Opportunities to strengthen respiratory virus surveillance systems in Australia: lessons learned from the COVID-19 response.

Abstract: Disease surveillance data was critical in supporting public health decisions throughout the coronavirus disease 2019 (COVID-19) pandemic. At the same time, the unprecedented circumstances of the pandemic revealed many shortcomings of surveillance systems for viral respiratory pathogens. Strengthening of surveillance systems was identified as a priority for the recently established Australian Centre for Disease Control, which represents a critical opportunity to review pre-pandemic and pandemic surveillance practices, and to decide on future priorities, during both pandemic and inter-pandemic periods. On 20 October 2022, we ran a workshop with experts from the academic and government sectors who had contributed to the COVID-19 response in Australia on 'The role of surveillance in epidemic response', at the University of New South Wales, Sydney, Australia. Following the workshop, we developed five recommendations to strengthen respiratory virus surveillance systems in Australia, which we present here. Our recommendations are not intended to be exhaustive. We instead chose to focus on data types that are highly valuable yet typically overlooked by surveillance planners. Three of the recommendations focus on data collection activities that support the monitoring and prediction of disease impact and the effectiveness of interventions (what to measure) and two focus on surveillance methods and capabilities (how to measure). Implementation of our recommendations would enable more robust, timely, and impactful epidemic analysis.

Estimating measures to reduce the transmission of SARS-CoV-2 in Australia to guide a 'National Plan' to reopening.

The availability of COVID-19 vaccines promised a reduction in the severity of disease and relief from the strict public health and social measures (PHSMs) imposed in many countries to limit spread and burden of COVID-19. We were asked to define vaccine coverage thresholds for Australia's transition to easing restrictions and reopening international borders. Using evidence of vaccine effectiveness against the then-circulating Delta variant, we used a mathematical model to determine coverage targets. The absence of any COVID-19 infections in many sub-national jurisdictions in Australia posed particular methodological challenges. We used a novel metric called Transmission Potential (TP) as a proxy measure of the population-level effective reproduction number. We estimated TP of the Delta variant under a range of PHSMs, test-trace-isolate-quarantine (TTIQ) efficiencies, vaccination coverage thresholds, and age-based vaccine allocation strategies. We found that high coverage across all ages (≥70%) combined with ongoing TTIQ and minimal PHSMs was sufficient to avoid lockdowns. At lesser coverage (≤60%) rapid case escalation risked overwhelming of the health sector or the need to reimpose stricter restrictions. Maintaining low case numbers was most beneficial for health and the economy, and at higher coverage levels (≥80%) further easing of restrictions was deemed possible. These results directly informed easing of COVID-19 restrictions in Australia.

Estimating the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission in Australia.

BACKGROUND: Australian states and territories used test-trace-isolate-quarantine (TTIQ) systems extensively in their response to the COVID-19 pandemic in 2020-2021. We report on an analysis of Australian case data to estimate the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission. METHODS: Our analysis uses a novel mathematical modelling framework and detailed surveillance data on COVID-19 cases including dates of infection and dates of isolation. First, we directly translate an empirical distribution of times from infection to isolation into reductions in potential for onward transmission during periods of relatively low caseloads (tens to hundreds of reported cases per day). We then apply a simulation approach, validated against case data, to assess the impact of case-initiated contact tracing on transmission during a period of relatively higher caseloads and system stress (up to thousands of cases per day). RESULTS: We estimate that under relatively low caseloads in the state of New South Wales (tens of cases per day), TTIQ contributed to a 54% reduction in transmission. Under higher caseloads in the state of Victoria (hundreds of cases per day), TTIQ contributed to a 42% reduction in transmission. Our results also suggest that case-initiated contact tracing can support timely quarantine in times of system stress (thousands of cases per day). CONCLUSION: Contact tracing systems for COVID-19 in Australia were highly effective and adaptable in supporting the national suppression strategy from 2020-21, prior to the emergence of the Omicron variant in November 2021. TTIQ systems were critical to the maintenance of the strong suppression strategy and were more effective when caseloads were (relatively) low.

Individual variation in vaccine immune response can produce bimodal distributions of protection.

The ability for vaccines to protect against infectious diseases varies among individuals, but computational models employed to inform policy typically do not account for this variation. Here we examine this issue: we implement a model of vaccine efficacy developed in the context of SARS-CoV-2 in order to evaluate the general implications of modelling correlates of protection on the individual level. Due to high levels of variation in immune response, the distributions of individual-level protection emerging from this model tend to be highly dispersed, and are often bimodal. We describe the specification of the model, provide an intuitive parameterisation, and comment on its general robustness. We show that the model can be viewed as an intermediate between the typical approaches that consider the mode of vaccine action to be either "all-or-nothing" or "leaky". Our view based on this analysis is that individual variation in correlates of protection is an important consideration that may be crucial to designing and implementing models for estimating population-level impacts of vaccination programs.

COVID-19 vaccine coverage targets to inform reopening plans in a low incidence setting.

Since the emergence of SARS-CoV-2 in 2019 through to mid-2021, much of the Australian population lived in a COVID-19-free environment. This followed the broadly successful implementation of a strong suppression strategy, including international border closures. With the availability of COVID-19 vaccines in early 2021, the national government sought to transition from a state of minimal incidence and strong suppression activities to one of high vaccine coverage and reduced restrictions but with still-manageable transmission. This transition is articulated in the national 're-opening' plan released in July 2021. Here, we report on the dynamic modelling study that directly informed policies within the national re-opening plan including the identification of priority age groups for vaccination, target vaccine coverage thresholds and the anticipated requirements for continued public health measures-assuming circulation of the Delta SARS-CoV-2 variant. Our findings demonstrated that adult vaccine coverage needed to be at least 60% to minimize public health and clinical impacts following the establishment of community transmission. They also supported the need for continued application of test-trace-isolate-quarantine and social measures during the vaccine roll-out phase and beyond.

A modelling approach to estimate the transmissibility of SARS-CoV-2 during periods of high, low, and zero case incidence.

Against a backdrop of widespread global transmission, a number of countries have successfully brought large outbreaks of COVID-19 under control and maintained near-elimination status. A key element of epidemic response is the tracking of disease transmissibility in near real-time. During major outbreaks, the effective reproduction number can be estimated from a time-series of case, hospitalisation or death counts. In low or zero incidence settings, knowing the potential for the virus to spread is a response priority. Absence of case data means that this potential cannot be estimated directly. We present a semi-mechanistic modelling framework that draws on time-series of both behavioural data and case data (when disease activity is present) to estimate the transmissibility of SARS-CoV-2 from periods of high to low - or zero - case incidence, with a coherent transition in interpretation across the changing epidemiological situations. Of note, during periods of epidemic activity, our analysis recovers the effective reproduction number, while during periods of low - or zero - case incidence, it provides an estimate of transmission risk. This enables tracking and planning of progress towards the control of large outbreaks, maintenance of virus suppression, and monitoring the risk posed by re-introduction of the virus. We demonstrate the value of our methods by reporting on their use throughout 2020 in Australia, where they have become a central component of the national COVID-19 response.

COVID-19 Highlights the Need for More Effective Wildlife Trade Legislation.

Zoonosis-based epidemics are inevitable unless we revisit our relationship with the natural world, protect habitats, and regulate wildlife trade, including live animals and non-sustenance products. To prevent future zoonoses, governments must establish effective legislation addressing wildlife trade, protection of habitats, and reduction of the wildlife-livestock-human interface.

Simultaneous-count models to estimate abundance from counts of unmarked individuals with imperfect detection.

We developed a method to estimate population abundance from simultaneous counts of unmarked individuals over multiple sites. We considered that at each sampling occasion, individuals in a population could be detected at 1 of the survey sites or remain undetected and used either multinomial or binomial simultaneous-count models to estimate abundance, the latter being equivalent to an N-mixture model with one site. We tested model performance with simulations over a range of detection probabilities, population sizes, growth rates, number of years, sampling occasions, and sites. We then applied our method to 3 critically endangered vulture species in Cambodia to demonstrate the real-world applicability of the model and to provide the first abundance estimates for these species in Cambodia. Our new approach works best when existing methods are expected to perform poorly (i.e., few sites and large variation in abundance among sites) and if individuals may move among sites between sampling occasions. The approach performed better when there were >8 sampling occasions and net probability of detection was high (>0.5). We believe our approach will be useful in particular for simultaneous surveys at aggregation sites, such as roosts. The method complements existing approaches for estimating abundance of unmarked individuals and is the first method designed specifically for simultaneous counts.

Modelos de Conteo Simultáneo para Estimar la Abundancia a partir de Conteos de Individuos No Marcados con Detección Imperfecta Resumen Desarrollamos un método para estimar la abundancia poblacional a partir de conteos simultáneos de individuos sin marcaje en múltiples sitios. Consideramos que en cada ocasión de muestreo los individuos de una población podrían ser detectados en uno de los sitios de censos o podrían permanecer sin ser detectados y usamos modelos de conteo simultáneo multinomial o binomial para estimar la abundancia, con el binomial como equivalente a un modelo de mezcla N con un solo sitio. Probamos el desempeño del modelo con simulaciones en un rango de probabilidades de detección, tamaños poblacionales, tasas de crecimiento, número de años, ocasiones de muestreo, y sitios. Después aplicamos nuestro método a tres especies de buitre que se encuentran en peligro crítico en Camboya para demostrar cuán aplicable es el modelo en el mundo real y para proporcionar las primeras estimaciones de abundancia para estas especies en Camboya. Nuestra nueva estrategia trabaja de mejor manera cuando se espera que los modelos existentes tengan un desempeño pobre (es decir, pocos sitios y una gran variación en la abundancia entre sitios) y si los individuos podrían moverse de un sitio a otro entre cada ocasión de muestreo. La estrategia tuvo un mejor desempeñó cuando hubo >8 ocasiones de muestreo y la probabilidad neta de detección fue alta (>0.5). Creemos que nuestra estrategia será especialmente útil para censos simultáneos en sitios de agregación, como los nidos. El método complementa las estrategias existentes para estimar la abundancia de individuos sin marcaje y es el primer método diseñado específicamente para conteos simultáneos.

Demographic collapse and low genetic diversity of the Irrawaddy dolphin population inhabiting the Mekong River.

In threatened wildlife populations, it is important to determine whether observed low genetic diversity may be due to recent anthropogenic pressure or the consequence of historic events. Historical size of the Irrawaddy dolphin (Orcaella brevirostris) population inhabiting the Mekong River is unknown and there is significant concern for long-term survival of the remaining population as a result of low abundance, slow reproduction rate, high neonatal mortality, and continuing anthropogenic threats. We investigated population structure and reconstructed the demographic history based on 60 Irrawaddy dolphins samples collected between 2001 and 2009. The phylogenetic analysis indicated reciprocal monophyly of Mekong River Orcaella haplotypes with respect to haplotypes from other populations, suggesting long-standing isolation of the Mekong dolphin population from other Orcaella populations. We found that at least 85% of all individuals in the two main study areas: Kratie and Stung Treng, bore the same mitochondrial haplotype. Out of the 21 microsatellite loci tested, only ten were polymorphic and exhibited very low levels of genetic diversity. Both individual and frequency-based approaches suggest very low and non-significant genetic differentiation of the Mekong dolphin population. Evidence for recent bottlenecks was equivocal. Some results suggested a recent exponential decline in the Mekong dolphin population, with the current size being only 5.2% of the ancestral population. In order for the Mekong dolphin population to have any potential for long-term survival, it is imperative that management priorities focus on preventing any further population fragmentation or genetic loss, reducing or eliminating anthropogenic threats, and promoting connectivity between all subpopulations.

Clostridium difficile infection in cystic fibrosis: an uncommon but life-threatening complication.

Adults with cystic fibrosis (CF) have significant rates of asymptomatic Clostridium difficile carriage and are frequently exposed to risk factors for C. difficile infection (CDI). Despite this, the rate of reported CDI in CF is low. We describe three cases of near fatal CDI in adults with CF and review the literature regarding presentation, management, and recurrence prevention. Early recognition is important as the clinical presentation may be atypical and the illness can be severe and even life-threatening. Management can be complicated by respiratory and nutritional failure. CF-related gastrointestinal dysfunction may alter the typical host-pathogen interaction between patient and C. difficile, potentially explaining the low rates of CDI and atypical presentation.

Inefficiency in macromolecular transport of SCS-based microcapsules affects viability of primary human mesenchymal stem cells but not of immortalized cells.

Microcapsules made of sodium cellulose sulphate (SCS) and poly-diallyl-dimethyl-ammonium chloride (pDADMAC) have been employed to encapsulate a wide range of established cell lines for several applications. However, little is known about the encapsulation of primary cells including human mesenchymal stem cells (hMSCs). Human MSCs are of interest in regenerative medicine applications due to pro-angiogenic, anti-inflammatory and immunomodulatory properties, which result from paracrine effects of this cell type. In the present work we have encapsulated primary hMSCs and hMSC-TERT immortalized cells and compared their behavior and in vitro angiogenic potential. We found that, although both cell types were able to secret angiogenic factors such as VEGF, there was a marked reduction of primary hMSC viability compared to hMSC-TERT cells when cultured in these microcapsules. Moreover, this applied to other primary cell cultures such as primary human fibroblasts but not to other cell lines such as human embryonic kidney 293 (HEK293) cells. We found that the microcapsule membrane had a molecular weight cut-off below a critical size, which caused impairment in the diffusion of essential nutrients and had a more detrimental effect on the viability of primary cell cultures compared to cell lines and immortalized cells.

Inhaled antibiotics for pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. OBJECTIVES: To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work and improves their long-term survival. SEARCH METHODS: We searched ClinicalTrials.gov and the Australia and New Zealand Clinical Trials Registry for relevant trials. Date of last search: 15 March 2012We also searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 01 June 2012. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. Authors of the included trials were contacted for more information. MAIN RESULTS: Six trials with 208 participants were included in the review. Trials were heterogenous in design and interventions (however, all included trials compared inhaled versus intravenous antibiotic regimens). Risk of bias was difficult to assess in most trials. Results were not fully reported and only limited data were available for analysis. Four trials reported some results on forced expiratory volume at one second and found no significant differences between the inhaled antibiotic and the comparison intervention. In two of these trials using 300 mg of inhaled tobramycin, the change in forced expiratory volume at one second was similar to intravenous tobramycin; and in one trial the time until the next exacerbation was not different. No important adverse effects were reported. AUTHORS' CONCLUSIONS: There is little useful high-level evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations.

Cystic fibrosis in Australia, 2009: results from a data registry.

OBJECTIVES: To describe the demographics, clinical features and outcomes among people with cystic fibrosis (CF) in Australia and to estimate incidence of the disease. DESIGN AND SETTING: Cross-sectional analysis using data from the Australian Cystic Fibrosis Data Registry for 2009. MAIN OUTCOME MEASURES: Numbers of diagnoses, pulmonary and anthropometric measurements, microbiological culture results, rates of hospitalisation and transplantation, and numbers of medical complications and deaths. RESULTS: In 2009, data were submitted on 2986 people (48% female). Median age was 17.6 years and 49% of people were aged 18 years or over. Seventy-eight people were newly diagnosed. Fourteen people died and 14 people underwent lung transplantation in the year. Lung function and nutrition were relatively normal among children but deteriorated (more rapidly) among adolescents. With increasing age, progressive respiratory disease was apparent, and the frequency of CF-related complications and use of health care resources increased. In all age groups, there was a wide range in severity of lung disease and nutritional status. CONCLUSIONS: CF remains a progressive respiratory disease and is associated with multisystem complications. The acceleration in disease severity in adolescence and early adulthood suggests that better treatment at these stages is required to further improve survival.

Effectiveness of ophthalmic solution preservatives: a comparison of latanoprost with 0.02% benzalkonium chloride and travoprost with the sofZia preservative system.

BACKGROUND: Although in vitro and in vivo laboratory studies have suggested that benzalkonium chloride (BAK) in topical ophthalmic solutions may be detrimental to corneal epithelial cells, multiple short- and long-term clinical studies have provided evidence supporting the safety of BAK. Despite the conflicting evidence, BAK is the most commonly used preservative in ophthalmic products largely due to its proven antimicrobial efficacy. This study was designed to characterize the antimicrobial performance of two commonly used topical ocular hypotensive agents that employ different preservative systems: latanoprost 0.005% with 0.02% BAK and travoprost 0.004% with sofZia, a proprietary ionic buffer system. METHODS: Each product was tested for antimicrobial effectiveness by European Pharmacopoeia A (EP-A) standards, the most stringent standards of the three major compendia, which specify two early sampling time points (6 and 24 hours) not required by the United States Pharmacopeia or Japanese Pharmacopoeia. Aliquots were inoculated with between 10(5) and 10(6) colony-forming units of the test organisms: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Aspergillus brasiliensis. Sampling and enumeration were conducted at protocol-defined time points through 28 days. RESULTS: BAK-containing latanoprost met EP-A criteria by immediately reducing all bacterial challenge organisms to the test sensitivity and fungal challenges within the first six hours while the preservative activity of travoprost with sofZia did not. Complete bacterial reduction by travoprost with sofZia was not shown until seven days into the test, and fungal reduction never exceeded the requisite 2 logs during the 28-day test. Travoprost with sofZia also did not meet EP-B criteria due to its limited effectiveness against Staphylococcus aureus. Both products satisfied United States and Japanese pharmacopoeial criteria. CONCLUSIONS: Latanoprost with 0.02% BAK exhibited more effective microbial protection than travoprost with sofZia using rates of microbial reduction, time to no recovery for all challenges and evaluation against EP-A criteria as measures. The rapid and complete reduction of all microbial challenges demonstrates that antimicrobial activity of latanoprost with 0.02% BAK exceeds that of travoprost with sofZia preservative system in these products and provides a more protective environment in the event of contamination and subsequent exposure to microorganisms during use.

Inhaled antibiotics for long-term therapy in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection that contributes to lung damage in people with cystic fibrosis (CF). OBJECTIVES: To examine the evidence that inhaled antibiotic treatment in people with CF reduces frequency of exacerbations of infection, and improves lung function, quality of life and survival. To examine adverse effects of inhaled antibiotic treatment. SEARCH STRATEGY: Trials were identified from the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register.Last search: 31 January 2011. SELECTION CRITERIA: Trials were selected if inhaled antibiotic treatment was used for at least four weeks in people with CF, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias and extracted data from these trials. MAIN RESULTS: The searches identified 176 citations to 78 trials. Nineteen trials, with 1724 participants, met the inclusion criteria. Adequate meta-analysis was not possible because of the variability of study design and reporting of results. Seventeen trials with 1562 participants compared an inhaled antibiotic with placebo or usual treatment for a duration between 1 and 32 months. Inhaled tobramycin was studied in eight trials. Lung function (measured as forced expired volume in one second) was higher and exacerbations of lung infection (by different measures) were less in the antibiotic-treated group. Resistance to antibiotics increased more in the antibiotic-treated group than in placebo group when results were reported. No auditory or renal impairment was found; analysis showed tinnitus, voice alteration, hemoptysis and cough were more frequent with tobramycin than placebo. One trial, compared tobramycin with colistin in 115 participants, after one month the mean difference in forced expiratory volume at one second was 6.33 (95% confidence interval -0.04 to 12.70) favouring tobramycin. AUTHORS' CONCLUSIONS: Inhaled antibiotic treatment probably improves lung function and reduces exacerbation rate, but a pooled estimate of the level of benefit is not possible. The best evidence is for inhaled tobramycin. More evidence, from trials of longer duration, is needed to determine whether this benefit is maintained and to determine the significance of development of antibiotic-resistant organisms.

Randomized trial of a decision aid for patients with cystic fibrosis considering lung transplantation.

RATIONALE: We developed an evidence-based decision aid for patients with advanced cystic fibrosis considering referral for lung transplantation. OBJECTIVES: To prospectively evaluate whether use of the decision aid increased knowledge about the options, improved realistic expectations, and decreased decisional conflict in adult patients. METHODS: We performed a single-blind randomized controlled trial involving 149 adult patients with cystic fibrosis with an FEV(1)

Respiratory infections and lung function in an Australian Aboriginal community.

BACKGROUND AND OBJECTIVE: To investigate the association between serological evidence of past infections with common respiratory pathogens and lung function in members of an isolated community of Aborigines from tropical coastal north-western Australia. METHODS: FEV(1) and FVC were assessed by dry bellows spirometer. Serum IgG titres to 11 common respiratory pathogens were assayed. Smoking history was assessed by questionnaire. Reciprocal positive IgG titres were taken as >or=10 for all pathogens with the exception of Legionella spp. (>or=40) and Burkholderia pseudomallei (>or=20). Linear regression analysis examined associations between titres and lung function after adjustment for age, height, gender and smoking, separately for adults (age > 17 years) and children. RESULTS: An increased total number of positive IgG titres was significantly associated with reduced FEV(1) (P = 0.01) and FEV(1)/FVC ratio (P = 0.01) suggesting the presence of airflow obstruction. This association was independent of age, gender, height, weight and smoking status. CONCLUSIONS: The burden of past respiratory infections may be an important determinant of airway function in this Aboriginal community.