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1.  Clinical severity of human infections with avian influenza A(H7N9) virus, winter 2013–2014 
Assessing the severity of emerging infections is challenging because of potential biases in case ascertainment. In the second epidemic of human infections with avian influenza A(H7N9) virus in China in 2013–14, we estimated that the risk of death among hospitalized H7N9 cases was 48% (95% credibility interval: 42%–54%). Using data on symptomatic cases identified through national sentinel influenza-like illness surveillance, we estimated that the risk of death among symptomatic H7N9 cases was 0.10% (95% credibility interval: 0.029%–3.6%). These estimates of severity were quite similar to previous estimates for the first epidemic wave of human infections with H7N9 in 2013.
PMCID: PMC4454636  PMID: 25523971
avian influenza A(H7N9) virus; clinical severity; epidemiology; public health
2.  Association between Severity of MERS-CoV Infection and Incubation Period 
Emerging Infectious Diseases  2016;22(3):526-528.
We analyzed data for 170 patients in South Korea who had laboratory-confirmed infection with Middle East respiratory syndrome coronavirus. A longer incubation period was associated with a reduction in the risk for death (adjusted odds ratio/1-day increase in incubation period 0.83, 95% credibility interval 0.68–1.03).
doi:10.3201/eid2203.151437
PMCID: PMC4766874  PMID: 26890291
Middle East respiratory syndrome; Middle East respiratory syndrome coronavirus; MERS-CoV; coronavirus; viruses; incubation period; infection; illness; severity; South Korea
3.  Live Poultry Exposure and Public Response to Influenza A(H7N9) in Urban and Rural China during Two Epidemic Waves in 2013-2014 
PLoS ONE  2015;10(9):e0137831.
Background
The novel influenza A(H7N9) virus has caused 2013 spring and 2013–2014 winter waves of human infections since its first emergence in China in March 2013. Exposure to live poultry is a risk factor for H7N9 infection. Public psychobehavioral responses often change during progression of an epidemic.
Methods
We conducted population-based surveys in southern China to examine human exposure to live poultry, and population psychological response and behavioral changes in the two waves. In Guangzhou, an urban area of Guangdong province, we collected data using telephone surveys with random digit dialing in May-June 2013 and again in December 2013 to January 2014. In Zijin county, a rural area of the same province, we used door-to-door surveys under a stratified sampling design in July 2013 and again in December 2013 to January 2014. All responses were weighted by age and sex to the respective adult populations.
Findings
Around half of the urban respondents (53.8%) reported having visited LPMs in the previous year in the first survey, around double that reported in the second survey (27.7%). In the rural surveys, around half of the participants reported raising backyard poultry in the past year in the first survey, increasing to 83.2% participants in the second survey. One third of urban subjects supported the permanent closure of LPMs in the first and second surveys, and factors associated with support for closure included female sex, higher level of worry towards H7N9, and worry induced by a hypothetical influenza-like illness.
Conclusions
Our study indicated high human exposure to live poultry and low support for permanent closure of markets in both urban and rural residents regardless of increased worry during the epidemic.
doi:10.1371/journal.pone.0137831
PMCID: PMC4569561  PMID: 26367002
4.  Association Between Antibody Titers and Protection Against Influenza Virus Infection Within Households 
The Journal of Infectious Diseases  2014;210(5):684-692.
Background. Previous studies have established that antibody titer measured by the hemagglutination-inhibiting (HAI) assay is correlated with protection against influenza virus infection, with an HAI titer of 1:40 generally associated with 50% protection.
Methods. We recruited index cases with confirmed influenza virus infection from outpatient clinics, and followed up their household contacts for 7–10 days to identify secondary infections. Serum samples collected from a subset of household contacts were tested by HAI and microneutralization (MN) assays against prevalent influenza viruses. We analyzed the data using an individual hazard-based transmission model that adjusted for age and vaccination history.
Results. Compared to a reference group with antibody titers <1:10, we found that HAI titers of 1:40 against influenza A(H1N1) and A(H3N2) were associated with 31% (95% confidence interval [CI], 13%–46%) and 31% (CI, 1%–53%) protection against polymerase chain reaction (PCR)–confirmed A(H1N1) and A(H3N2) virus infection, respectively, while an MN titer of 1:40 against A(H3N2) was associated with 49% (95% CI, 7%–81%) protection against PCR-confirmed A(H3N2) virus infection.
Conclusions. An HAI titer of 1:40 was associated with substantially less than 50% protection against PCR-confirmed influenza virus infection within households, perhaps because of exposures of greater duration or intensity in that confined setting.
doi:10.1093/infdis/jiu186
PMCID: PMC4148604  PMID: 24676208
antibody; immunity; influenza; transmission
5.  Interpreting sero-epidemiological studies for influenza in a context of non-bracketing sera 
Epidemiology (Cambridge, Mass.)  2016;27(1):152-158.
Background
In influenza epidemiology, analysis of paired sera collected from people before and after influenza seasons has been used for decades to study the cumulative incidence of influenza virus infections in populations. However, interpretation becomes challenging when sera are collected after the start or before the end of an epidemic, and do not neatly bracket the epidemic.
Methods
Serum samples were collected longitudinally in a community-based study. Most participants provided their first serum after the start of circulation of influenza A(H1N1)pdm09 virus in 2009. We developed a Bayesian hierarchical model to correct for non-bracketing sera and estimate the cumulative incidence of infection from the serological data and surveillance data in Hong Kong.
Results
We analysed 4843 sera from 2097 unvaccinated participants in the study, collected from April 2009 through December 2010. After accounting for non-bracketing, we estimated that the cumulative incidence of H1N1pdm09 virus infection was 45.1% (95% credible interval, CI: 40.2%, 49.2%), 16.5% (95% CI: 13.0%, 19.7%) and 11.3% (95% CI: 5.9%, 17.5%) for children 0–18y, adults 19–50y and older adults >50y respectively. Including all available data substantially increased precision compared to a simpler analysis based only on sera collected at 6-month intervals in a subset of participants.
Conclusions
We developed a framework for the analysis of antibody titers that accounted for the timing of sera collection with respect to influenza activity and permitted robust estimation of the cumulative incidence of infection during an epidemic.
doi:10.1097/EDE.0000000000000408
PMCID: PMC4825848  PMID: 26427725
7.  Infection Fatality Risk of the Pandemic A(H1N1)2009 Virus in Hong Kong 
American Journal of Epidemiology  2013;177(8):834-840.
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.
doi:10.1093/aje/kws314
PMCID: PMC3658096  PMID: 23459950
death; human influenza; severity
8.  Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis 
PLoS Medicine  2016;13(3):e1001975.
Background
China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010–2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6–71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China.
Methods and Findings
We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7–US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9–US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%–14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%–84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%–19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%–50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010–2013.
Conclusions
Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0–US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192–US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known.
Using surveillance and survey data, Joseph T. Wu and colleagues assess the cost-effectiveness of routine pediatric EV71 vaccination in China.
Editors' Summary
Background
Since 2007, outbreaks of hand, foot, and mouth disease (HFMD)—a contagious infection that mainly affects young children—have been occurring annually in China. Between 2010 and 2014, China accounted for 9.8 million of the 11.3 million cases of HFMD reported to the World Health Organization (WHO); in 2012, HFMD was the leading notifiable disease in China among children under five years old. HFMD is caused by a group of viruses called enteroviruses that are transmitted through contact with the mucus produced when an infected individual coughs or sneezes, through contact with the feces of an infected person, and through contact with contaminated surfaces. Good hygiene and frequent handwashing can reduce the spread of HFMD. The characteristic symptoms of HFMD are a non-itchy red rash with blisters on the hands and feet and painful mouth ulcers. There is no cure for HFMD, and most infected children get better within 7–10 days. However, some individuals develop potentially fatal complications such as encephalitis (infection and inflammation of the brain).
Why Was This Study Done?
In China, enterovirus 71 (EV71) causes most laboratory-confirmed fatal cases of HFMD. Routine vaccination against EV71 during the first few months of life might therefore be one way to reduce China’s HFMD burden. In clinical trials, three inactivated monovalent EV71 vaccines made in China were shown to be safe and highly efficacious against EV71-associated HFMD (inactivated monovalent vaccines contain a single virus strain that cannot replicate; exposure to the vaccine “primes” the immune system to respond quickly when challenged with live virus, thereby preventing infection with that virus). However, before implementing routine EV71 vaccination, it is important to know whether this intervention is a good value for the money it would cost. For example, how much money needs to be spent on vaccination to save one life? In this cost-effectiveness analysis (a study that estimates the costs and health effects of a medical intervention), the researchers assess the value for money of routine vaccination of young children against EV71 in China.
What Did the Researchers Do and Find?
The researchers characterized the health and economic burden of EV71-associated HFMD in China using the national surveillance database, HFMD laboratory test results, and information on household costs and health utility loss associated with HFMD cases (health utility is a number that is assigned to a state of health; perfect health and death have utility values of 1 and 0, respectively) collected in a caregiver survey. They then used a mathematical model to estimate the effective vaccine cost (EVC; vaccine cost divided by efficacy) below which routine pediatric vaccination would be cost-effective; WHO defines a cost-effective intervention as one in which the incremental cost-effectiveness ratio (the incremental costs of introducing an intervention divided by the incremental benefits accrued by that introduction) is between one and three times the country’s gross domestic product (GDP) per capita. Routine pediatric vaccination was cost-effective in the researchers’ base-case analysis—which assumed a willingness-to-pay threshold of one times GDP per capita—if the EVC was below US$17.9. Increasing the willingness-to-pay threshold to three times GDP per capita increased the EVC below which routine vaccination would be cost-effective by 58%–84%, whereas excluding consideration of the productivity loss of parents/caregivers while caring for a child with HFMD reduced the EVC below which routine vaccination would be cost-effective by 10%–14%.
What Do These Findings Mean?
The validity of these findings depends on the assumptions included in the mathematical model and on the accuracy of the data fed into the model. However, routine pediatric EV71 vaccination remained cost-effective at broadly similar EVCs in sensitivity analyses in which the assumptions built into the model were altered. Overall, these findings suggest that routine pediatric EV71 vaccination would be very cost-effective in China provided the cost of immunization (including the cost of the vaccine and all the logistical and administration costs of vaccination) is below between US$12.0 and US$18.3 per vaccination; because the different vaccines have different efficacies, the exact value depends on which vaccine is used for vaccination. Thus, with 16 million births each year, the annual costs for routine pediatric EV71 vaccination in China should not exceed US$192–US$293 million. Importantly, when combined with the findings of a previous study in which the same researchers showed large geographical variations in the risk of EV71-associated HFMD across China, these findings can help policymakers identify those regions in China where EV71 vaccination is likely to be most cost-effective.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001975.
A PLOS Medicine Research Article by Takahashi et al. provides information about the patterns of HFMD outbreaks in China
The US Centers for Disease Control and Prevention provides information on hand, foot, and mouth disease (in English and Spanish), including a podcast on the condition
The UK National Health Service Choices website provides detailed information on hand, foot, and mouth disease
Further information about hand, foot, and mouth disease is provided by the World Health Organization (including up-to-date HFMD surveillance reports from China), the Nemours Foundation (in English and Spanish), and MedlinePlus (in English and Spanish)
A WHO guide on cost-effectiveness analysis is available
doi:10.1371/journal.pmed.1001975
PMCID: PMC4792415  PMID: 26978565
9.  Analysis of potential changes in seriousness of influenza A and B viruses in Hong Kong from 2001 to 2011 
Epidemiology and infection  2015;143(4):766-771.
SUMMARY
Continued monitoring of the seriousness of influenza viruses is a public health priority. We applied time series regression models to data on cardio-respiratory mortality rates in Hong Kong from 2001 through 2011. We used surveillance data on outpatient consultations for influenza-like illness, and laboratory detections of influenza types/subtypes to construct proxy measures of influenza activity. In the model we allowed the regression coefficients for influenza to drift over time, and adjusted for temperature and humidity. The regression coefficient for influenza A(H3N2) increased significantly in 2005. The regression coefficients for influenza A(H1N1) and B were relatively stable over the period. Our model suggested an increase in seriousness of A(H3N2) in 2005, the year after the appearance of the A/Fujian/411/2002(H3N2)-like virus when the drifted A/California/7/2004(H3N2)-like virus appeared. Ongoing monitoring of mortality and influenza activity could permit identification of future changes in seriousness of influenza virus infections.
doi:10.1017/S0950268814001472
PMCID: PMC4391961  PMID: 25703399
human influenza; seriousness; death
10.  Association between the Severity of Influenza A(H7N9) Virus Infections and Length of the Incubation Period 
PLoS ONE  2016;11(2):e0148506.
Background
In early 2013, a novel avian-origin influenza A(H7N9) virus emerged in China, and has caused sporadic human infections. The incubation period is the delay from infection until onset of symptoms, and varies from person to person. Few previous studies have examined whether the duration of the incubation period correlates with subsequent disease severity.
Methods and Findings
We analyzed data of period of exposure on 395 human cases of laboratory-confirmed influenza A(H7N9) virus infection in China in a Bayesian framework using a Weibull distribution. We found a longer incubation period for the 173 fatal cases with a mean of 3.7 days (95% credibility interval, CrI: 3.4–4.1), compared to a mean of 3.3 days (95% CrI: 2.9–3.6) for the 222 non-fatal cases, and the difference in means was marginally significant at 0.47 days (95% CrI: -0.04, 0.99). There was a statistically significant correlation between a longer incubation period and an increased risk of death after adjustment for age, sex, geographical location and underlying medical conditions (adjusted odds ratio 1.70 per day increase in incubation period; 95% credibility interval 1.47–1.97).
Conclusions
We found a significant association between a longer incubation period and a greater risk of death among human H7N9 cases. The underlying biological mechanisms leading to this association deserve further exploration.
doi:10.1371/journal.pone.0148506
PMCID: PMC4757028  PMID: 26885816
11.  Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination 
PLoS Medicine  2016;13(2):e1001958.
Background
Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.
Methods and Findings
Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.
Conclusions
The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.
Using time series susceptible–infected–recovered (TSIR) epidemic models, Saki Takahashi and colleagues investigate hand, foot, and mouth disease dynamics and the projected effect of vaccination in China.
Editors' Summary
Background
Hand, foot, and mouth disease (HFMD)—a common ailment that mainly affects young children—is caused by a group of enteroviruses (Enterovirus A species), which are close relatives of polioviruses (Enterovirus C species). Enteroviruses are divided into various viral serotypes (variants defined by molecules on their surface that are recognized by the immune system), and the most common serotypes that cause HFMD are Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Enteroviruses spread from person to person through contact with the mucus or saliva produced when an infected individual coughs or sneezes, with the feces or the fluid from vesicles of an infected individual, and through contact with contaminated surfaces. Frequent handwashing and good hygiene practices can reduce the spread of HFMD. Symptoms of HFMD include fever, sore throat, a non-itchy red rash with small blisters on the hands and feet, and painful mouth ulcers. HFMD is usually a self-limiting illness, and most children recover within 7–10 days. A small proportion of patients infected with EV-A71 develop severe complications such as meningitis (infection of the membranes around the brain and spinal cord) or encephalitis (infection of the brain). Currently, there is no specific treatment for HFMD, and vaccines are not yet available for routine use.
Why Was This Study Done?
HFMD is increasingly common in East and Southeast Asia. China, for example, reported 9 million cases of HFMD between 2008 and 2013. Vaccination is a specific and effective way to reduce the burden of HFMD in China. In three clinical trials, inactivated monovalent EV-A71 vaccines made in China were highly efficacious against EV-A71-associated HFMD but provided no protection against CV-A16-associated HFMD (an inactivated monovalent vaccine contains a single virus strain that is unable to replicate; exposure to the vaccine “primes” the immune system to respond quickly when challenged with live virus, thereby preventing infection with that virus). So, before these vaccines can be used for routine vaccination of infants, it is important to know whether vaccination with EV-A71 will alter the burden of HFMD caused by other enterovirus serotypes. In particular, it is important to know whether infection with EV-A71 provides cross-protection against CV-A16 and whether infections with CV-A16 or other serotypes might increase following vaccination against EV-A71 because of increased circulation of these viruses in the population (serotype replacement). Here, the researchers use mathematical models to assess the effect of vaccination against EV-A71-associated HFMD in China and the potential risk of serotype replacement by CV-A16.
What Did the Researchers Do and Find?
The researchers used weekly data on HFMD incidence collected in 31 Chinese provinces between 2009 and 2013 to develop a two-serotype time series susceptible–infected–recovered epidemic model (a model in which individuals are born, become susceptible to a disease, become infected and infectious with the disease, and recover). The model accurately simulated the epidemic cycles of EV-A71- and CV-A16-associated HFMD for the 31 provinces and the seasonal transmission patterns in both northern and southern Chinese provinces. It provided an estimate of cross-protection following infection with EV-A71 or CV-A16 of ten weeks in 68% of the population (an average duration of cross-protection of 6.77 weeks). The estimated basic reproduction number (the average number of additional cases one case of an infectious disease generates in an otherwise uninfected population) across China for both serotypes was 25, which means that vaccination coverage levels of above 96% are required to achieve population-level immunity. Finally, the model predicted a decrease in EV-A71-associated HFMD incidence with higher rates of EV-A71 vaccination and suggested that CV-A16 incidence following EV-A71 vaccination would be comparable to or only slightly higher than its incidence before vaccination.
What Do These Findings Mean?
These findings suggest that herd immunity (indirect protection from infectious disease that occurs when most of a population has become immune to an infection, thereby providing some protection for the rare individuals who are not immune) is driving the dynamics of the HFMD epidemic caused by multiple enterovirus serotypes in China. Moreover, they suggest that the infection with EV-A71 or CV-A16 serotype can provide temporary immunity against each the other serotype and that serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the reduction in the burden of EV-A71-associated HFMD produced by vaccination. The accuracy of these findings depends on the assumptions included in the model and the quality and quantity of data used to run the models. However, the researchers suggest that a mass EV-A71 vaccination campaign targeted at infants and young children should greatly reduce the burden of HFMD in China, provided a high vaccination uptake level is achieved.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001958.
The US Centers for Disease Control and Prevention provide information on hand, foot, and mouth disease (in English and Spanish), including a podcast on the condition
The UK National Health Service Choices website provides detailed information on hand, foot, and mouth disease
Further information about hand, foot, and mouth disease is provided by the World Health Organization (including up-to-date HFMD surveillance reports from China), the Nemours Foundation (in English and Spanish), and MedlinePlus (in English and Spanish)
The Government of the Hong Kong Special Administrative Region Department of Health Centre for Health Protection provides information on hand, foot, and mouth disease
doi:10.1371/journal.pmed.1001958
PMCID: PMC4755668  PMID: 26882540
12.  Quantification of Influenza Virus RNA in Aerosols in Patient Rooms 
PLoS ONE  2016;11(2):e0148669.
Background
The potential for human influenza viruses to spread through fine particle aerosols remains controversial. The objective of our study was to determine whether influenza viruses could be detected in fine particles in hospital rooms.
Methods and Findings
We sampled the air in 2-bed patient isolation rooms for four hours, placing cyclone samplers at heights of 1.5m and 1.0m. We collected ten air samples each in the presence of at least one patient with confirmed influenza A virus infection, and tested the samples by reverse transcription polymerase chain reaction. We recovered influenza A virus RNA from 5/10 collections (50%); 4/5 were from particles>4 μm, 1/5 from 1–4 μm, and none in particles<1 μm.
Conclusions
Detection of influenza virus RNA in aerosols at low concentrations in patient rooms suggests that healthcare workers and visitors might have frequent exposure to airborne influenza virus in proximity to infected patients. A limitation of our study was the small sample size. Further studies should be done to quantify the concentration of viable influenza virus in healthcare settings, and factors affecting the detection of influenza viruses in fine particles in the air.
doi:10.1371/journal.pone.0148669
PMCID: PMC4743992  PMID: 26849130
13.  Excess Mortality Impact of Two Epidemics of Pandemic Influenza A(H1N1pdm09) Virus in Hong Kong 
Influenza and other respiratory viruses  2013;8(1):10.1111/irv.12196.
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.
doi:10.1111/irv.12196
PMCID: PMC3877676  PMID: 24373289
excess mortality; impact; pandemic; influenza; H1N1pdm09
14.  Increases in absenteeism among health care workers in Hong Kong during influenza epidemics, 2004–2009 
BMC Infectious Diseases  2015;15:586.
Background
Acute respiratory infections (ARI) are a major cause of sickness absenteeism among health care workers (HCWs) and contribute significantly to overall productivity loss particularly during influenza epidemics. The purpose of this study is to quantify the increases in absenteeism during epidemics including the 2009 influenza A(H1N1)pdm09 pandemic.
Methods
We analysed administrative data to determine patterns of sickness absence among HCWs in Hong Kong from January 2004 through December 2009, and used multivariable linear regression model to estimate the excess all-cause and ARI-related sickness absenteeism rates during influenza epidemics.
Results
We found that influenza epidemics prior to the 2009 pandemic and during the 2009 pandemic were associated with 8.4 % (95 % CI: 5.6–11.2 %) and 57.7 % (95 % CI: 54.6–60.9 %) increases in overall sickness absence, and 26.5 % (95 % CI: 21.4–31.5 %) and 90.9 % (95 % CI: 85.2–96.6 %) increases in ARI-related sickness absence among HCWs in Hong Kong, respectively. Comparing different staff types, increases in overall absenteeism were highest among medical staff, during seasonal influenza epidemic periods (51.3 %, 95 % CI: 38.9–63.7 %) and the pandemic mitigation period (142.1 %, 95 % CI: 128.0–156.1 %).
Conclusions
Influenza epidemics were associated with a substantial increase in sickness absence and productivity loss among HCWs in Hong Kong, and there was a much higher rate of absenteeism during the 2009 pandemic. These findings could inform better a more proactive workforce redistribution plans to allow for sufficient surge capacity in annual epidemics, and for pandemic preparedness.
doi:10.1186/s12879-015-1316-y
PMCID: PMC4696217  PMID: 26715075
Acute respiratory infections; Health care workers; Sickness absence; Influenza; Pandemic
15.  The R292K Mutation That Confers Resistance to Neuraminidase Inhibitors Leads to Competitive Fitness Loss of A/Shanghai/1/2013 (H7N9) Influenza Virus in Ferrets 
The Journal of Infectious Diseases  2014;210(12):1900-1908.
Background
Neuraminidase (NA) inhibitors are the only licensed therapeutic option for human zoonotic H7N9 infections. An NA-R292K mutation that confers broad-spectrum resistance to NA inhibitors has been documented in H7N9 patients after treatment.
Methods
We evaluated the transmission potential of a human influenza A H7N9 isolate with a NA-R292K mutation in the ferret model followed by genotyping assay to monitor its competitive fitness in vivo.
Results
Plaque-purified A/Shanghai/1/2013 wild-type and NA-R292K viruses transmitted at comparable efficiency to direct or respiratory droplet contact ferrets. In ferrets inoculated with the plaque-purified A/Shanghai/1/2013 NA-R292K virus with dominant K292 (94%), the resistant K292 genotype was outgrown by the wild-type R292 genotype during the course of infection. Transmission of the resistant K292 genotype was detected in 3/4 direct contact and 3/4 respiratory droplet contact ferrets at early time points but was gradually replaced by the wild-type genotype. In the respiratory tissues of inoculated or infected ferrets, the wild-type R292 genotype dominated in the nasal turbinate, whereas the resistant K292 genotype was more frequently detected in the lungs.
Conclusions
The NA inhibitor-resistant H7N9 virus with the NA-R292K mutation may transmit among ferrets but showed compromised fitness in vivo while in competition with the wild-type virus.
doi:10.1093/infdis/jiu353
PMCID: PMC4296180  PMID: 24951824
H7N9 influenza virus; R292K NA mutation; neuraminidase inhibitors; resistance; transmission; ferrets
16.  Case fatality risk of influenza A(H1N1pdm09): a systematic review 
Epidemiology (Cambridge, Mass.)  2013;24(6):10.1097/EDE.0b013e3182a67448.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/EDE.0b013e3182a67448
PMCID: PMC3809029  PMID: 24045719
17.  Estimation of the Association Between Antibody Titers and Protection Against Confirmed Influenza Virus Infection in Children 
The Journal of Infectious Diseases  2013;208(8):1320-1324.
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.
doi:10.1093/infdis/jit372
PMCID: PMC3778972  PMID: 23908481
antibody; immunity; influenza; vaccine; children
18.  Years of Life Lost in the First Wave of the 2009 Influenza A(H1N1) Pandemic in Hong Kong 
American Journal of Epidemiology  2013;178(8):1313-1318.
The impact of influenza pandemics might be overestimated; the published studies of years of life lost (YLL) have typically ignored the presence of underlying chronic conditions or health risk behaviors in most deaths. We used data on deaths involving laboratory-confirmed 2009 influenza A(H1N1) virus infection that occurred between April 2009 and May 2010 in Hong Kong, China, to adjust for these underlying risk factors. Life expectancy was corrected with hazard-based modifications to the life tables. The excess hazards posed by underlying risk factors were added to the “baseline” age-specific hazards in the local life tables to reflect the life expectancy associated with each underlying risk factor. Of 72 deceased persons with laboratory-confirmed 2009 influenza A(H1N1) virus infection, 56% had underlying risk factors. We estimated that the 2009 pandemic was associated with 1,540 (95% confidence interval: 1,350, 1,630) YLL after adjustment for age and underlying risk factors. This figure is approximately 25% lower than the YLL estimate of 2,080 derived after adjustment for age but not for risk factors. Our analysis demonstrates the potential scale of bias in YLL estimation if underlying risk factors are ignored. The estimation of YLL with correction for underlying risk factors in addition to age could also provide a framework for similar calculations elsewhere.
doi:10.1093/aje/kwt120
PMCID: PMC3792731  PMID: 23978528
influenza; pandemics; underlying risk factors; years of life lost
19.  Influenza vaccine effectiveness: potential of the test-negative design. A systematic review 
Expert review of vaccines  2014;13(12):1571-1591.
SUMMARY
Background
The test-negative design is a variant of the case control study being increasingly used to study influenza vaccine effectiveness. In these studies, patients with influenza-like illness are tested for influenza. Vaccine coverage is compared between those testing positive versus those testing negative to estimate vaccine effectiveness.
Objectives
We reviewed features in the design, analysis and reporting of 85 published test-negative studies.
Data sources
Studies were identified from PubMed, reference lists and email updates.
Study eligibility
All studies using the test-negative design reporting end-of-season estimates were included.
Study appraisal
Design features that may affect the validity and comparability of reported estimates were reviewed, including setting, study period, source population, case definition, exposure and outcome ascertainment and statistical model.
Results
There was considerable variation in the analytic approach, with 68 unique statistical models identified among the studies.
Conclusion
Harmonisation of analytic approaches may improve the potential for pooling vaccine effectiveness estimates.
doi:10.1586/14760584.2014.966695
PMCID: PMC4277796  PMID: 25348015
influenza; vaccine effectiveness; public health; case control; test-negative study
20.  Live Bird Exposure among the General Public, Guangzhou, China, May 2013 
PLoS ONE  2015;10(12):e0143582.
Background
A novel avian-origin influenza A(H7N9) caused a major outbreak in Mainland China in early 2013. Exposure to live poultry was believed to be the major route of infection. There are limited data on how the general public changes their practices regarding live poultry exposure in response to the early outbreak of this novel influenza and the frequency of population exposure to live poultry in different areas of China.
Methodology
This study investigated population exposures to live birds from various sources during the outbreak of H7N9 in Guangzhou city, China in 2013 and compared them with those observed during the 2006 influenza A(H5N1) outbreak. Adults were telephone-interviewed using two-stage sampling, stratified by three residential areas of Guangzhou: urban areas and two semi-rural areas in one of which (Zengcheng) A(H7N9) virus was detected in a chicken from wet markets. Logistic regression models were built to describe practices protecting against avian influenza, weighted by age and gender, and then compare these practices across residential areas in 2013 with those from a comparable 2006 survey.
Principal Findings
Of 1196 respondents, 45% visited wet markets at least daily and 22.0% reported buying live birds from wet markets at least weekly in April-May, 2013, after the H7N9 epidemic was officially declared in late March 2013. Of those buying live birds, 32.3% reported touching birds when buying and 13.7% would slaughter the poultry at home. Although only 10.1% of the respondents reported raising backyard birds, 92.1% of those who did so had physical contact with the birds they raised. Zengcheng respondents were less likely to report buying live birds from wet markets, but more likely to buy from other sources when compared to urban respondents. Compared with the 2006 survey, the prevalence of buying live birds from wet markets, touching when buying and slaughtering birds at home had substantially declined in the 2013 survey.
Conclusion/Significance
Although population exposures to live poultry were substantially fewer in 2013 compared to 2006, wet markets and backyard poultry remained the two major sources of live bird exposures for the public in Guangzhou in 2013. Zengcheng residents seemed to have reduced buying live birds from wet markets but not from other sources in response to the detection of H7N9 virus in wet markets.
doi:10.1371/journal.pone.0143582
PMCID: PMC4666652  PMID: 26623646
21.  Quantifying Protection Against Influenza Virus Infection Measured by Hemagglutination-inhibition Assays in Vaccine Trials 
Epidemiology (Cambridge, Mass.)  2015;27(1):143-151.
Supplemental Digital Content is available in the text.
Background:
Correlations between hemagglutination-inhibition titers (hereafter “titers”) and protection against infection have been identified in historical studies. However, limited information is available about the dynamics of how titer influences protection.
Methods:
Titers were measured in randomized, placebo-controlled vaccine trials in Hong Kong among pediatrics during September 2009–December 2010 and the United States among adults during Oct 2007–April 2008. Intermediate unobserved titers were imputed using three interpolation methods. As participants were recruited at different times leading to varying exposure to infection relative to entry, a modified proportional hazards model was developed to account for staggered entry into the studies and to quantify the correlation of titers with protection against influenza infections, adjusting for waning in titers. The model was fitted using Markov chain Monte Carlo and importance sampling.
Results:
A titer of 1:40 was associated with a reduced infection risk of 40%–70% relative to a titer of 1:10, depending on the circulating strain; the corresponding protection associated with a titer of 1:80 was 54%–84%. Results were robust across interpolation methods. The trivalent-inactivated vaccine reduced cumulative incidence of influenza B and influenza A(H3N2) infections by six percentage points (pp; 95% credible interval = 2 pp, 10 pp) and 1 pp (95% credible interval = 0.3 pp, 2 pp) respectively, but not for influenza A(H1N1)pdm09. The live-attenuated vaccine showed little efficacy against influenza A(H3N2) infections.
Conclusions:
Titers are correlated with protection against influenza infections. The trivalent inactivated vaccine can reduce the risk of influenza A(H3N2) and influenza B infections in the community.
doi:10.1097/EDE.0000000000000402
PMCID: PMC4658669  PMID: 26427723
22.  The Global Influenza Hospital Surveillance Network (GIHSN): a new platform to describe the epidemiology of severe influenza 
Background
Influenza is a global public health problem. However, severe influenza only recently has been addressed in routine surveillance.
Objectives
The Global Influenza Hospital Surveillance Network (GIHSN) was established to study the epidemiology of severe influenza in consecutive seasons in different countries. Our objective is to describe the GIHSN approach and methods.
Methods
The GIHSN uses prospective active surveillance to identify consecutive influenza admissions in permanent residents of well-defined geographic areas in sites around the world. A core common protocol is followed. After consent, data are collected on patient characteristics and clinical outcomes, respiratory swabs are obtained, and the presence of influenza virus and subtype or lineage is ascertained by polymerase chain reaction. Data are collated and analyzed at the GIHSN coordination center.
Results
The GIHSN has run its activities for two consecutive influenza seasons, 2012–2013 and 2013–2014, and hospitals in Brazil, China, France, Russian Federation, Turkey, and Spain have been involved in one or both seasons. Consistency on the application of the protocol and heterogeneity for the first season have been addressed in two previous publications. During both seasons, 19 677 eligible admissions were recorded; 11 843 (60%) were included and tested, and 2713 (23%) were positive for influenza: 991 (37%) A(H1N1); 807 (30%) A(H3N2); 583 (21%) B/Yamagata; 56 (2%) B/Victoria and 151 (6%) influenza A; and 125 (5%) influenza B were not characterized.
Conclusions
The GIHSN is a platform that provides information on severe influenza worldwide, applying a common core protocol and a consistent case definition.
doi:10.1111/irv.12335
PMCID: PMC4605407  PMID: 26198771
Hospital; influenza epidemiology; surveillance network
23.  Comparative epidemiology of human infections with avian influenza A(H7N9) and A(H5N1) viruses in China 
Lancet  2013;382(9887):129-137.
Background
The novel influenza A(H7N9) virus recently emerged, while influenza A(H5N1) virus has infected humans since 2003 in mainland China. Both infections are thought to be predominantly zoonotic. We compared the epidemiologic characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China to date.
Methods
An integrated database was constructed with information on demographic, epidemiological, and clinical variables of laboratory-confirmed A(H7N9) and A(H5N1) cases that were reported to the Chinese Center for Disease Control and Prevention up to May 24, 2013. We described disease occurrence by age, sex and geography and estimated key epidemiologic parameters.
Findings
Among 130 and 43 patients with confirmed A(H7N9) and A(H5N1) respectively, the median ages were 62y and 26y. In urban areas, 74% of cases of both viruses were male whereas in rural areas the proportions were 62% for A(H7N9) and 33% for A(H5N1). Among cases of A(H7N9) and A(H5N1), 75% and 71% reported recent exposure to poultry. The mean incubation periods of A(H7N9) and A(H5N1) were 3.1 and 3.3 days, respectively. On average, 21 and 18 contacts were traced for each A(H7N9) case in urban and rural areas respectively; compared to 90 and 63 for A(H5N1). The hospitalization fatality risk was 35% (95% CI: 25%, 44%) for A(H7N9) and 70% (95% CI: 56%, 83%) for A(H5N1).
Interpretation
The sex ratios in urban compared to rural cases are consistent with poultry exposure driving the risk of infection. However the difference in susceptibility to serious illness with the two different viruses remains unexplained, given that most A(H7N9) cases were in older adults while most A(H5N1) cases were in younger individuals.
Funding
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.
doi:10.1016/S0140-6736(13)61171-X
PMCID: PMC3777567  PMID: 23803488
24.  Effect of Live Poultry Market Closure on Avian Influenza A(H7N9) Virus Activity in Guangzhou, China, 2014 
Emerging Infectious Diseases  2015;21(10):1784-1793.
Temporary closure and disinfection can rapidly reduce levels of infectious virus in these settings.
We assessed the effect of closing live poultry markets in China on influenza A(H7N9) virus detection and viability. Intensive sampling was carried out before, during, and after a 2-week citywide market closure; the markets were cleaned and disinfected at the beginning of the closure period. Swab samples were collected at different sites within the markets and tested for H7N9 by real-time reverse transcription PCR and culture. During the closure, H7N9 viral RNA detection and isolation rates in retail markets decreased by 79% (95% CI 64%–88%) and 92% (95% CI 58%–98%), respectively. However, viable H7N9 virus could be cultured from wastewater samples collected up to 2 days after the market closure began. Our findings indicates that poultry workers and the general population are constantly exposed to H7N9 virus at these markets and that market closure and disinfection rapidly reduces the amount of viable virus.
doi:10.3201/eid2110.150623
PMCID: PMC4593444  PMID: 26402310
avian influenza; influenza; respiratory infections; H7N9; live poultry markets; dressed poultry markets; market closure; disinfection; surveillance; retail markets; interventions; control; Guangzhou; Guangdong Province; China; southern China; viruses; zoonoses; human exposure; transmission
25.  The epidemiological and public health research response to 2009 pandemic influenza A(H1N1): experiences from Hong Kong 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1750-2659.2012.00420.x
PMCID: PMC3705741  PMID: 22883352

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