Delay-adjusted age- and sex-specific case fatality rates for COVID-19 in South Korea: Evolution in the estimated risk of mortality throughout the epidemic.

OBJECTIVES: The aim of this study was to estimate delay-adjusted case fatality rates (CFRs) for COVID-19 in South Korea, and evaluate how these estimates have evolved over time throughout the epidemic. METHODS: Public data from the Korea Centers for Disease Control and Prevention (KCDC) were used to estimate age- and sex-specific CFRs for COVID-19 in South Korea up to June 12, 2020. We applied statistical methods previously developed to adjust for the delay between diagnosis and death, and presented both delay-adjusted and crude (unadjusted) CFRs throughout the epidemic. RESULTS: The overall estimated delay-adjusted CFR was 2.39% (3.05% for males and 1.92% for females). Within each age strata where deaths were reported, males were found to have significantly higher CFRs than females. The estimated CFRs increased substantially from age 60 years in males and from 70 years in females. Both the delay-adjusted and crude CFRs were found to have evolved substantially, particularly early in the epidemic, converging only from mid-April 2020. CONCLUSIONS: The CFRs for South Korea provide an estimate of mortality risk in a setting where case ascertainment is likely to be more complete. The evolution in CFRs throughout the epidemic highlights the need for caution when interpreting CFRs calculated at a given time point.

Estimating seasonal variation in Australian pertussis notifications from 1991 to 2016: evidence of spring to summer peaks.

Unlike for many other respiratory infections, the seasonality of pertussis is not well understood. While evidence of seasonal fluctuations in pertussis incidence has been noted in some countries, there have been conflicting findings including in the context of Australia. We investigated this issue by analysing the seasonality of pertussis notifications in Australia using monthly data from January 1991 to December 2016. Data were made available for all states and territories in Australia except for the Australian Capital Territory and were stratified into age groups. Using a time-series decomposition approach, we formulated a generalised additive model where seasonality is expressed using cosinor terms to estimate the amplitude and peak timing of pertussis notifications in Australia. We also compared these characteristics across different jurisdictions and age groups. We found evidence that pertussis notifications exhibit seasonality, with peaks observed during the spring and summer months (November-January) in Australia and across different states and territories. During peak months, notifications are expected to increase by about 15% compared with the yearly average. Peak notifications for children <5 years occurred 1-2 months later than the general population, which provides support to the theory that older household members remain an important source of pertussis infection for younger children. In addition, our results provide a more comprehensive spatial picture of seasonality in Australia, a feature lacking in previous studies. Finally, our findings suggest that seasonal forcing may be useful to consider in future population transmission models of pertussis.

Pneumonia hospitalisation and case-fatality rates in older Australians with and without risk factors for pneumococcal disease: implications for vaccine policy.

Community-acquired pneumonia (CAP) results in substantial numbers of hospitalisations and deaths in older adults. There are known lifestyle and medical risk factors for pneumococcal disease but the magnitude of the additional risk is not well quantified in Australia. We used a large population-based prospective cohort study of older adults in the state of New South Wales (45 and Up Study) linked to cause-specific hospitalisations, disease notifications and death registrations from 2006 to 2015. We estimated the age-specific incidence of CAP hospitalisation (ICD-10 J12-18), invasive pneumococcal disease (IPD) notification and presumptive non-invasive pneumococcal CAP hospitalisation (J13 + J18.1, excluding IPD), comparing those with at least one risk factor to those with no risk factors. The hospitalised case-fatality rate (CFR) included deaths in a 30-day window after hospitalisation. Among 266 951 participants followed for 1 850 000 person-years there were 8747 first hospitalisations for CAP, 157 IPD notifications and 305 non-invasive pneumococcal CAP hospitalisations. In persons 65-84 years, 54.7% had at least one identified risk factor, increasing to 57.0% in those ⩾85 years. The incidence of CAP hospitalisation in those ⩾65 years with at least one risk factor was twofold higher than in those without risk factors, 1091/100 000 (95% confidence interval (CI) 1060-1122) compared with 522/100 000 (95% CI 501-545) and IPD in equivalent groups was almost threefold higher (18.40/100 000 (95% CI 14.61-22.87) vs. 6.82/100 000 (95% CI 4.56-9.79)). The CFR increased with age but there were limited difference by risk status, except in those aged 45 to 64 years. Adults ⩾65 years with at least one risk factor have much higher rates of CAP and IPD suggesting that additional risk factor-based vaccination strategies may be cost-effective.

Within-season influenza vaccine waning suggests potential net benefits to delayed vaccination in older adults in the United States.

BACKGROUND: There is growing evidence that there is within (intra-) season waning of influenza vaccine protection in older adults, suggesting there may be a benefit to giving influenza vaccine closer to the time of increased infection risk. We aimed to quantitatively evaluate the impact of modifying the timing of influenza vaccination in U.S. older adults. METHODS: Using historical data (2010/2011-2015/2016, inclusive) on influenza activity and vaccine uptake, we explore the optimal time to begin vaccinating older adults (≥65 years) in the U.S. to maximize prevention of influenza. We modelled the effect of changing the timing of vaccination by estimating the percentage change to the current disease burden and used this to calculate the estimated optimal week to begin vaccination in the U.S. RESULTS: When we assumed a relatively slower waning protection rate (over 52 weeks), the estimated optimal time to begin vaccinating those aged ≥65 years varied between mid-August (week 34, 2012-2013) and mid-late October (week 43, 2011-2012) depending on the season, resulting in 0.44% and 5.11% of the current disease burden prevented respectively. Under faster waning (over 26 weeks), the estimated optimal week varied between early September (week 37, 2012-2013) and mid-November (week 47, 2011-2012), resulting in 3.69% and 11.97% of the current disease burden prevented respectively. CONCLUSIONS: While it is difficult to determine the ideal time to start to vaccinate due to substantial variation in timing of individual seasons, we found that there are potentially substantial benefits to minimizing the time between vaccination and influenza activity in U.S. older adults. Modest delays in immunization were beneficial in the seasons we evaluated. If further evidence suggests fast waning, longer delays may be warrant as in these scenarios the timing of the current vaccination was often very suboptimal.

The role of timeliness in the cost-effectiveness of older adult vaccination: A case study of pneumococcal conjugate vaccine in Australia.

While the impact of the timeliness of vaccine administration has been well-studied for childhood vaccinations, there has been little detailed quantitative analysis on the potential impact of the timeliness of vaccinations in older adults. The aim of this study was to explore the impact of implementing more realistic observed uptake distributions, taking into the account reduced vaccine efficacy but higher pneumococcal disease burden with increasing age beyond 65 years. A multi-cohort Markov model was constructed to evaluate the cost-effectiveness of a pneumococcal (PCV13) immunisation program in Australia, assuming two different uptake modelling approaches. The approach using an estimate of observed uptake was compared with a scenario in which the total cumulative uptake was delivered at the recommended age of vaccination. We found these two approaches produced different results both in terms of cases prevented and cost-effectiveness. The impact of the non-timely uptake in adult programs may sometimes have positive and other times negative effects, depending on several factors including the age-specific disease rates and the duration of vaccine protection. Our study highlights the importance of using realistic assumptions around uptake (including non-timely vaccination) when estimating the impact of vaccination in adults.

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in older Australians.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been funded under the Australia National Immunisation Program (NIP) since January 2005 for those aged >65years and other risk groups. In 2016, PCV13 was accepted by the Pharmaceutical Benefits Advisory Committee (PBAC) as a replacement for a single dose of PPV23 in older Australian adults. METHODS: A single-cohort deterministic multi-compartment (Markov) model was developed describing the transition of the population between different invasive and non-invasive pneumococcal disease related health states. We applied a healthcare system perspective with costs (Australian dollars, A$) and health effects (measured in quality adjusted life-years, QALYs) attached to model states and discounted at 5% annually. We explored replacement of PPV23 with PCV13 at 65years as well as other age based vaccination strategies. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS: In a single cohort, we estimated PCV13 vaccination at the age of 65years to cost ∼A$11,120,000 and prevent 39 hospitalisations and 6 deaths from invasive pneumococcal disease and 180 hospitalisations and 10 deaths from community acquired pneumonia. The PCV13 program had an incremental cost-effectiveness ratio of ∼A$88,100 per QALY gained when compared to a no-vaccination, whereas PPV23 was ∼A$297,200 per QALY gained. To fall under a cost-effectiveness threshold of A$60,000 per QALY, PCV13 would have to be priced below ∼A$46 per dose. The cost-effectiveness of PCV13 in comparison to PPV23 was ∼A$35,300 per QALY gained. CONCLUSION: In comparison to no-vaccination, we found PCV13 use in those aged 65years was unlikely to be cost-effective unless the vaccine price was below A$46 or a longer duration of protection can be established. However, we found that in comparison to the PPV23, vaccination with PCV13 was cost-effective. This partly reflects the poor value for money estimated for PPV23 use in Australia.

Beyond expectations: Post-implementation data shows rotavirus vaccination is likely cost-saving in Australia.

BACKGROUND: Universal vaccination against rotavirus was included in the funded Australian National Immunisation Program in July 2007. Predictive cost-effectiveness models assessed the program before introduction. METHODS: We conducted a retrospective economic evaluation of the Australian rotavirus program using national level post-implementation data on vaccine uptake, before-after measures of program impact and published estimates of excess intussusception cases. These data were used as inputs into a multi-cohort compartmental model which assigned cost and quality of life estimates to relevant health states, adopting a healthcare payer perspective. The primary outcome was discounted cost per quality adjusted life year gained, including or excluding unspecified acute gastroenteritis (AGE) hospitalisations. RESULTS: Relative to the baseline period (1997-2006), over the 6years (2007-2012) after implementation of the rotavirus program, we estimated that ∼77,000 hospitalisations (17,000 coded rotavirus and 60,000 unspecified AGE) and ∼3 deaths were prevented, compared with an estimated excess of 78 cases of intussusception. Approximately 90% of hospitalisations prevented were in children <5years, with evidence of herd protection in older age groups. The program was cost-saving when observed changes (declines) in both hospitalisations coded as rotavirus and as unspecified AGE were attributed to the rotavirus vaccine program. The adverse impact of estimated excess cases of intussusception was far outweighed by the benefits of the program. CONCLUSION: The inclusion of herd impact and declines in unspecified AGE hospitalisations resulted in the value for money achieved by the Australian rotavirus immunisation program being substantially greater than predicted bypre-implementation models, despite the potential increased cases of intussusception. This Australian experience is likely to be relevant to high-income countries yet to implement rotavirus vaccination programs.

Estimating the critical immunity threshold for preventing hepatitis A outbreaks in men who have sex with men.

Several outbreaks of hepatitis A in men who have sex with men (MSM) were reported in the 1980s and 1990s in Australia and other countries. An effective hepatitis A virus (HAV) vaccine has been available in Australia since 1994 and is recommended for high-risk groups including MSM. No outbreaks of hepatitis A in Australian MSM have been reported since 1996. In this study, we aimed to estimate HAV transmissibility in MSM populations in order to inform targets for vaccine coverage in such populations. We used mathematical models of HAV transmission in a MSM population to estimate the basic reproduction number (R 0) and the probability of an HAV epidemic occurring as a function of the immune proportion. We estimated a plausible range for R 0 of 1·71-3·67 for HAV in MSM and that sustained epidemics cannot occur once the proportion immune to HAV is greater than ~70%. To our knowledge this is the first estimate of R 0 and the critical population immunity threshold for HAV transmission in MSM. As HAV is no longer endemic in Australia or in most other developed countries, vaccination is the only means of maintaining population immunity >70%. Our findings provide impetus to promote HAV vaccination in high-risk groups such as MSM.

Retrospective economic evaluation of childhood 7-valent pneumococcal conjugate vaccination in Australia: Uncertain herd impact on pneumonia critical.

BACKGROUND: Retrospective cost-effectiveness analyses of vaccination programs using routinely collected post-implementation data are sparse by comparison with pre-program analyses. We performed a retrospective economic evaluation of the childhood 7-valent pneumococcal conjugate vaccine (PCV7) program in Australia. METHODS: We developed a deterministic multi-compartment model that describes health states related to invasive and non-invasive pneumococcal disease. Costs (Australian dollars, A$) and health effects (quality-adjusted life years, QALYs) were attached to model states. The perspective for costs was that of the healthcare system and government. Where possible, we used observed changes in the disease rates from national surveillance and healthcare databases to estimate the impact of the PCV7 program (2005-2010). We stratified our cost-effectiveness results into alternative scenarios which differed by the outcome states included. Parameter uncertainty was explored using probabilistic sensitivity analysis. RESULTS: The PCV7 program was estimated to have prevented ∼5900 hospitalisations and ∼160 deaths from invasive pneumococcal disease (IPD). Approximately half of these were prevented in adults via herd protection. The incremental cost-effectiveness ratio was ∼A$161,000 per QALY gained when including only IPD-related outcomes. The cost-effectiveness of PCV7 remained in the range A$88,000-$122,000 when changes in various non-invasive disease states were included. The inclusion of observed changes in adult non-invasive pneumonia deaths substantially improved cost-effectiveness (∼A$9000 per QALY gained). CONCLUSION: Using the initial vaccine price negotiated for Australia, the PCV7 program was unlikely to have been cost-effective (at conventional thresholds) unless observed reductions in non-invasive pneumonia deaths in the elderly are attributed to it. Further analyses are required to explore this finding, which has significant implications for the incremental benefit achievable by adult PCV programs.

A review of economic evaluations of 13-valent pneumococcal conjugate vaccine (PCV13) in adults and the elderly.

The 13-valent pneumococcal conjugated vaccine (PCV13) is already recommended for some adult groups and is being considered for wider use in many countries. In order to identify the strengths and limitations of the existing economic evaluation studies of PCV13 in adults and the elderly a literature review was conducted. The majority of the studies identified (9 out of 10) found that PCV13 was cost-effective in adults and/or the elderly. However, these results were based on assumptions that could not always be informed by robust evidence. Key uncertainties included the efficacy of PCV13 against non-invasive pneumonia and the herd immunity effect of childhood vaccination programs. Emerging trial evidence on PCV13 in adults from the Netherlands offers the ability to parameterize future economic evaluations with empirical efficacy data. However, it is important that these estimates are used thoughtfully when they are transferred to other settings.

Revisiting Styblo's law: could mathematical models aid in estimating incidence from prevalence data?

Estimation of the true incidence of tuberculosis (TB) is challenging. The approach proposed by Styblo in 1985 is known to be inaccurate in the modern era where there is widespread availability of treatment for TB. This study re-examines the relationship of incidence to prevalence and other disease indicators that can be derived from surveys. We adapt a simple, previously published model that describes the epidemiology of TB in the presence of treatment to investigate a revised ratio-based approach to estimating incidence. We show that, following changes to treatment programmes for TB, the ratio of incidence to prevalence reaches an equilibrium value rapidly; long before other model indicators have stabilized. We also show that this ratio relies on few parameters but is strongly dependent on, and requires knowledge of, the efficacy and timeliness of treatment.

Control of varicella in the post-vaccination era in Australia: a model-based assessment of catch-up and infant vaccination strategies for the future.

In Australia, varicella vaccine was universally funded in late 2005 as a single dose at 18 months. A school-based catch-up programme for children aged 10-13 years without a history of infection or vaccination was funded until 2015, when those eligible for universal infant vaccination would have reached the age of high school entry. This study projects the impact of discontinuing catch-up vaccination on varicella and zoster incidence and morbidity using a transmission dynamic model, in comparison with alternative policy options, including two-dose strategies. At current vaccine coverage (83% at 2 years and 90% at 5 years), ceasing the adolescent catch-up programme in 2015 was projected to increase varicella-associated morbidity between 2035 and 2050 by 39%. Although two-dose infant programmes had the lowest estimated varicella morbidity, the incremental benefit from the second dose fell by 70% if first dose coverage increased from 83% to 95% by age 24 months. Overall zoster morbidity was predicted to rise after vaccination, but differences between strategies were small. Our results suggest that feasibility of one-dose coverage approaching 95% is an important consideration in estimating incremental benefit from a second dose of varicella vaccine.

Economic evaluations of implemented vaccination programmes: key methodological challenges in retrospective analyses.

Post-implementation evaluation should play an important role in assessing the success of public health programmes; however, the value for money achieved by vaccine programmes after introduction has received relatively little attention to date. In this article we explore the methodological challenges in these analyses and offer direction for future evaluations in the area. We identify alternative approaches to addressing these challenges, which include the estimation of disease changes attributable to vaccination efforts, the hypothetical no vaccination comparator scenario and the full benefit achieved by implemented vaccination programmes. We also outline other important considerations such as the evolution of prices over time. Further work needs to be done to explore these issues and to determine how the application of different approaches may impact on the results of evaluations in various circumstances. As retrospective analyses are likely to become more frequent and influential, it is important that both the benefits and the limitations of post-implementation evaluations are recognised and understood. We argue that it would be useful to establish a methodological framework to provide standards and guidance on how to undertake such analyses in the future.

Changes in seroprevalence to hepatitis A in Victoria, Australia: a comparison of three time points.

Serological data provide an important measure of past exposure and immunity to hepatitis A virus (HAV) infection in a population. National serosurveys from developed countries have typically indicated a decline in HAV seroprevalence over time as sanitation levels improve. We examined trends in the seroepidemiology of HAV antibodies in Victoria, Australia, drawing on cross-sectional samples taken at three time points over a 20-year period. Stored sera from 1988 (n=753), 1998 (n=1091), and 2008 (n=791) from persons aged 1-69 years were obtained from the state of Victoria, Australia. The within-year population adjusted results show a significant trend of increasing population HAV seroprevalence over time from 34.3% (95% CI 31.7-36.9) in 1988, to 40.0% (95% CI 37.1-42.8) in 1998 and 55.1% (95% CI 52.1-58.1) in 2008, P<0.0001. A particularly noticeable rise in population seroprevalence was observed between 1998 and 2008 for those aged 5-39 years. The increase in HAV seropositivity over time is in contrast to the declining rates of disease notification in Australia. Based on comparisons with other Australian data, it appears the increase in population seroprevalence over the last two decades is unlikely to be due to endemic transmission of infection. Instead, other factors, including increases in travel to HAV endemic regions, migration to Australia from HAV endemic regions and vaccine uptake are more likely causes. Ongoing monitoring of serological HAV profiles in the population is required to determine future policy direction to prevent increased burden.

Modelling the impact of one-dose vs. two-dose vaccination regimens on the epidemiology of varicella zoster virus in Australia.

We examined the impact of one-dose vs. two-dose vaccination strategies on the epidemiology of varicella zoster virus (VZV) in Australia, using a mathematical model. Strategies were assessed in terms of varicella (natural and breakthrough) and zoster incidence, morbidity, average age of infection and vaccine effectiveness (VE). Our modelling results suggest that compared to a one-dose vaccination strategy (Australia's current vaccination schedule), a two-dose strategy is expected to not only produce less natural varicella cases (5% vs. 13% of pre-vaccination state, respectively) but also considerably fewer breakthrough varicella cases (only 11.4% of one-dose strategy). Therefore a two-dose infant vaccination programme would be a better long-term strategy for Australia.

Influenza-attributable mortality in Australians aged more than 50 years: a comparison of different modelling approaches.

This study aimed to compare systematically approaches to estimating influenza-attributable mortality in older Australians. Using monthly age-specific death data together with viral surveillance counts for influenza and respiratory syncytial virus, we explored two of the most frequently used methods of estimating excess influenza-attributable disease: Poisson and Serfling regression models. These approaches produced consistent age and temporal patterns in estimates of influenza-attributable mortality in older Australians but some variation in the magnitude of the disease burden. Of Australians aged >50 years, average annual estimated influenza-attributable deaths (all cause) ranged from 2314 to 3457 for the Serfling and Poisson regression models, respectively. The excess influenza-attributable disease burden was substantial under all approaches.

Leukotriene B(4) promotes reactive oxidant generation and leukocyte adherence during acute hypoxia.

Acute systemic hypoxia produces rapid leukocyte adherence in the rat mesenteric microcirculation, although the underlying mechanisms are not fully known. Hypoxia is known to increase reactive oxygen species (ROS) generation, which could result in formation of the lipid inflammatory mediator leukotriene B(4) (LTB(4)). The goal of this study was to examine the role of LTB(4) in hypoxia-induced microvascular alterations. Using intravital microscopy, we determined the effect of the LTB(4) antagonist, LTB(4)-dimethyl amide (LTB(4)-DMA), on ROS generation and leukocyte adherence in mesenteric venules during hypoxia. Exogenous LTB(4) increased ROS generation to 144 +/- 8% compared with control values and also promoted leukocyte adherence. These responses to LTB(4) were blocked by pretreating the mesentery with LTB(4)-DMA. Leukopenia did not significantly attenuate the LTB(4)-induced increase in ROS generation (142 +/- 12.1%). LTB(4)-DMA substantially, though not completely, reduced hypoxia-induced ROS generation from 66 +/- 18% to 11 +/- 4% above control values. Hypoxia-induced leukocyte adherence was significantly attenuated by LTB(4)-DMA. Our results support a role for LTB(4) in the mechanism of hypoxia-induced ROS generation and leukocyte adherence in the rat mesenteric microcirculation.

The effect of nitric oxide inhibition on blood pressure depends on rat strain.

BACKGROUND: Nitric oxide is a continuously released endothelium-derived vasodilator and plays an important role in the maintenance of blood pressure (BP). Rat strains appear to differ in their resting BP and their response to the intravenous administration of N(omega)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. The presence of diabetes and hypertension also leads to differences in BP responses to l-NAME. We postulated that the contribution of NO to resting BP varies between rat strains and certain strains may be more sensitive to the effects of NO blockade. METHODS: Blood pressure was continuously measured using a carotid arterial catheter and the responses to l-NAME were compared in anesthetized Lewis and Sprague-Dawley rats during a 2-h control period and a 2-h experimental period. l-NAME was given by a 50 mg/kg bolus followed by a 10 mg/kg/h infusion via a mesenteric vein. RESULTS: During the control period, the Lewis animals had lower systolic and diastolic BPs of 103 +/- 1 and 80 +/- 1 mm Hg compared with 127 +/- 1 and 105 +/- 1 mm Hg measured in Sprague-Dawley rats (P < 0.01). Although l-NAME infusion increased systolic BP in both strains compared with control values (P < 0.00005), the magnitude was significantly greater in Sprague-Dawley than Lewis animals (P = 0.0142); additionally, the BP was unstable in the Lewis animals. Furthermore, pulse pressure decreased during l-NAME in Lewis animals but increased in Sprague-Dawley animals (P < 0.00005). There were no significant changes in serum concentrations of aspartate transaminase nor of nitrite plus nitrate after l-NAME in either group. CONCLUSION: These results indicate that the effect of l-NAME on systemic BP differs markedly in Sprague-Dawley and Lewis rats, suggesting that the role of nitric oxide in regulation of resting vascular resistance may differ significantly between these rat strains. Rat strain is an important consideration for valid comparisons between studies.