anaesthesia for bronchoscopy. The primary outcome was subject comfort. Secondary outcomes included willingness to undergo a repeat procedure if necessary and level of sedation assessed clinically and by bispectral index (BIS) monitoring. RESULTS: There was no significant difference between subject comfort scores (difference -0.01, 95% CI -0.63-0.61 on a 10-point scale; p=0.97) or willingness to undergo a repeat procedure (97.7% versus 91.8%, 95% CI -4.8-15.5%; p=0.37). Deeper levels of sedation in the general anaesthesia cohort was confirmed with both clinical and BIS monitoring. There was no significant difference in diagnostic accuracy (conscious sedation 93.9%, 95% CI 80.4-98.3% versus general anaesthesia 86.5%, 95% CI 72.0-94.1%; p=0.43). There were more complications (29.6%, 95% CI 18.2-44.2% versus 6.1%, 95% CI 2.1-16.5%; p<0.01) in the general anaesthesia group. There was no relationship between high BIS scores and subject discomfort. BIS levels <40 during a procedure were associated with increased complications. CONCLUSION: Conscious sedation is not inferior to general anaesthesia in providing patient comfort during bronchoscopy, despite lighter sedation, and is associated with fewer complications and comparable diagnostic accuracy. BIS monitoring may have a role in preventing complications associated with deeper sedation.

Development and Evaluation of the Supportive Needs Assessment Tool for Cirrhosis (SNAC).

BACKGROUND: We report the development and psychometric testing of a Supportive Needs Assessment tool for Cirrhosis (SNAC). METHODS: The 50-item SNAC was administered to patients (n=465) diagnosed with cirrhosis recruited from five metropolitan hospitals in Queensland, Australia. Items were assessed for ceiling and floor effects, and exploratory factor analysis was used to assess the factor structure. Identified factors were assessed for internal consistency and convergent validity to validated psychosocial tools. RESULTS: Exploratory factor analysis identified 4 factors (39 items), which together accounted for 49.2% of the total variance. The 39-item SNAC met the requirements of a needs assessment tool and identified a range of needs important to patients with cirrhosis that were grouped in four subscales: "Psychosocial issues", "Practical and physical needs", "Information needs", and "Lifestyle changes". Cronbach's alpha values for the four subscales ranged from 0.64 to 0.92. Convergent validity was supported by a strong correlation between the total SNAC score and that of the Chronic Liver Disease Questionnaire (CLDQ; Spearman rho -0.68; p<0.001), and moderate correlations with the Distress Thermometer (Spearman rho 0.53; p<0.001) and seven subscales of a generic health-related quality of life instrument (Short Form 36; Spearman rho ranged from -0.48 to -0.57; p<0.001). The SNAC discriminated patient groups with respect to sex (p=0.013), age group (p<0.001), and hospital admission status (admitted vs not; p<0.001). CONCLUSION: These data provide initial evidence for the validity and reliability of the SNAC, an instrument designed to measure type and amount of perceived unmet practical and psychological needs of people diagnosed with cirrhosis.

Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis.

BACKGROUND: Current diagnostic methods for the diagnosis of Cystic fibrosis (CF)-associated liver disease (CFLD) are non-specific and assessment of disease progression is difficult prior to the advent of advanced disease with portal hypertension. This study investigated the potential of Supersonic shear-wave elastography (SSWE) to non-invasively detect CFLD and assess hepatic fibrosis severity in children with CF. METHODS: 125 children were enrolled in this study including CFLD (n = 55), CF patients with no evidence of liver disease (CFnoLD = 41) and controls (n = 29). CFLD was diagnosed using clinical, biochemical and imaging best-practice guidelines. Advanced CFLD was established by the presence of portal hypertension and/or macronodular cirrhosis on ultrasound. Liver stiffness measurements (LSM) were acquired using SSWE and diagnostic performance for CFLD detection was evaluated alone or combined with aspartate aminotransferase-to-platelet ratio index (APRI). RESULTS: LSM was significantly higher in CFLD (8.1 kPa, IQR = 6.7-11.9) versus CFnoLD (6.2 kPa, IQR = 5.6-7.0; P < 0.0001) and Controls (5.3 kPa, IQR = 4.9-5.8; P < 0.0001). LSM was also increased in CFnoLD versus Controls (P = 0.0192). Receiver Operating Characteristic (ROC) curve analysis demonstrated good diagnostic accuracy for LSM in detecting CFLD using a cut-off = 6.85 kPa with an AUC = 0.79 (Sensitivity = 75%, Specificity = 71%, P < 0.0001). APRI also discriminated CFLD (AUC = 0.74, P = 0.004). Classification and regression tree modelling combining LSM + APRI showed 14.8 times greater odds of accurately predicting CFLD (AUC = 0.84). The diagnostic accuracy of SSWE for discriminating advanced disease was excellent with a cut-off = 9.05 kPa (AUC = 0.95; P < 0.0001). CONCLUSIONS: SSWE-determined LSM shows good diagnostic accuracy in detecting CFLD in children, which was improved when combined with APRI. SSWE alone discriminates advanced CFLD.

Long-term morbidity and mortality following bloodstream infection: A systematic literature review.

OBJECTIVES: Bloodstream infection results in significant short-term morbidity and mortality. No literature review has studied the long-term outcome following a bloodstream infection. This PROSPERO registered systematic review evaluated studies, which measured the association of a bloodstream infection with long-term morbidity and mortality. METHODS: Databases were systematically searched for studies of adult patients reporting morbidity and/or mortality one year or more following a bloodstream infection in comparison to a matched cohort without a bloodstream infection. RESULTS: Ten observational studies were included in the final analysis. Five studies assessed only mortality, two assessed morbidity and mortality and three studies assessed morbidity only. The one year mortality ranged from between 8 and 48% for patients with bloodstream infection. The pooled risk ratio of death at one year was significantly higher for patients with bloodstream infection when compared to the matched cohort (RR 4.04 [95% CI 1.84-8.87]). CONCLUSIONS: Bloodstream infection was associated with poor long-term outcome measured at one year when compared to matched controls. More evidence is needed to determine if this association is causative.

Efficacy of a trivalent influenza vaccine against seasonal strains and against 2009 pandemic H1N1: A randomized, placebo-controlled trial.

BACKGROUND: Before pandemic H1N1 vaccines were available, the potential benefit of existing seasonal trivalent inactivated influenza vaccines (IIV3s) against influenza due to the 2009 pandemic H1N1 influenza strain was investigated, with conflicting results. This study assessed the efficacy of seasonal IIV3s against influenza due to 2008 and 2009 seasonal influenza strains and against the 2009 pandemic H1N1 strain. METHODS: This observer-blind, randomized, placebo-controlled study enrolled adults aged 18-64years during 2008 and 2009 in Australia and New Zealand. Participants were randomized 2:1 to receive IIV3 or placebo. The primary objective was to demonstrate the efficacy of IIV3 against laboratory-confirmed influenza. Participants reporting an influenza-like illness during the period from 14days after vaccination until 30 November of each study year were tested for influenza by real-time reverse transcription polymerase chain reaction. RESULTS: Over a study period of 2years, 15,044 participants were enrolled (mean age±standard deviation: 35.5±14.7years; 54.4% female). Vaccine efficacy of the 2008 and 2009 IIV3s against influenza due to any strain was 42% (95% confidence interval [CI]: 30%, 52%), whereas vaccine efficacy against influenza due to the vaccine-matched strains was 60% (95% CI: 44%, 72%). Vaccine efficacy of the 2009 IIV3 against influenza due to the 2009 pandemic H1N1 strain was 38% (95% CI: 19%, 53%). No vaccine-related deaths or serious adverse events were reported. Solicited local and systemic adverse events were more frequent in IIV3 recipients than placebo recipients (local: IIV3 74.6% vs placebo 20.4%, p<0.001; systemic: IIV3 46.6% vs placebo 39.1%, p<0.001). CONCLUSIONS: The 2008 and 2009 IIV3s were efficacious against influenza due to seasonal influenza strains and the 2009 IIV3 demonstrated moderate efficacy against influenza due to the 2009 pandemic H1N1 strain. Funded by CSL Limited, ClinicalTrials.gov identifier NCT00562484.

Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children.

A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons≥18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population≥6 months to <18 years of age. Subjects were stratified as follows: Cohort A (≥6 months to <3 years); Cohort B (≥3 years to <9 years); and Cohort C (≥9 years to <18 years). The subject's age and influenza vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts.

Safety and tolerability of a 2009 trivalent inactivated split-virion influenza vaccine in infants, children and adolescents.

OBJECTIVE: To evaluate the safety of CSL's split-virion inactivated trivalent 2009 Southern Hemisphere formulation influenza vaccine (TIV) in children. METHODS: We enrolled 1992 healthy children into three groups: Cohorts A, ≥ 6 months to <3 years; B, ≥ 3 years to <9 years; and C, ≥ 9 years to <18 years. Children received one or two doses of 0.25 ml (22.5 µg haemagglutinin) or 0.5 ml (45 µg) TIV, depending on age and prior vaccination history. We collected post-vaccination solicited adverse event (AE) data (days 0-6), including fever (temperature: ≥ 37.5°C axilla, ≥ 38.0°C oral), unsolicited AEs (days 0-29) and serious AEs (SAEs) and new-onset chronic illnesses (NOCIs; to day 180 after last vaccination). RESULTS: At least one solicited AE was reported by 80%/78%/78% of children in Cohorts A, B and C, respectively. Systemic AEs were more common among Cohort A (72% of participants), and local AEs were more common among Cohort C (71% of participants). Fever was more common in younger cohorts, in influenza vaccine-naïve children (29% of Cohort A receiving their first dose), and following first compared with second doses. Severe fever following a first dose prevented 20 participants receiving their second scheduled vaccine dose. A 7-month-old participant had a single uncomplicated febrile convulsion on the day of vaccination. CONCLUSIONS: Nearly 80% of subjects reported at least one solicited AE following immunization. Fever prevalence was highest in vaccine-naïve Cohort A participants, similar to other paediatric studies using CSL vaccine. Further research to understand fever-related AEs in children following CSL's TIV is recommended.

Safety and immunogenicity of an inactivated thimerosal-free influenza vaccine in infants and children.

OBJECTIVE: Few prospective studies of inactivated split virion influenza vaccine have been conducted in infants and children. Our objective was to evaluate the safety, reactogenicity and immunogenicity of a thimerosal-free inactivated influenza vaccine (Fluvax; CSL Limited, Parkville, Australia) in children aged 6 months to <9 years. METHODS: A prospective, open-label, phase III clinical trial was conducted in 298 healthy children previously unvaccinated with influenza, commencing in the Southern Hemisphere 2005 autumn. Participants were divided into two groups (Group A: > or =6 months to <3 years; Group B: > or =3 years to <9 years), and received two doses of the 2005 vaccine, and one dose of the 2006 vaccine one year later (Group A: 0.25 ml per dose; Group B: 0.5 ml per dose). Vaccine safety and reactogenicity was evaluated for 30 days after each dose. Immunogenicity was assessed using hemagglutination inhibition and single radial hemolysis assays. RESULTS: There were no withdrawals due to adverse events (AEs). The majority of solicited local and systemic AEs were of mild severity. A maximum intensity of severe was reported for injection site pain and fever by only 3.0% and 3.4% of participants, respectively. The vaccine was immunogenic for all antigens, with > or =95% of both younger and older children achieving seroprotection after dose 2. CONCLUSIONS: This thimerosal-free inactivated influenza vaccine had a favorable safety profile and was immunogenic in children aged > or =6 months and <9 years. Primary and booster vaccination produced consistently immunogenic responses including in children under 3 years of age receiving 0.25 ml doses of vaccine.