Verification of measles elimination in Australia: Application of World Health Organization regional guidelines.

BACKGROUND: The World Health Organization (WHO) Western Pacific Region (WPR) Guidelines on verification of measles elimination were established in 2012. This article outlines Australia's approach to addressing the guideline's five lines of evidence, which led to formal verification of elimination by the WHO Regional Verification Commission (RVC) in March 2014. METHODS: The criteria were addressed using national measles notifications, data from selected laboratories, the national childhood immunization register, and three national serosurveys (1998/1999, 2002, 2007). RESULTS: Australia met or exceeded all indicator targets with either national or sentinel data. Laboratory and epidemiological surveillance were of high quality, with 85% of cases documented as imported/import-related (target 80%); coverage with the first dose of measles vaccine was close to 94% in 2008-2012 and second dose coverage increased to 91% in 2012 (target >95%). There is ongoing commitment by the Australian Government to increase immunization coverage, and the absence of sustained transmission of any single measles genotype was demonstrated. CONCLUSIONS: This is the first documentation of the successful application of the WPR RVC guidelines. The indicators afford some flexibility but appear to provide appropriate rigor to judge achievement of measles elimination. Our experience could assist other countries seeking to verify their elimination status.

Seasonal influenza vaccine effectiveness estimates: Development of a parsimonious case test negative model using a causal approach.

BACKGROUND: Influenza vaccine effectiveness (VE) is increasingly estimated using the case-test negative study design. Cases have a symptom complex consistent with influenza and test positive for influenza, while non-cases have the same symptom complex but test negative. We aimed to determine a parsimonious logistic regression model for this study design when applied to patients in the community. METHODS: To determine the minimum covariate set required, we used a previously published systematic review to find covariates and restriction criteria commonly included in case-test negative logistic regression models. Covariates were assessed for inclusion using a directed acyclic graph. We used data from the Victorian Influenza Sentinel Practice Network from 2007 to 2013, excluding the pandemic year of 2009, to test the model. VE was estimated as (1-adjusted OR) * 100%. Changes in model fit from addition of specified covariates were examined. Restriction criteria were examined using change in VE estimate. VE was estimated for each year, all years aggregated, and for influenza type and sub-type. RESULTS: Using publicly available software, the directed acyclic graph indicated that covariates specifying age, time within the influenza season, immunocompromising comorbid conditions and year or study site, where applicable, were required for closure. The inclusion of sex was not required. Inclusions and exclusions were validated when testing the variables (when collected) with our data. Restriction by time between onset and swab was supported by the data. VE for all years aggregated was estimated as 53% (95%CI 38, 64). VE was estimated as 42% (95%CI 19, 59) for H3N2, 75% (95%CI 51, 88) for H1N1pdm09 and 63% (95%CI 38, 79) for influenza B. CONCLUSION: Theoretical covariates specified by the directed acyclic graph were validated when tested against surveillance data. A parsimonious model using the case test negative design allows regular estimates of VE and aggregated estimates by year.

Quantifying differences in the epidemic curves from three influenza surveillance systems: a nonlinear regression analysis.

Influenza surveillance enables systematic collection of data on spatially and demographically heterogeneous epidemics. Different data collection mechanisms record different aspects of the underlying epidemic with varying bias and noise. We aimed to characterize key differences in weekly incidence data from three influenza surveillance systems in Melbourne, Australia, from 2009 to 2012: laboratory-confirmed influenza notified to the Victorian Department of Health, influenza-like illness (ILI) reported through the Victorian General Practice Sentinel Surveillance scheme, and ILI cases presenting to the Melbourne Medical Deputising Service. Using nonlinear regression, we found that after adjusting for the effects of geographical region and age group, characteristics of the epidemic curve (including season length, timing of peak incidence and constant baseline activity) varied across the systems. We conclude that unmeasured factors endogenous to each surveillance system cause differences in the disease patterns recorded. Future research, particularly data synthesis studies, could benefit from accounting for these differences.

Decreased varicella and increased herpes zoster incidence at a sentinel medical deputising service in a setting of increasing varicella vaccine coverage in Victoria, Australia, 1998 to 2012.

We performed an ecological study using sentinel consultation data from a medical deputising service to assess the impact of increasing coverage with childhood varicella vaccine on the incidence risk of varicella and zoster in the population served by the deputising service in Victoria, Australia from 1998 to 2012. Following a successful vaccination programme, the incidence of varicella in Australia was modelled to decrease and the incidence of zoster to increase, based on a theoretical decrease in boosting of zoster immunity following a decrease in wild varicella virus circulation due to vaccination. Incidence risks (consultation proportions for varicella and zoster) were directly age-standardised to the Melbourne population in 2000, when varicella vaccine was first available. Age-standardised varicella incidence risk peaked in 2000 and halved by 2012. Age-standardised zoster incidence risk remained constant from 1998 to 2002, but had almost doubled by 2012. The increase in zoster consultations largely reflected increases in people younger than 50 years-old. Although causality cannot be inferred from ecological studies, it is generally agreed that the decrease in varicella incidence is due to increasing varicella vaccine coverage. The possible indirect effect of the vaccine on zoster incidence is less clear and ongoing monitoring of zoster is required.

Moderate influenza vaccine effectiveness in Victoria, Australia, 2011.

We used a sentinel general practitioner (GP) network to conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness (ILI) in Victoria, Australia in 2011. The test negative variation of the case control study design was used to estimate effectiveness for seasonal trivalent influenza vaccine. Cases and controls were ILI patients that tested positive and negative for influenza, respectively. Vaccination status was recorded by GPs and vaccine effectiveness (VE) was calculated as (1-adjusted odds ratio)x100%. There were 529 patients included in the study, of which 29% were influenza positive. Twelve percent of study participants were reported as vaccinated, 6% of cases and 15% of controls. Adjusted VE against all influenza was 56%, but not statistically significant. There was generally little variation in VE estimates when stratified by virus type and subtype, which is consistent with good matches between circulating strains and the vaccine strains. The VE was higher among adults of working age than among children.

Hospitalized community-acquired pneumonia in the elderly: an Australian case-cohort study.

This study describes the epidemiology of community-acquired pneumonia (CAP) in elderly Australians for the first time. Using a case-cohort design, cases with CAP were in-patients aged > or = 65 years with ICD-10-AM codes J10-J18 admitted over 2 years to two tertiary hospitals. The cohort sample was randomly selected from all hospital discharges, frequency-matched to cases by month. Logistic regression was used to estimate risk ratios for factors predicting CAP or associated mortality. A total of 4772 in-patients were studied. There were 1952 cases with CAP that represented 4% of all elderly admissions: mean length of stay was 9.0 days and 30-day mortality was 18%. Excluding chest radiograph, 520/1864 (28%) cases had no investigations performed. The strongest predictors of CAP were previous pneumonia, history of other respiratory disease, and aspiration. Intensive-care-unit admission, renal disease and increasing age were the strongest predictors of mortality, while influenza vaccination conferred protection. Hospitalization with CAP in the elderly is common, frequently fatal and a considerable burden to the Australian community. Investigation is ad hoc and management empirical. Influenza vaccination is associated with reduced mortality. Patient characteristics can predict risk of CAP and subsequent mortality.

Varicella infection--evidence for peak activity in summer months.

This study aimed to identify seasonal variations in the presentation of primary varicella infection in susceptible patients in Victoria (a temperate region in south-east Australia) by analysing Victorian hospital admissions data and medical locum service data from the years preceding the introduction of a universally offered vaccination, complemented by available surveillance data from the neighbouring state, of South Australia. Contrary to the conventional assumption, which is based on observations in temperate regions elsewhere in the world, we found no consistent evidence of seasonal peaks during late winter and early spring for varicella infection in Victoria. This finding may have implications for prevention in temperate regions elsewhere in the world wherever estimations of local seasonal trends have been based on international experiences.

ICD-10 codes are a valid tool for identification of pneumonia in hospitalized patients aged > or = 65 years.

This study examines the validity of using ICD-10 codes to identify hospitalized pneumonia cases. Using a case-cohort design, subjects were randomly selected from monthly cohorts of patients aged > or = 65 years discharged from April 2000 to March 2002 from two large tertiary Australian hospitals. Cases had ICD-10-AM codes J10-J18 (pneumonia); the cohort sample was randomly selected from all discharges, frequency matched to cases by month. Codes were validated against three comparators: medical record notation of pneumonia, chest radiograph (CXR) report and both. Notation of pneumonia was determined for 5098/5101 eligible patients, and CXR reports reviewed for 3349/3464 (97%) patients with a CXR. Coding performed best against notation of pneumonia: kappa 0.95, sensitivity 97.8% (95% CI 97.1-98.3), specificity 96.9% (95% CI 96.2-97.5), positive predictive value (PPV) 96.2% (95% CI 95.4-97.0) and negative predictive value (NPV) 98.2% (95% CI 97.6-98.6). When medical record notation of pneumonia is used as the standard, ICD-10 codes are a valid method for retrospective ascertainment of hospitalized pneumonia cases and appear superior to use of complexes of symptoms and signs, or radiology reports.

Mumps and rubella: a year of enhanced surveillance and laboratory testing.

In Victoria (Australia) surveillance for mumps and rubella has historically been passive, with most notified cases clinically diagnosed. In July 2001, the Victorian Department of Human Services implemented an enhanced surveillance system focusing on improved laboratory testing. We tested 85% of notifications and only 9% of all mumps and 27% of rubella notifications were laboratory confirmed. While most notified cases were children who had been clinically diagnosed, we found most laboratory-confirmed cases were in adults. The positive predictive value of the clinical case definition was low: mumps (10%); rubella (22%). These results highlight the value of laboratory confirmation of the diagnosis when mumps and rubella are rare, failure to do so is likely to overestimate disease incidence.

Measles immunity among young adults in Victoria.

Measles outbreaks in Victoria in 1999 and 2001 have suggested that a substantial proportion of young Victorian adults may be susceptible to measles infection. We performed a serosurvey of 300 18-30-year-old healthy blood donors and 312 sera retrieved after diagnostic testing for a non-rash illness in patients of the same age group, with the aim of estimating the proportion of young adults in Victoria immune to measles. We also aimed to define more precisely the birth cohorts at risk of measles infection, with cohorts reflecting the measles immunisation policies of previous years. There was no significant difference in measles immunity between the 300 blood donors (79.0%, 95% confidence interval 73.9-83.5) and the 312 patients whose sera had been stored (84.0%, 95% CI 79.4-87.9, p=0.11). There was, however, a significant difference in immunity by birth cohort. In the combined results from both samples, the proportion of people born between 1968 and 1974 who were immune to measles was 88.4 per cent (95% CI 84.1-91.6) while the proportion of those born between 1975 and 1981 was 74.1 per cent (95% CI 68.7-79.1). This study confirms that a substantial proportion of young Victorian adults are susceptible to measles, but also demonstrates that those born between 1975 and 1981 are more likely to be non-immune than those born before 1975. A review of published Australian data supports this conclusion and confirms the need for a measles control program aimed at young adults.

Investigation of optimal specimen type and sampling time for detection of measles virus RNA during a measles epidemic.

At various times postonset of rash, 74 patients positive for measles virus-specific immunoglobulin M provided samples for detection of measles virus RNA by a reverse transcriptase PCR. Of lymphocytes, urine, throat swab, and serum specimens, throat swab specimens were optimal for detection of measles virus RNA during the first 2 weeks after the rash.

A serosurvey evaluation of the school-based measles 'catch-up' immunisation campaign in Victorian school-aged children.

OBJECTIVE: To determine the proportion of Victorian primary school students protected against measles infection one year after the completion of the measles 'catch-up' immunisation campaign of 1998 and to compare this with the proportion of year 9 and 10 (aged 14-16 years) students. DESIGN & SETTING: Three-stage random cluster survey in Victorian primary and secondary schools. MAIN OUTCOME MEASURES: Proportion of primary and year 9 and 10 secondary school students protected against measles infection one year after the completion of the mass 'catch-up' immunisation campaign. SECONDARY OUTCOMES: the proportion of both primary and year 9 and 10 secondary school students protected against both mumps and rubella. RESULTS: Of 1,037 Victorian primary and 2,357 years 9 and 10 secondary school students invited to participate in this study, 403 (39%) and 752 (32%) respectively provided a blood specimen for serological testing for antibodies against measles, mumps and rubella. 94.8% (95% confidence interval, 91.5, 96.9) of primary school and 93.1% (90.9, 94.8) of year 9 and 10 students were protected against measles infection. CONCLUSION: One year after the completion of the school-based measles 'catch-up' immunisation campaign the level of protection in Victorian primary school aged students is sufficient to prevent the continuing circulation of measles virus within this age group. The proportion of year 9 and 10 secondary school students protected against measles is also probably sufficient to prevent continuing circulation of wild type virus in Victoria, even though this age group was not specifically targeted by the 'catch-up' campaign.

The age-specific prevalence of human parvovirus immunity in Victoria, Australia compared with other parts of the world.

The age-specific immunity to human parvovirus infection was estimated in Victoria, Australia using prospectively collected samples from the Royal Children's Hospital, the Royal Women's Hospital and the Australian Red Cross Blood Service and from sera stored at the Victorian Infectious Diseases Reference Laboratory (VIDRL). All testing was performed at VIDRL using a commercial enzyme-linked immunosorbent assay (Biotrin). Of the 824 sera tested, 28% of those drawn from people aged 0-9 years contained protective antibodies to human parvovirus. This rose to 51% in the next decade of life. There was then a slow rise to about 78% immunity over 50 years of age. An analysis of all requests for parvovirus serology at VIDRL from 1992 to 1998 suggested that parvovirus tended to occur in 4-year cycles, with 2 epidemic years followed by 2 endemic years. A review of published reports of parvovirus immunity suggested that parvovirus infection may be more common, with a correspondingly higher proportion of the community immune, in temperate as opposed to tropical countries.

Enhanced measles surveillance during an interepidemic period in Victoria.

OBJECTIVE: To describe results of the first two years of enhanced measles surveillance in Victoria. DESIGN: Case series identified through enhanced measles surveillance. PARTICIPANTS AND SETTING: All measles cases notified to the Disease Control Section, Department of Human Services, Victoria, in 1997 and 1998. MAIN OUTCOME MEASURES: Proportion of notified cases laboratory confirmed as measles, rubella, or human parvovirus infection; identification of clusters (two or more linked cases of measles); and utility of the National Health and Medical Research Council clinical case definition for suspected measles. RESULTS: Rates of laboratory testing of notified cases improved after introduction of a paediatric phlebotomy service in July 1997, from 21 of 90 notified patients (23%) in the preceding six months, to 258 of 317 notified patients (81%) between July 1997 and December 1998. Of the 317, only 19 (6%) were laboratory confirmed with measles, while a further 26 (8%) were laboratory confirmed with human parvovirus infection (18) or rubella (8). Three clusters of measles, involving 11 cases, were identified during 1998. Use of the NHMRC case definition did not greatly improve the positive predictive value for diagnosis of measles above that of notification alone (14% versus 8%). CONCLUSIONS: Circulation of measles virus in Victoria in 1997 and 1998 appeared minimal. In this interepidemic period most notified cases of measles were not measles; to identify true cases, surveillance during an interepidemic period must include laboratory testing of notified cases.

Measles outbreak in young adults in Victoria, 1999.

OBJECTIVES: To describe an outbreak of measles in Victoria. DESIGN: Case series with cases identified through enhanced passive surveillance and outbreak-related active surveillance. SETTING: State of Victoria, 1999. MAIN OUTCOME MEASURES: Number of cases; epidemiological links and patterns of transmission; patient demographic features and vaccination status; complications. RESULTS: 75 cases were identified (74 laboratory-confirmed; and one epidemiologically linked to a laboratory-confirmed case), with onset between 11 February and 2 May 1999. The first case was in a 21-year-old woman who had recently holidayed in Bali and worked at a large cinema complex in Melbourne. Sixteen cases occurred in people who had contact with the index case at the cinema on one evening. The outbreak spread to regional Victoria and South Australia. Median age of patients was 22 years; 64 (85%) were born between 1968 and 1981, with only one patient in the age group targeted by the primary school component of the 1998 Australian Measles Control Campaign; this child had not been vaccinated. More than a third of patients (28) were hospitalised (total, 97 inpatient days), and five were healthcare workers. CONCLUSIONS: This outbreak was caused by international importation of measles virus. It highlights the change in epidemiology of measles in Australia, from a disease of childhood to one predominantly affecting young adults. A strong two-dose childhood vaccination program, vigilant surveillance, and rapid response to outbreaks will continue to be the basis of measles control, but better protection for young adults should be considered.

What is the cause of a rash after measles-mumps-rubella vaccination?

Surveillance and laboratory confirmation of measles will increase in importance as Australia implements enhanced measles control. We describe a 17-month-old child with fever and rash after measles-mumps-rubella vaccination. Detection of vaccine-strain measles virus in his urine by polymerase chain reaction confirmed the diagnosis of a vaccine reaction rather than wild-type measles. We propose that measles virus should be sought and identified as vaccine or wild-type virus when the relationship between vaccination and measles-like illness is uncertain.

Thrombin inhibitors based on [5,5] trans-fused indane lactams.

A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.