A Randomized Trial of Two 2-Dose Influenza Vaccination Strategies for Patients Following Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous hematopoietic stem cell transplantation (autoHCT) patients. METHODS: A randomized, single-blind, controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomized 1:1 to high-dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or 2 SD vaccines (SD-SD arm) 4 weeks apart. Hemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2, and 6 months post-first dose. Evaluable primary outcomes were seroprotection (HI titer ≥40) and seroconversion (4-fold titer increase) rates and secondary outcomes were geometric mean titers (GMTs), GMT ratios (GMRs), adverse events, influenza-like illness (ILI), and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion. RESULTS: Sixty-eight patients were enrolled (34/arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentages of patients achieving seroprotection were 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all P > .05), and 78.8% and 97.1% for influenza-B/Yamagata (P = .03), respectively. Seroconversion rates, GMTs and GMRs, and number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR, 4.3; 95% CI, 1.2-14.9; P = .02). CONCLUSIONS: High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either 2-dose vaccine schedules. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12619000617167.

Viral Respiratory Tract Infections in Allogeneic Hematopoietic Stem Cell Transplantation Recipients in the Era of Molecular Testing.

Viral respiratory tract infection (vRTI) is a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to assess the epidemiologic characteristics, risk factors, and outcomes of vRTI occurring in the period from conditioning to 100 days after allo-HSCT in the era of molecular testing. This study was a retrospective record review of patients who underwent allo-HSCT at Royal Melbourne Hospital between January 2010 and December 2015. Symptomatic patients were tested using respiratory multiplex polymerase chain reaction (PCR). Logistic regression and Kaplan-Meier analysis were used to identify risk factors for vRTI and the risk of death or intensive care unit (ICU) admission, respectively. A total of 382 patients were reviewed, and 65 episodes of vRTI were identified in 56 patients (14.7%). Rhinovirus accounted for the majority of infections (69.2%). The majority of episodes presented initially with upper respiratory tract infection (58.5%), with 28.9% of them progressing to lower respiratory tract infection. Eleven episodes (16.9%) were associated with ICU admission. There were no deaths directly due to vRTI. Previous autologous HSCT was associated with an increased risk of vRTI (odds ratio, 2.1; 95% confidence interval, 1.0 to 4.1). The risks of death (P = .47) or ICU admission (P = .65) were not significantly different by vRTI status. vRTI is common in the first 100 days after allo-HSCT and is associated with ICU admission.

Influenza viruses received and tested by the Melbourne WHO Collaborating Centre for Reference and Research on Influenza annual report, 2015.

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System, the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 5,557 influenza positive samples during 2015. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. In 2015, influenza B viruses predominated over influenza A(H1)pdm09 and A(H3) viruses, accounting for a total of 58% of all viruses analysed. The vast majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2015. However, phylogenetic analysis of a selection of viruses indicated that the majority of circulating A(H3) viruses were genetically distinct from the WHO recommended strain for 2015, resulting in an update to the recommended vaccine strain for the Southern Hemisphere for 2016. With an increasing predominance of B/Victoria lineage viruses over B/Yamagata lineage viruses through the course of 2015, WHO also updated the recommended influenza B strain in the trivalent influenza vaccine for 2016. Of more than 3,300 samples tested for resistance to the neuraminidase inhibitors oseltamivir and zanamivir, only 1 A(H1)pdm09 virus showed highly reduced inhibition by oseltamivir. The Centre undertook primary isolation of candidate vaccine viruses directly into eggs, and in 2015 a total of 45 viruses were successfully isolated in eggs.

Concordance of interim and final estimates of influenza vaccine effectiveness: a systematic review.

The World Health Organization's Global Influenza Surveillance and Response System meets twice a year to generate a recommendation for the composition of the seasonal influenza vaccine. Interim vaccine effectiveness (VE) estimates provide a preliminary indication of influenza vaccine performance during the season and may be useful for decision making. We reviewed 17 pairs of studies reporting 33 pairs of interim and final estimates using the test-negative design to evaluate whether interim estimates can reliably predict final estimates. We examined features of the study design that may be correlated with interim estimates being substantially different from their final estimates and identified differences related to change in study period and concomitant changes in sample size, proportion vaccinated and proportion of cases. An absolute difference of no more than 10% between interim and final estimates was found for 18 of 33 reported pairs of estimates, including six of 12 pairs reporting VE against any influenza, six of 10 for influenza A(H1N1)pdm09, four of seven for influenza A(H3N2) and two of four for influenza B. While we identified inconsistencies in the methods, the similarities between interim and final estimates support the utility of generating and disseminating preliminary estimates of VE while virus circulation is ongoing.

Daily COVID-19 employee attestations at a large quaternary hospital in Melbourne, Australia - Limitations and lessons learnt.

BACKGROUND: As one of the many measures to limit the potentially infectious persons entering healthcare settings, the Victorian Department of Health (DH) introduced a daily attestation between 2020 and 2022. Upon entry to a health service, employees were required to confirm they were free from symptoms related to COVID-19 and did not have contact with a confirmed COVID-19 case in the previous 7-14 days. METHODS: We performed a retrospective analysis of employee attestations and SARS-CoV-2 tests performed between 1/6/2021 and 14/2/2022 at the main campus of the Royal Melbourne Hospital. RESULTS: We found the proportion of SARS-CoV-2 positive employees identified through workplace attestation was low (1.3%). Most SARS-CoV-2 positive employees analysed in this study (94%) were asymptomatic. DISCUSSION: Although the proportion of SARS-CoV-2 positive employees identified was low, attestations may have deterred unwell employees from presenting to work. Proactively monitoring employee attestations, such as measuring and reporting the number of symptomatic attestations, may make this a more useful tool.

Performance of hospital-based contact tracing for COVID-19 during Australia's second wave.

BACKGROUND: Hospital-based contact tracing aims to limit spread of COVID-19 within healthcare facilities. In large outbreaks, this can stretch resources and workforce due to quarantine of uninfected staff. We analysed the performance of a manual contact tracing system for healthcare workers (HCW) at a multi-site healthcare facility in Melbourne, Australia, from June-September 2020, during an epidemic of COVID-19. METHODS: All HCW close contacts were quarantined for 14 days, and tested around day 11, if not already diagnosed with COVID-19. We examined the prevalence and timing of symptoms in cases detected during quarantine, described this group as proportions of all close contacts and of all cases, and used logistic regression to assess factors associated with infection. RESULTS: COVID-19 was diagnosed during quarantine in 52 furloughed HCWs, from 483 quarantine episodes (11%), accounting for 19% (52/270) of total HCW cases. In 361 exposures to a clear index case, odds of infection were higher after contact with an infectious patient compared to an infectious HCW (aOR: 4.69, 95% CI: 1.98-12.14). Contact with cases outside the workplace increased odds of infection compared to workplace contact only (aOR: 7.70, 95% CI: 2.63-23.05). We estimated 30%, 78% and 95% of symptomatic cases would develop symptoms by days 3, 7, and 11 of quarantine, respectively. CONCLUSION: In our setting, hospital-based contact tracing detected and contained a significant proportion of HCW cases, without excessive quarantine of uninfected staff. Effectiveness of contact tracing is determined by a range of dynamic factors, so system performance should be monitored in real-time.

Excess respiratory mortality and hospitalizations associated with influenza in Australia, 2007-2015.

BACKGROUND: Influenza is the most common vaccine-preventable disease in Australia, causing significant morbidity and mortality. We assessed the burden of influenza across all ages in terms of influenza-associated mortality and hospitalizations using national mortality, hospital-discharge and influenza surveillance data. METHODS: Influenza-associated excess respiratory mortality and hospitalization rates from 2007 to 2015 were estimated using generalized additive models with a proxy of influenza activity based on syndromic and laboratory surveillance data. Estimates were made for each age group and year. RESULTS: The estimated mean annual influenza-associated excess respiratory mortality was 2.6 per 100 000 population [95% confidence interval (CI): 1.8, 3.4 per 100 000 population]. The excess annual respiratory hospitalization rate was 57.4 per 100 000 population (95% CI: 32.5, 82.2 per 100 000 population). The highest mortality rates were observed among those aged ≥75 years (35.11 per 100 000 population; 95% CI: 19.93, 50.29 per 100 000 population) and hospitalization rates were also highest among older adults aged ≥75 years (302.95 per 100 000 population; 95% CI: 144.71, 461.19 per 100 000 population), as well as children aged <6 months (164.02 per 100 000 population; 95% CI: -34.84, 362.88 per 100 000 population). Annual variation was apparent, ranging from 1.0 to 3.9 per 100 000 population for mortality and 24.2 to 94.28 per 100 000 population for hospitalizations. Influenza A contributed to almost 80% of the average excess respiratory hospitalizations and 60% of the average excess respiratory deaths. CONCLUSIONS: Influenza causes considerable burden to all Australians. Expected variation was observed among age groups, years and influenza type, with the greatest burden falling to older adults and young children. Understanding the current burden is useful for understanding the potential impact of mitigation strategies, such as vaccination.

A second external quality assessment of isolation and identification of influenza viruses in cell culture in the Asia Pacific region highlights improved performance by participating laboratories.

Influenza viruses must be amplified in cell culture for detailed antigenic analysis and for phenotypic assays assessing susceptibility to antiviral drugs or for other assays. Following on from the first external quality assessment (EQA) for isolation and identification of influenza viruses using cell culture techniques in 2016, a follow up EQA was performed in 2019 for National Influenza Centres (NICs) in the World Health Organization (WHO) South East Asia and Western Pacific Regions. Nineteen WHO NICs performed influenza virus isolation and identification techniques on an EQA panel comprising 16 samples, containing influenza A or B viruses and negative control samples. One sample was used exclusively to assess capacity to measure a hemagglutination titer and the other 15 samples were used for virus isolation and subsequent identification. Virus isolation from EQA samples was generally detected by assessment of cytopathic effect and/or hemagglutination assay while virus identification was determined by real time RT-PCR, hemagglutination inhibition and/or immunofluorescence assays. For virus isolation from EQA samples, 6/19 participating laboratories obtained 15/15 correct results in the first EQA (2016) compared to 11/19 in the follow up (2019). For virus identification in isolates derived from EQA samples, 6/19 laboratories obtained 15/15 correct results in 2016 compared to 13/19 in 2019. Overall, NIC laboratories in the Asia Pacific Region showed a significant improvement between 2016 and 2019 in terms of the correct results reported for isolation from EQA samples and identification of virus in isolates derived from EQA samples (p=0.01 and p=0.02, respectively).

Impact of prior vaccination on antibody response and influenza-like illness among Australian healthcare workers after influenza vaccination in 2016.

BACKGROUND: Epidemiological studies suggest that influenza vaccine effectiveness decreases with repeated administration. We examined antibody responses to influenza vaccination among healthcare workers (HCWs) by prior vaccination history and determined the incidence of influenza infection. METHODS: HCWs were vaccinated with the 2016 Southern Hemisphere quadrivalent influenza vaccine. Serum samples were collected pre-vaccination, 21-28 days and 7 months post-vaccination. Influenza antibody titres were measured at each time-point using the haemagglutination inhibition (HI) assay. Immunogenicity was compared by prior vaccination history. RESULTS: A total of 157 HCWs completed the study. The majority were frequently vaccinated, with only 5 reporting no prior vaccinations since 2011. Rises in titres for all vaccine strains among vaccine-naïve HCWs were significantly greater than rises observed for HCWs who received between 1 and 5 prior vaccinations (p < 0.001, respectively). Post-vaccination GMTs against influenza A but not B strains decreased as the number of prior vaccinations increased from 1 to 5. There was a significant decline in GMTs post-season for both B lineages. Sixty five (41%) HCWs reported at least one influenza-like illness episode, with 6 (4%) identified as influenza positive. CONCLUSIONS: Varying serological responses to influenza vaccination were observed among HCWs by prior vaccination history, with vaccine-naïve HCWs demonstrating greater post-vaccination responses against A(H3N2).

Annual report on influenza viruses received and tested by the Melbourne WHO Collaborating Centre for Reference and Research on Influenza in 2016

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 4,247 human influenza positive samples during 2016. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties and also propagated in qualified cells and hens eggs for potential seasonal influenza vaccine virus candidates. In 2016, influenza A(H3) viruses predominated over influenza A(H1)pdm09 and B viruses, accounting for a total of 51% of all viruses analysed. The vast majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2016. However, phylogenetic analysis of a selection of viruses indicated that the majority of circulating A(H3) viruses had undergone some genetic drift relative to the WHO recommended strain for 2016. Of more than 3,000 samples tested for resistance to the neuraminidase inhibitors oseltamivir and zanamivir, six A(H1)pdm09 viruses and two B/Victoria lineage viruses showed highly reduced inhibition to oseltamivir.

Report on influenza viruses received and tested by the Melbourne WHO Collaborating Centre for Reference and Research on Influenza in 2017

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a record total of 5866 human influenza positive samples during 2017. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties and were propagated in qualified cells and hens' eggs for use as potential seasonal influenza vaccine virus candidates. In 2017, influenza A(H3) viruses predominated over influenza A(H1)pdm09 and B viruses, accounting for a total of 54% of all viruses analysed. The majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2017. However, phylogenetic analysis indicated that the majority of circulating A(H3) viruses had undergone genetic drift relative to the WHO recommended vaccine strain for 2017. Of 3733 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, only two A(H1)pdm09 viruses and one A(H3) virus showed highly reduced inhibition by oseltamivir, while just one A(H1)pdm09 virus showed highly reduced inhibition by zanamivir.

The first external quality assessment of isolation and identification of influenza viruses in cell culture in the Asia Pacific region, 2016.

BACKGROUND: The isolation and propagation of influenza viruses from clinical specimens are essential tools for comprehensive virologic surveillance. Influenza viruses must be amplified in cell culture for detailed antigenic analysis and for phenotypic assays assessing susceptibility to antiviral drugs or for other assays. OBJECTIVES: To conduct an external quality assessment (EQA) of proficiency for isolation and identification of influenza viruses using cell culture techniques among National Influenza Centres (NICs) in the World Health Organisation (WHO) South East Asia and Western Pacific Regions. STUDY DESIGN: Twenty-one NICs performed routine influenza virus isolation and identification techniques on a proficiency testing panel comprising 16 samples, containing influenza A or B viruses and negative control samples. One sample was used exclusively to determine their capacity to measure hemagglutination titer and the other 15 samples were used for virus isolation and identification. RESULTS: All NICs performed influenza virus isolation using Madin Darby canine kidney (MDCK) or MDCK-SIAT-1 cells. If virus growth was detected, the type, subtype and/or lineage of virus present in isolates was determined using immunofluorescence, RT-PCR and/or hemagglutination inhibition (HI) assays. Most participating laboratories could detect influenza virus growth and could identify virus amplified from EQA samples. However, some laboratories failed to isolate and identify viruses from EQA samples that contained lower titres of virus, highlighting issues regarding the sensitivity of influenza virus isolation methods between laboratories. CONCLUSION: This first round of EQA was successfully conducted by NICs in the Asia Pacific Region, revealing good proficiency in influenza virus isolation and identification.

Influenza vaccination responses: Evaluating impact of repeat vaccination among health care workers.

OBJECTIVE: To compare the antibody response to influenza between health care workers (HCWs) who have received multiple vaccinations (high vaccination group) and those who have received fewer vaccinations (low vaccination group). DESIGN: Prospective serosurvey. SETTING: Tertiary referral hospital. PARTICIPANTS: Healthcare workers. METHODS: Healthcare workers were vaccinated with the 2015 southern hemisphere trivalent influenza vaccine. Influenza antibody titres were measured pre-vaccination, 21-28days post-vaccination and 6months post-vaccination. Antibody titres were measured using the haemagglutination inhibition assay. Levels of seropositivity and estimated geometric mean titres were calculated. RESULTS: Of the 202 HCWs enrolled, 182 completed the study (143 high vaccination and 39 low vaccination). Both vaccination groups demonstrated increases in post-vaccination geometric mean titres, with greater gains in the low vaccination group. Seropositivity remained high in both high and low vaccination groups post-vaccination. The highest fold rise was observed among HCWs in the low vaccination group against the H3N2 component of the vaccine. CONCLUSIONS: Both high and low vaccination groups in our study demonstrated protective antibody titres post-vaccination. The findings from the current study are suggestive of decreased serological response among highly vaccinated HCWs. More studies with larger sample sizes and a greater number of people in the vaccine-naïve and once-vaccinated groups are required to confirm or refute these findings before making any policy changes.

The impact of antimicrobial allergy labels on antimicrobial usage in cancer patients.

BACKGROUND: Antibiotic allergy labels are associated with sub-optimal prescribing patterns and poorer clinical outcomes in non-cancer populations, but the effect of labelling on antimicrobial usage in patients with cancer is unknown. FINDINGS: A retrospective review of hospitalized patients admitted to the Peter MacCallum Cancer Centre (2010-2012) identified 23 % of cancer patients (n = 198) with an antimicrobial allergy label (AA). Comparison of those with an antimicrobial allergy label to those without demonstrated increased antibiotic use per admission (3 vs. 2, p = 0.01), increased fluoroquinolone use (11 % vs. 6 %, p < 0.05), increased antibiotic course duration (15 vs. 13 days, p = 0.09), higher readmission rates (53 % vs. 28 %, p < 0.001) and poorer concordance with prescribing guidelines (47 % vs. 91 %, p < 0.001). Patients in the AA group on multivariate analysis had a higher number of antibiotics employed, longer duration of antibiotic therapy and higher rate of readmission. CONCLUSIONS: Antimicrobial usage, including the use of restricted antibiotics, is higher in patients with cancer. Antibiotic de-labelling strategies in cancer patients must be evaluated to aid antimicrobial stewardship initiatives.