Hong Kong experienced two large epidemics of pandemic influenza A(H1N1pdm09). We used regression methods to estimate the excess mortality associated with each epidemic. The first epidemic of H1N1pdm09 peaked in September 2009 and was associated with 2.11 (95% confidence interval (CI): −8.03, 11.75) excess all-cause deaths per 100,000 population. The second epidemic of H1N1pdm09 in early 2011 was associated with 4.81 (95% CI: −0.72, 10.68) excess deaths per 100,000 population. More than half of the estimated excess all-cause deaths were attributable to respiratory causes in each epidemic. The reasons for substantial impact in the second wave remain to be clarified.
excess mortality; impact; pandemic; influenza; H1N1pdm09
During the 2009 influenza pandemic, uncertainty surrounding the seriousness of human infections with the H1N1pdm09 virus hindered appropriate public health response. One measure of seriousness is the case fatality risk, defined as the probability of mortality among people classified as cases.
We conducted a systematic review to summarize published estimates of the case fatality risk of the pandemic influenza H1N1pdm09 virus. Only studies that reported population-based estimates were included.
We included 77 estimates of the case fatality risk from 50 published studies, about one-third of which were published within the first 9 months of the pandemic. We identified very substantial heterogeneity in published estimates, ranging from less than 1 to more than 10,000 deaths per 100,000 cases or infections. The choice of case definition in the denominator accounted for substantial heterogeneity, with the higher estimates based on laboratory-confirmed cases (point estimates= 0–13,500 per 100,000 cases) compared with symptomatic cases (point estimates= 0–1,200 per 100,000 cases) or infections (point estimates=1–10 per 100,000 infections). Risk based on symptomatic cases increased substantially with age.
Our review highlights the difficulty in estimating the seriousness of infection with a novel influenza virus using the case fatality risk. In addition, substantial variability in age-specific estimates complicates the interpretation of the overall case fatality risk and comparisons among populations. A consensus is needed on how to define and measure the seriousness of infection before the next pandemic.
Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection and are used to specify criteria for vaccine licensure. In a randomized, controlled trial of seasonal influenza vaccination in 773 children aged 6–17 years, we estimated that HAI titers of 1:40 against A(H1N1)pdm09 and B(Victoria lineage) were associated with 48% (95% confidence interval [CI], 30%–62%) and 55% (95% CI, 32%–70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers.
antibody; immunity; influenza; vaccine; children
In recent years Hong Kong has invested in research infrastructure to appropriately respond to novel infectious disease epidemics. Research from Hong Kong made a strong contribution to the international response to the 2009 influenza A(H1N1) pandemic (pH1N1). Summarizing, describing and reviewing the Hong Kong's response to the 2009 pandemic, this article aimed to identify key elements of a real-time research response.
A systematic search in PubMed and EMBASE for research into the infection dynamics and natural history, impact or control of pH1N1 in Hong Kong. Eligible articles were analyzed according to their scope.
55 articles were included in the review. Transmissibility of pH1N1 was similar in Hong Kong to elsewhere, and only a small fraction of infections were associated with severe disease. School closures were effective in reducing pH1N1 transmission, oseltamivir was effective for treatment of severe cases while convalescent plasma therapy has the potential to mitigate future pandemics.
There was a rapid and comprehensive research response to pH1N1 in Hong Kong, providing important information on the epidemiology of the novel virus with relevance internationally as well as locally. The scientific knowledge gained through these detailed studies of pH1N1 is now being used to revise and update pandemic plans. The experiences of the research response in Hong Kong could provide a template for the research response to future emerging and reemerging disease epidemics.
We conducted a population survey in Hong Kong to gauge psychological and behavioral responses to the threat of influenza A(H7N9) and support for closure of live poultry markets. We found low anxiety and low levels of exposure to live poultry but mixed support for permanent closure of the markets.
avian influenza A(H7N9); influenza; viruses; Hong Kong; public health; behavioral response; psychological response; community; H7N9; survey; respiratory infections; live poultry markets; poultry; birds
One measure of the severity of a pandemic influenza outbreak at the individual level is the risk of death among people infected by the new virus. However, there are complications in estimating both the numerator and denominator. Regarding the numerator, statistical estimates of the excess deaths associated with influenza virus infections tend to exceed the number of deaths associated with laboratory-confirmed infection. Regarding the denominator, few infections are laboratory confirmed, while differences in case definitions and approaches to case ascertainment can lead to wide variation in case fatality risk estimates. Serological surveillance can be used to estimate the cumulative incidence of infection as a denominator that is more comparable across studies. We estimated that the first wave of the influenza A(H1N1)pdm09 virus in 2009 was associated with approximately 232 (95% confidence interval: 136, 328) excess deaths of all ages in Hong Kong, mainly among the elderly. The point estimates of the risk of death on a per-infection basis increased substantially with age, from below 1 per 100,000 infections in children to 1,099 per 100,000 infections in those 60–69 years of age. Substantial variation in the age-specific infection fatality risk complicates comparison of the severity of different influenza strains.
death; human influenza; severity
China's one-child-per-couple policy, introduced in 1979, led to profound demographic changes for nearly a quarter of the world's population. Several decades later, the consequences include decreased fertility rates, population aging, decreased household sizes, changes in family structure, and imbalanced sex ratios. The epidemiology of communicable diseases may have been affected by these changes since the transmission dynamics of infectious diseases depend on demographic characteristics of the population. Of particular interest is influenza because China and Southeast Asia lie at the center of a global transmission network of influenza. Moreover, changes in household structure may affect influenza transmission. Is it possible that the pronounced demographic changes that have occurred in China have affected influenza transmission?
Methods and Findings
To address this question, we developed a continuous-time, stochastic, individual-based simulation model for influenza transmission. With this model, we simulated 30 years of influenza transmission and compared influenza transmission rates in populations with and without the one-child policy control. We found that the average annual attack rate is reduced by 6.08% (SD 2.21%) in the presence of the one-child policy compared to a population in which no demographic changes occurred. There was no discernible difference in the secondary attack rate, −0.15% (SD 1.85%), between the populations with and without a one-child policy. We also forecasted influenza transmission over a ten-year time period in a population with a two-child policy under a hypothesis that a two-child-per-couple policy will be carried out in 2015, and found a negligible difference in the average annual attack rate compared to the population with the one-child policy.
This study found that the average annual attack rate is slightly lowered in a population with a one-child policy, which may have resulted from a decrease in household size and the proportion of children in the population.
Hong Kong experienced two large epidemics of pandemic influenza A(H1N1pdm09). We used regression methods to estimate the excess mortality associated with each epidemic. The first epidemic of H1N1pdm09 peaked in September 2009 and was associated with 2·13 [95% confidence interval (CI): −8·08, 11·82] excess all-cause deaths per 100 000 population. The second epidemic of H1N1pdm09 in early 2011 was associated with 4·72 [95% CI: −0·70, 10·50] excess deaths per 100 000 population. More than half of the estimated excess all-cause deaths were attributable to respiratory causes in each epidemic. The reasons for substantial impact in the second wave remain to be clarified.
Excess mortality; H1N1pdm09; impact; influenza; pandemic
Background. Although deaths associated with laboratory-confirmed influenza virus infections are rare, the excess mortality burden of influenza estimated from statistical models may more reliably quantify the impact of influenza in a population.
Methods. We applied age-specific multiple linear regression models to all-cause and cause-specific mortality rates in Hong Kong from 1998 through 2009. The differences between estimated mortality rates in the presence or absence of recorded influenza activity were used to estimate influenza-associated excess mortality.
Results. The annual influenza-associated all-cause excess mortality rate was 11.1 (95% confidence interval [CI], 7.2–14.6) per 100 000 person-years. We estimated an average of 751 (95% CI, 488–990) excess deaths associated with influenza annually from 1998 through 2009, with 95% of the excess deaths occurring in persons aged ≥65 years. Most of the influenza-associated excess deaths were from respiratory (53%) and cardiovascular (18%) causes. Influenza A(H3N2) epidemics were associated with more excess deaths than influenza A(H1N1) or B during the study period.
Conclusions. Influenza was associated with a substantial number of excess deaths each year, mainly among the elderly, in Hong Kong in the past decade. The influenza-associated excess mortality rates were generally similar in Hong Kong and the United States.
In a randomized controlled trial, we administered seasonal trivalent inactivated influenza vaccine (TIV) or placebo to subjects 6–15 years of age in two consecutive years. Receipt of TIV in year 2 induced seroprotection in most subjects. Among 39 children who received TIV in the second year, receipt of TIV in the first year was associated with lower antibody titer rises in the second year to seasonal influenza A(H1N1) and A(H3N2) strains for which the vaccine strains remained unchanged. Antibody response to a different influenza B strain in the second year was unaffected by receipt of TIV in the first year.
vaccination; influenza; antibody response; children
Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households.
We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.
With economic development and population aging, ischaemic heart disease (IHD) is becoming a leading cause of mortality with widening inequalities in China. To forewarn the trends in China we projected IHD trends in the most economically developed part of China, i.e., Hong Kong.
Based on sex-specific IHD mortality rates from 1976 to 2005, we projected mortality rates by neighborhood-level socio-economic position (i.e., low- or high-income groups) to 2020 in Hong Kong using Poisson age-period-cohort models with autoregressive priors.
In the low-income group, age-standardized IHD mortality rates among women declined from 33.3 deaths in 1976–1980 to 19.7 per 100,000 in 2016–2020 (from 55.5 deaths to 34.2 per 100,000 among men). The rates in the high-income group were initially higher in both sexes, particularly among men, but this had reversed by the end of the study periods. The rates declined faster for the high-income group than for the low-income group in both sexes. The rates were projected to decline faster in the high-income group, such that by the end of the projection period the high-income group would have lower IHD mortality rates, particularly for women. Birth cohort effects varied with sex, with a marked upturn in IHD mortality around 1945, i.e., for the first generation of men to grow up in a more economically developed environment. There was no such upturn in women. Birth cohort effects were the main drivers of change in IHD mortality rates.
IHD mortality rates are declining in Hong Kong and are projected to continue to do so, even taking into account greater vulnerability for the first generation of men born into a more developed environment. At the same time social disparities in IHD have reversed and are widening, partly as a result of a cohort effect, with corresponding implications for prevention.
The household secondary attack proportion is commonly used to measure the transmissibility of an infectious disease.
We analyzed the final outbreak distributions of pandemic A(H1N1), seasonal A(H1N1) and A(H3N2) infections identified in paired sera collected from members of 117 Hong Kong households in April and August-October 2009.
The estimated community probability of infection overall was higher for children than adults; the probability was similar for pandemic A(H1N1) and seasonal A(H3N2) influenza. The household secondary attack proportion for pandemic A(H1N1) was higher in children than adults, whereas for seasonal A(H3N2) it was similar in children and adults. The estimated secondary attack proportions were similar for seasonal A(H3N2) and pandemic A(H1N1) after excluding persons with higher baseline antibody titers from analysis.
Pandemic and seasonal influenza A viruses had similar age-specific transmissibility in a cohort of initially uninfected households after adjustment for baseline immunity.
During the 2009 H1N1 pandemic (pH1N1), morbidity and mortality sparing was observed among the elderly population; it was hypothesized that this age group benefited from immunity to pH1N1 due to cross-reactive antibodies generated from prior infection with antigenically similar influenza viruses. Evidence from serologic studies and genetic similarities between pH1N1 and historical influenza viruses suggest that the incidence of pH1N1 cases should drop markedly in age cohorts born prior to the disappearance of H1N1 in 1957, namely those at least 52–53 years old in 2009, but the precise range of ages affected has not been delineated.
Methods and Findings
To test for any age-associated discontinuities in pH1N1 incidence, we aggregated laboratory-confirmed pH1N1 case data from 8 jurisdictions in 7 countries, stratified by single year of age, sex (when available), and hospitalization status. Using single year of age population denominators, we generated smoothed curves of the weighted risk ratio of pH1N1 incidence, and looked for sharp drops at varying age bandwidths, defined as a significantly negative second derivative. Analyses stratified by hospitalization status and sex were used to test alternative explanations for observed discontinuities. We found that the risk of laboratory-confirmed infection with pH1N1 declines with age, but that there was a statistically significant leveling off or increase in risk from about 45 to 50 years of age, after which a sharp drop in risk occurs until the late fifties. This trend was more pronounced in hospitalized cases and in women and was independent of the choice in smoothing parameters. The age range at which the decline in risk accelerates corresponds to the cohort born between 1951–1959 (hospitalized) and 1953–1960 (not hospitalized).
The reduced incidence of pH1N1 disease in older individuals shows a detailed age-specific pattern consistent with protection conferred by exposure to influenza A/H1N1 viruses circulating before 1957.
Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in June 2014 in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines.
Guinness World Record; hand hygeine; Hand Sanitizing; campaign fatigue
A novel influenza A(H7N9) virus has emerged in China during the past few months. Inter-species zoonotic transmission appears to be the predominant route of spread. Live poultry markets (LPMs) in the major cities of Shanghai, Hangzhou, Huzhou and Nanjing, where the majority of cases have occurred, were swiftly closed as a precautionary public health measure. Our objective was to quantify the impact of LPM closure in reducing bird-to-human transmission of avian influenza A(H7N9) virus.
We used data on the illness onset dates and geographical locations of laboratory-confirmed influenza A(H7N9) cases that were officially announced by 7 June 2013. We constructed a statistical model to explain the patterns in incident cases reported in each city based on the assumption of a constant force of infection prior to closure, and a different constant force of infection after closure. We fitted the model using Markov chain Monte Carlo methods.
There were 85 confirmed influenza A(H7N9) cases in Shanghai, Hangzhou, Huzhou and Nanjing out of a total of 130 confirmed cases in mainland China by 7 June 2013. Closure of LPMs in those four cities reduced the risk of human infections by 97%–99% (range 68%–100%) in each city. Given that LPMs were the predominant source of influenza A(H7N9) exposure in those locations, we estimated the mean incubation period to be 3.3 days.
LPM closures were extremely effective in controlling human risk of influenza A(H7N9). If the influenza A(H7N9) epizootic/epidemic continues, LPM closure should be sustained in at-risk areas and implemented in any urban areas where influenza A(H7N9) reappears in future. In the longer term, evidence-based discussions and deliberations about the role of central slaughtering of all live poultry should be renewed.
Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health.
Serial cross-sectional data on antibody levels to 2009 pandemic influenza A (H1N1) virus from a population can be used to estimate the infection attack rates and immunity against future infection in the community.
Between April and December 2009, we obtained 12,217 serum specimens from blood donors (16–59 yo), 2,520 from hospital outpatients (5–59yo), and 917 from subjects of a community pediatric cohort study (5–14yo). We estimated infection attack rates by comparing the proportions of specimens with antibody titers ≥1:40 by viral microneutralization before and after the first wave of the pandemic. Estimates were validated using paired sera from 324 individuals that spanned the first wave. Combining these estimates with epidemiologic surveillance data, we calculated the proportion of infections that led to hospitalization, intensive care admission, and death.
We found that 3.3% and 14% of 5–59 yo had antibody titers ≥1:40 before and after the first wave. The overall attack rate was 10.7% with the following age-stratification: 43.4% in 5–14 yo, 15.8% in 15–19 yo, 11.8% in 20–29 yo, and 4–4.6% in 30–59 yo. Case-hospitalization rates were 0.47%–0.87% among 5–59 yo. Case-ICU and case-fatality rates increased from 7.9 and 0.4 per 100,000 infections in 5–14 yo to 75 and 26.5 per 100,000 infections in 50–59 yo.
Almost half of all school-children in Hong Kong were infected during the first wave. Compared to school-children aged 5–14, older adults aged 50–59 had 9.5 and 66 times higher risk of ICU admission and death if infected.
Influenza; serology; attack rate; case-fatality rate; public health
Timely estimation of the transmissibility of a novel pandemic influenza virus was a public health priority in 2009.
We extended methods for prospective estimation of the effective reproduction number, (Rt), over time in an emerging epidemic to allow for reporting delays and repeated importations. We estimated Rt based on case notifications and hospitalizations associated with laboratory-confirmed pandemic (H1N1) 2009 virus infections in Hong Kong from June through October 2009
Rt declined from around 1.4–1.5 at the start of the local epidemic to around 1.1–1.2 later in the summer, suggesting changes in transmissibility perhaps related to school vacations or seasonality. Estimates of Rt based on hospitalizations of confirmed H1N1 cases closely matched estimates based on case notifications.
Real-time monitoring of the effective reproduction number is feasible and can provide useful information to public health authorities for situational awareness and calibration of mitigation strategies.
Great strides have been made exploring and exploiting new and different sources of disease surveillance data and developing robust statistical methods for analyzing the collected data. However, there has been less research in the area of dissemination. Proper dissemination of surveillance data can facilitate the end user's taking of appropriate actions, thus maximizing the utility of effort taken from upstream of the surveillance-to-action loop.
The aims of the study were to develop a generic framework for a digital dashboard incorporating features of efficient dashboard design and to demonstrate this framework by specific application to influenza surveillance in Hong Kong.
Based on the merits of the national websites and principles of efficient dashboard design, we designed an automated influenza surveillance digital dashboard as a demonstration of efficient dissemination of surveillance data. We developed the system to synthesize and display multiple sources of influenza surveillance data streams in the dashboard. Different algorithms can be implemented in the dashboard for incorporating all surveillance data streams to describe the overall influenza activity.
We designed and implemented an influenza surveillance dashboard that utilized self-explanatory figures to display multiple surveillance data streams in panels. Indicators for individual data streams as well as for overall influenza activity were summarized in the main page, which can be read at a glance. Data retrieval function was also incorporated to allow data sharing in standard format.
The influenza surveillance dashboard serves as a template to illustrate the efficient synthesization and dissemination of multiple-source surveillance data, which may also be applied to other diseases. Surveillance data from multiple sources can be disseminated efficiently using a dashboard design that facilitates the translation of surveillance information to public health actions.
Dashboard; dissemination; surveillance; influenza
Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no comparable quantitative data on naturally-acquired infections.
In a community-based study in Hong Kong in 2008, we followed up initially well individuals to quantify trends in viral shedding based on culture and reverse transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection.
Trends in symptom scores more closely matched changes in molecular viral loads measured by RT-PCR for influenza A than influenza B. For influenza A virus infections, replicating viral loads measured by culture declined to undetectable levels earlier after illness onset than molecular viral loads. Most viral shedding occurred during the first 2–3 days after illness onset and we estimated that 1–8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding by RT-PCR were asymptomatic, and viral shedding was low in these cases.
Our results suggest that ‘silent spreaders’ (i.e. individuals who are infectious while asymptomatic or pre-symptomatic) may be less important in the spread of influenza epidemics than previously thought.
influenza; viral shedding; infectiousness
Estimates of the clinical-onset serial interval of human influenza infection (time between onset of symptoms in an index case and a secondary case) are used to inform public health policy and to construct mathematical models of influenza transmission. We estimate the serial interval of laboratory-confirmed influenza transmission in households.
Index cases were recruited after reporting to a primary healthcare center with symptoms. Members of their households were followed up with repeated home visits.
Assuming a Weibull model and accounting for selection bias inherent in our field study design, we used symptom-onset times from 14 pairs of infector/infectee to estimate a mean serial interval of 3.6 days (95% confidence interval = 2.9–4.3 days), with standard deviation 1.6 days.
The household serial interval of influenza may be longer than previously estimated. Studies of the complete serial interval, based on transmission in all community contexts, are a priority.
Large clinical trials have demonstrated the therapeutic efficacy of oseltamivir against influenza. Here we assessed its indirect effectiveness in reducing household secondary transmission in an incident cohort of influenza index cases and their household members.
We recruited index outpatients whose rapid tests for influenza were positive in 2007 and 2008. Household contacts were followed for 7–10 days during 3–4 home visits to monitor symptoms. Nose and throat swabs were collected and tested for influenza by reverse transcription polymerase chain reaction (RT-PCR) or viral culture.
We followed 384 index cases and their household contacts. Index cases who took oseltamivir within 24 hours of symptom onset halved the time to symptom alleviation (adjusted acceleration factor (AF) 0.56; 95% CI: 0.42, 0.76). Oseltamivir treatment was not associated with statistically significant reduction in the duration of viral shedding. Household contacts of index cases who had taken oseltamivir within 24 hours of onset had a non-statistically significant lower risk of developing laboratory-confirmed infection (adjusted odds ratio (OR) 0.54; 95% CI: 0.11, 2.57) and a marginally statistically significant lower risk of clinical illness (adjusted OR 0.52; 95% CI: 0.25, 1.08) compared to contacts of index cases who did not take oseltamivir.
Oseltamivir treatment is effective in reducing the duration of symptoms but evidence for household reduction in transmission of influenza virus was inconclusive.
Influenza; oseltamivir; antiviral; public health
Closure of live poultry markets was implemented in areas affected by the influenza virus A(H7N9) outbreak in China during winter, 2013–14. Our analysis showed that closing live poultry markets in the most affected cities of Guangdong and Zhejiang provinces was highly effective in reducing the risk for H7N9 infection in humans.
Avian influenza A(H7N9); viruses; live poultry markets; public health; China