Effectiveness of Enterovirus 71 inactivated vaccines against hand, foot, and mouth disease: A test-negative case-control study.

The Enterovirus A71 (EV-A71) vaccine was introduced in China in December 2015 as a preventive measure against hand, foot, and mouth disease (HFMD) caused by EV-A71. However, the effectiveness of the vaccine (VE) in real-world settings needs to be evaluated. We conducted a test-negative case-control study to assess the effectiveness of EV-A71 vaccines in preventing EV-A71-associated HFMD. Children aged 6-71 months with HFMD were enrolled as participants. The case group comprised those who tested positive for EV-A71, while the control group comprised those who tested negative for EV-A71. To estimate VE, a logistic regression model was employed, adjusting for potential confounders including age, gender, and clinical severity. In total, 3223 children aged 6 to 71 months were included in the study, with 162 in the case group and 3061 in the control group. The proportion of children who received EV-A71 vaccination was significantly lower in the case group compared to the control group (p < .001). The overall VEadj was estimated to be 90.8%. The VEadj estimates for partially and fully vaccinated children were 90.1% and 90.9%, respectively. Stratified by age group, the VEadj estimates were 88.7% for 6 to 35-month-olds and 95.5% for 36 to 71-month-olds. Regarding disease severity, the VEadj estimates were 86.3% for mild cases and 100% for severe cases. Sensitivity analysis showed minimal changes in the VE point estimates, with most changing by no more than 1% point. Our study demonstrates a high level of vaccine effectiveness against EV-A71-HFMD, especially in severe cases. Active promotion of EV-A71 vaccination is an effective strategy in preventing EV-A71 infections.

A preliminary exploration for co-detecting RNA virus and STR type on capillary electrophoresis in forensic practice.

RNA virus infection such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection shows severe respiratory symptoms on human and could be an obvious individual characteristic for investigations in forensic science. As for biological samples suspected to contain RNA virus in forensic casework, it requires respective detection of viral RNA and human DNA: reverse transcriptase polymerase chain reaction and DNA type (short tandem repeat [STR] analysis). Capillary electrophoresis (CE) has been shown to be a versatile technique and used for a variety of applications, so we preliminarily explored the co-detection of RNA virus and STR type on CE by developing a system of co-detecting SARS-CoV-2 and STR type under ensuring both the efficiency of forensic DNA analysis and safety of the laboratory. This study investigated the development and validation of the system, including N and ORF1ab primer designs, polymerase chain reaction amplification, allelic ladder, CE detection, thermal cycling parameters, concordance, sensitivity, species specificity, precision, and contrived and real SARS-CoV-2 sample studies. Final results showed the system could simultaneously detect SARS-CoV-2 and STR type, further indicating that CE has possibilities in the multi-detection of RNA viruses/STR type to help to prompt individual characteristics (viral infection) and narrow the scope of investigation in forensic science.

Age-specific transmission for different virus serotypes of hand, foot and mouth disease and the impact of interventions in East China, 2009-2015.

Background: Hand, foot and mouth disease (HFMD) remains an important public health problem in China. Understandings of age-specific transmission for different virus serotypes of the disease and assessment of non-pharmaceutical interventions (NPI) for HFMD are helpful for disease control, but they have been seldom considered. Here we further investigate transmission dynamics of HFMD and quantify the effects of NPIs and vaccination on the disease transmission. Methods: We extracted information of reported HFMD cases from 2009 to 2015 in East China. Age-specific force of infection (FoI) was used to describe the transmission characteristics for serotypes (EV-A71, CV-A16 and other enterovirus). We used an age-structured Susceptible-Exposed-Infectious-Removed (SEIR) model to simulate how interventions affect HFMD outbreaks. Results: 4,096,270 HFMD cases were included, and 160619 cases were confirmed for virus serotypes. The peaks of infections always occurred in even-numbered years. CV-A16 and EV-A71 showed a similar trend, children aged 1 or 2 years generally had the highest FoI, but there were no clear patterns for other enterovirus. Simulations showed that school break could dramatically decline the average incidence. When combined with social interventions, it would further reduce the incidence, but the effect is not apparent. When vaccine rate is over or equal to 20%, the incidence would be lower than taking NPIs. Conclusion: More attention should be paid to children under 2 years of age in the prevention and control of HFMD. Compared to NPIs, vaccination is more effective.

Optimization of COVID-19 prevention and control measures during the Beijing 2022 Winter Olympics: a model-based study.

BACKGROUND: The continuous mutation of severe acute respiratory syndrome coronavirus 2 has made the coronavirus disease 2019 (COVID-19) pandemic complicated to predict and posed a severe challenge to the Beijing 2022 Winter Olympics and Winter Paralympics held in February and March 2022. METHODS: During the preparations for the Beijing 2022 Winter Olympics, we established a dynamic model with pulse detection and isolation effect to evaluate the effect of epidemic prevention and control measures such as entry policies, contact reduction, nucleic acid testing, tracking, isolation, and health monitoring in a closed-loop management environment, by simulating the transmission dynamics in assumed scenarios. We also compared the importance of each parameter in the combination of intervention measures through sensitivity analysis. RESULTS: At the assumed baseline levels, the peak of the epidemic reached on the 57th day. During the simulation period (100 days), 13,382 people infected COVID-19. The mean and peak values of hospitalized cases were 2650 and 6746, respectively. The simulation and sensitivity analysis showed that: (1) the most important measures to stop COVID-19 transmission during the event were daily nucleic acid testing, reducing contact among people, and daily health monitoring, with cumulative infections at 0.04%, 0.14%, and 14.92% of baseline levels, respectively (2) strictly implementing the entry policy and reducing the number of cases entering the closed-loop system could delay the peak of the epidemic by 9 days and provide time for medical resources to be mobilized; (3) the risk of environmental transmission was low. CONCLUSIONS: Comprehensive measures under certain scenarios such as reducing contact, nucleic acid testing, health monitoring, and timely tracking and isolation could effectively prevent virus transmission. Our research results provided an important reference for formulating prevention and control measures during the Winter Olympics, and no epidemic spread in the closed-loop during the games indirectly proved the rationality of our research results.

Compartmental structures used in modeling COVID-19: a scoping review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic, considered as the worst global public health event in nearly a century, has severely affected more than 200 countries and regions around the world. To effectively prevent and control the epidemic, researchers have widely employed dynamic models to predict and simulate the epidemic's development, understand the spread rule, evaluate the effects of intervention measures, inform vaccination strategies, and assist in the formulation of prevention and control measures. In this review, we aimed to sort out the compartmental structures used in COVID-19 dynamic models and provide reference for the dynamic modeling for COVID-19 and other infectious diseases in the future. MAIN TEXT: A scoping review on the compartmental structures used in modeling COVID-19 was conducted. In this scoping review, 241 research articles published before May 14, 2021 were analyzed to better understand the model types and compartmental structures used in modeling COVID-19. Three types of dynamics models were analyzed: compartment models expanded based on susceptible-exposed-infected-recovered (SEIR) model, meta-population models, and agent-based models. The expanded compartments based on SEIR model are mainly according to the COVID-19 transmission characteristics, public health interventions, and age structure. The meta-population models and the agent-based models, as a trade-off for more complex model structures, basic susceptible-exposed-infected-recovered or simply expanded compartmental structures were generally adopted. CONCLUSION: There has been a great deal of models to understand the spread of COVID-19, and to help prevention and control strategies. Researchers build compartments according to actual situation, research objectives and complexity of models used. As the COVID-19 epidemic remains uncertain and poses a major challenge to humans, researchers still need dynamic models as the main tool to predict dynamics, evaluate intervention effects, and provide scientific evidence for the development of prevention and control strategies. The compartmental structures reviewed in this study provide guidance for future modeling for COVID-19, and also offer recommendations for the dynamic modeling of other infectious diseases.

Impact of the coronavirus disease 2019 interventions on the incidence of hand, foot, and mouth disease in mainland China.

BACKGROUND: In early 2020, non-pharmaceutical interventions (NPIs) were implemented in China to reduce and contain the coronavirus disease 2019 (COVID-19) transmission. These NPIs might have also reduced the incidence of hand, foot, and mouth disease (HFMD). METHODS: The weekly numbers of HFMD cases and meteorological factors in 31 provincial capital cities and municipalities in mainland China were obtained from Chinese Center for Disease Control and Prevention (CCDC) and National Meteorological Information Center of China from 2016 to 2020. The NPI data were collected from local CDCs. The incidence rate ratios (IRRs) were calculated for the entire year of 2020, and for January-July 2020 and August-December 2020. The expected case numbers were estimated using seasonal autoregressive integrated moving average models. The relationships between kindergarten closures and incidence of HFMD were quantified using a generalized additive model. The estimated associations from all cities were pooled using a multivariate meta-regression model. FINDINGS: Stringent NPIs were widely implemented for COVID-19 control from January to July 2020, and the IRRs for HFMD were less than 1 in all 31 cities, and less than 0·1 for 23 cities. Overall, the proportion of HFMD cases reduced by 52·9% (95% CI: 49·3-55·5%) after the implementation of kindergarten closures in 2020, and this effect was generally consistent across subgroups. INTERPRETATION: The decrease in HFMD incidence was strongly associated with the NPIs for COVID-19. HFMD epidemic peaks were either absent or delayed, and the final epidemic size was reduced. Kindergarten closure is an intervention to prevent HFMD outbreaks. FUNDING: This research was supported by the National Natural Science Foundation of China (81973102 & 81773487), Public Health Talents Training Program of Shanghai Municipality (GWV-10.2-XD21), the Shanghai New Three-year Action Plan for Public Health (GWV-10.1-XK16), the Major Project of Scientific and Technical Winter Olympics from National Key Research and Development Program of China (2021YFF0306000), 13th Five-Year National Science and Technology Major Project for Infectious Diseases (2018ZX10725-509) and Key projects of the PLA logistics Scientific research Program (BHJ17J013).

Changing epidemiology of hand, foot, and mouth disease in China, 2013-2019: a population-based study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an important public health problem. A monovalent EV-A71 vaccine was launched in China in 2016. Previous studies showed that inactivated monovalent EV-A71 vaccines were highly efficient against HFMD associated with EV-A71 but not against HFMD with other etiologies, leading to a hypothesis that the introduction of EV-A71 vaccines might change the pathogen spectrum and epidemiological trend of HFMD. In this study, we described for the first time the changing epidemiological characteristics of HFMD after the launch of the EV-A71 vaccine. METHODS: We extracted individual-based epidemiological data on HFMD cases reported to the Chinese Center for Disease Control and Prevention between January 2013 and December 2019. We described the changing epidemiological characteristics of HFMD before and after vaccine launch according to the distribution of diseases characteristics (demographic, temporal, and geographical) and evaluated the potential changes in risk factors of severe patients. All analyses were stratified by the phase before and after vaccine launch, and by enterovirus serotype. FINDINGS: During 2013-2019, 15,316,710 probable cases of HFMD were reported. Of these, 787,197 (5·1%) were laboratory confirmed and 76,982 (0·5%) were severe. After the launch of the EV-A71 vaccine, the median age of HFMD patients infected with EV-A71 increased from 2·24 years (IQR:1·43, 3·56) to 2·81 years (IQR:1·58, 4·01). The proportion of patients less than 3 years of age decreased while the proportion of patients 3-5 years of age increased. There was a large decrease (60·7%) in the proportion of severe cases as well as a decline (28·3%) in HFMD patients infected with EV-A71. After the launch of the EV-A71 vaccine, the severe illness rate and mortality rate of HFMD patients in all age groups has decreased sharply, 62·20% and 83·78% respectively. The timing of the HFMD epidemic peak was delayed (1-2 months) . After the launch of EV-A71 vaccine, the risk of becoming a severe case for EV-A71 serotype was decreased, whereas that risk was instead increased for CV-A16 (from 0·17 (95% CI:0·16, 0·18) to 0·23 (95% CI:0·21, 0·25)) and other enterovirus compared to EV-A71 (from 0·38 (95% CI:0·37, 0·39) to 0·58 (95% CI:0·56, 0·61)). The longer the time from onset to diagnosis, the higher was the risk of being a severe case, but the effect size was decreased. INTERPRETATION: The introduction of the EV-A71 vaccine has effectively reduced the proportion of severe HFMD cases and mortality, but changes to the dominant serotypes should be closely monitored. Development of multivalent vaccines to avoid an increased case burden due to other enteroviruses is greatly needed. FUNDING: This research was supported by the National Natural Science Foundation of China (81973102, 81773487), Public Health Talents Training Program of Shanghai Municipality (GWV-10.2-XD21), the 5th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05), the Major Project of Scientific and Technical Winter Olympics from National Key Research and Development Program of China (2021YFF0306000), 13th Five-Year National Science and Technology Major Project for Infectious Diseases (2018ZX10725-509) and Key projects of the PLA logistics Scientific research Program (BHJ17J013).

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 to Close Contacts, China, January-February 2020.

We estimated the symptomatic, PCR-confirmed secondary attack rate (SAR) for 2,382 close contacts of 476 symptomatic persons with coronavirus disease in Yichang, Hubei Province, China, identified during January 23-February 25, 2020. The SAR among all close contacts was 6.5%; among close contacts who lived with an index case-patient, the SAR was 10.8%; among close-contact spouses of index case-patients, the SAR was 15.9%. The SAR varied by close contact age, from 3.0% for those <18 years of age to 12.5% for those >60 years of age. Multilevel logistic regression showed that factors significantly associated with increased SAR were living together, being a spouse, and being >60 years of age. Multilevel regression did not support SAR differing significantly by whether the most recent contact occurred before or after the index case-patient's onset of illness (p = 0.66). The relatively high SAR for coronavirus disease suggests relatively high virus transmissibility.

Risk factors for developing severe COVID-19 in China: an analysis of disease surveillance data.

BACKGROUND: COVID-19 has posed an enormous threat to public health around the world. Some severe and critical cases have bad prognoses and high case fatality rates, unraveling risk factors for severe COVID-19 are of significance for predicting and preventing illness progression, and reducing case fatality rates. Our study focused on analyzing characteristics of COVID-19 cases and exploring risk factors for developing severe COVID-19. METHODS: The data for this study was disease surveillance data on symptomatic cases of COVID-19 reported from 30 provinces in China between January 19 and March 9, 2020, which included demographics, dates of symptom onset, clinical manifestations at the time of diagnosis, laboratory findings, radiographic findings, underlying disease history, and exposure history. We grouped mild and moderate cases together as non-severe cases and categorized severe and critical cases together as severe cases. We compared characteristics of severe cases and non-severe cases of COVID-19 and explored risk factors for severity. RESULTS: The total number of cases were 12 647 with age from less than 1 year old to 99 years old. The severe cases were 1662 (13.1%), the median age of severe cases was 57 years [Inter-quartile range(IQR): 46-68] and the median age of non-severe cases was 43 years (IQR: 32-54). The risk factors for severe COVID-19 were being male [adjusted odds ratio (aOR) = 1.3, 95% CI: 1.2-1.5]; fever (aOR = 2.3, 95% CI: 2.0-2.7), cough (aOR = 1.4, 95% CI: 1.2-1.6), fatigue (aOR = 1.3, 95% CI: 1.2-1.5), and chronic kidney disease (aOR = 2.5, 95% CI: 1.4-4.6), hypertension (aOR = 1.5, 95% CI: 1.2-1.8) and diabetes (aOR = 1.96, 95% CI: 1.6-2.4). With the increase of age, risk for the severity was gradually higher [20-39 years (aOR = 3.9, 95% CI: 1.8-8.4), 40-59 years (aOR = 7.6, 95% CI: 3.6-16.3), ≥ 60 years (aOR = 20.4, 95% CI: 9.5-43.7)], and longer time from symtem onset to diagnosis [3-5 days (aOR = 1.4, 95% CI: 1.2-1.7), 6-8 days (aOR = 1.8, 95% CI: 1.5-2.1), ≥ 9 days(aOR = 1.9, 95% CI: 1.6-2.3)]. CONCLUSIONS: Our study showed the risk factors for developing severe COVID-19 with large sample size, which included being male, older age, fever, cough, fatigue, delayed diagnosis, hypertension, diabetes, chronic kidney diasease, early case identification and prompt medical care. Based on these factors, the severity of COVID-19 cases can be predicted. So cases with these risk factors should be paid more attention to prevent severity.

Assessing Asymptomatic, Presymptomatic, and Symptomatic Transmission Risk of Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: The relative contributions of asymptomatic, presymptomatic, and symptomatic transmission of severe acute respiratory syndrome coronavirus 2 have not been clearly measured, although control measures may differ in response to the risk of spread posed by different types of cases. METHODS: We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from 4 provinces and 1 municipality in China. We estimated the variation in risk of transmission over time and the severity of secondary infections by symptomatic status of the infector. RESULTS: There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included in the study. The secondary attack rates among close contacts of symptomatic and asymptomatic index cases were 4.1% (128 of 3136) and 1.1% (12 of 1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (odds ratio, 3.79; 95% confidence interval, 2.06-6.95). Approximately 25% (32 of 128) and 50% (6 of 12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. CONCLUSIONS: Asymptomatic and presymptomatic transmissions play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.

Daily mean temperature and HFMD: risk assessment and attributable fraction identification in Ningbo China.

BACKGROUND: Hand, foot, and mouth disease (HFMD) remains a significant public health issue, especially in developing countries. Many studies have reported the association between environmental temperature and HFMD. However, the results are highly heterogeneous in different regions. In addition, there are few studies on the attributable risk of HFMD due to temperature. OBJECTIVES: The study aimed to assess the association between temperature and HFMD incidence and to evaluate the attributable burden of HFMD due to temperature in Ningbo China. METHODS: The research used daily incidence of HFMD from 2014 to 2017 and distributed lag non-linear model (DLNM) to investigate the effects of daily mean temperature (Tmean) on HFMD incidence from lag 0 to 30 days, after controlling potential confounders. The lag effects and cumulative relative risk (CRR) were analyzed. Attributable fraction (AF) of HFMD incidence due to temperature was calculated. Stratified analysis by gender and age were also conducted. RESULTS: The significant associations between Tmean and HFMD incidence were observed in Ningbo for lag 0-30. Two peaks were observed at both low (5-11 °C) and high (16-29 °C) temperature scales. For low temperature scale, the highest CRR was 2.22 (95% CI: 1.61-3.07) at 7 °C on lag 0-30. For high temperature scale, the highest CRR was 3.54 (95% CI: 2.58-4.88) at 24 °C on lag 0-30. The AF due to low and high temperature was 5.23% (95% CI: 3.10-7.14%) and 39.55% (95% CI: 30.91-45.51%), respectively. There was no significant difference between gender- and age-specific AFs, even though the school-age and female children had slightly higher AF values. CONCLUSIONS: The result indicates that both high and low temperatures were associated with daily incidence of HFMD, and more burdens were caused by heat in Ningbo.

Regional-level risk factors for severe hand-foot-and-mouth disease: an ecological study from mainland China.

BACKGROUND: Severe hand-foot-and-mouth disease (HFMD) is a life-threatening contagious disease among young children and infants. Although enterovirus A71 has been well acknowledged to be the dominant cause of severe HFMD, there still remain other unidentified risk factors for severe HFMD. Previous studies mainly focused on identifying the individual-level risk factors from a clinical perspective, while rare studies aimed to clarify the association between regional-level risk factors and severe HFMD, which may be more important from a public health perspective. METHODS: We retrieved the clinical HFMD counts between 2008 and 2014 from the Chinese Center for Disease Control and Prevention, which were used to calculated the case-severity rate in 143 prefectural-level cities in mainland China. For each of those 143 cities, we further obtained city-specific characteristics from the China City Statistical Yearbook (social and economic variables) and the national meteorological monitoring system (meteorological variables). A Poisson regression model was then used to estimate the associations between city-specific characteristics (reduced by the principal component analysis to avoid multicollinearity) and the case-severity rate of HFMD. The above analysis was further stratified by age and gender to examine potential modifying effects and vulnerable sub-populations. RESULTS: We found that the case-severity rate of HFMD varied dramatically between cities, ranging from 0 to 8.09%. Cities with high case-severity rates were mainly clustered in Central China. By relating the case-severity rate to city-specific characteristics, we found that both the principal component characterized by a high level of social and economic development (RR = 0.823, 95%CI 0.739, 0.916) and another that characterized by warm and humid climate (RR = 0.771, 95%CI 0.619, 0.960) were negatively associated with the case-severity rate of HFMD. These estimations were consistent across age and gender sub-populations. CONCLUSION: Except for the type of infected pathogen, the case-severity rate of HFMD was closely related to city development and meteorological factor. These findings suggest that social and environmental factors may also play an important role in the progress of severe HFMD.

Basic Reproduction Number of Enterovirus 71 and Coxsackievirus A16 and A6: Evidence From Outbreaks of Hand, Foot, and Mouth Disease in China Between 2011 and 2018.

BACKGROUND: Enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16), and coxsackievirus A6 (CV-A6) are common serotypes causing hand, foot, and mouth disease (HFMD). Analyses on the basic reproduction number (R0) of common pathogens causing HFMD are limited and there are no related studies using field data from outbreaks in mainland China. METHODS: We estimated the pathogen-specific basic reproduction number based on laboratory-confirmed HFMD outbreaks (clusters of ≥10 HFMD cases) reported to the national surveillance system between 2011 and 2018. The reproduction numbers were calculated using a mathematical model and the cumulative cases during the initial growth periods. RESULTS: This study included 539 outbreaks, of which 198 were caused by EV-A71, 316 by CV-A16, and 25 by CV-A6. All 10 417 cases involved were children. Assuming the outbreaks occurred in closed systems and the incubation period is 5 days, the median (interquartile range [IQR]) R0 estimates of EV-A71, CV-A16, and CV-A6 were 5.06 (2.81, 10.20), 4.84 (3.00, 9.00), and 5.94 (3.27, 10.00). After adjusting for seroprevalences, the R0 (IQR) estimates for EV-A71, CV-A16 (optimistic and conservative scenarios), and CV-A6 were 12.60 (7.35, 25.40), 9.29 (6.01, 19.20), 15.50 (9.77, 30.40), and 25.80 (14.20, 43.50), respectively. We did not observe changes in the R0 of EV-A71 after vaccine licensure (P = .67). CONCLUSIONS: HFMD is highly transmissible when caused by the 3 most common serotypes. In mainland China, it primarily affects young children. Although a vaccine became available in 2016, we have not yet observed any related changes in the disease dynamics.

Evidence for pre-symptomatic transmission of coronavirus disease 2019 (COVID-19) in China.

BACKGROUND: Between mid-January and early February, provinces of mainland China outside the epicentre in Hubei province were on high alert for importations and transmission of COVID-19. Many properties of COVID-19 infection and transmission were still not yet established. METHODS: We collated and analysed data on 449 of the earliest COVID-19 cases detected outside Hubei province to make inferences about transmission dynamics and severity of infection. We analysed 64 clusters to make inferences on serial interval and potential role of pre-symptomatic transmission. RESULTS: We estimated an epidemic doubling time of 5.3 days (95% confidence interval (CI): 4.3, 6.7) and a median incubation period of 4.6 days (95% CI: 4.0, 5.2). We estimated a serial interval distribution with mean 5.7 days (95% CI: 4.7, 6.8) and standard deviation 3.5 days, and effective reproductive number was 1.98 (95% CI: 1.68, 2.35). We estimated that 32/80 (40%) of transmission events were likely to have occurred prior to symptoms onset in primary cases. Secondary cases in clusters had less severe illness on average than cluster primary cases. CONCLUSIONS: The majority of transmissions are occurring around illness onset in an infected person, and pre-symptomatic transmission does play a role. Detection of milder infections among the secondary cases may be more reflective of true disease severity.

Short-term effects of rainfall on childhood hand, foot and mouth disease and related spatial heterogeneity: evidence from 143 cities in mainland China.

BACKGROUND: Numerous studies have demonstrated the potential association between rainfall and hand, foot and mouth disease (HFMD), but the results are inconsistent. This study aimed to quantify the relationship between rainfall and HFMD based on a multicity study and explore the potential sources of spatial heterogeneity. METHODS: We retrieved the daily counts of childhood HFMD and the meteorological variables of the 143 cities in mainland China between 2009 and 2014. A common time series regression model was applied to quantify the association between rainfall and HFMD for each of the 143 cities. Then, we adopted the meta-regression model to pool the city-specific estimates and explore the sources of heterogeneity by incorporating city-specific characteristics. RESULTS: The overall pooled estimation suggested a nonlinear exposure-response relationship between rainfall and HFMD. Once rainfall exceeded 15 mm, the HFMD risk stopped increasing linearly and began to plateau with the excessive risk ratio (ERR) peaking at 21 mm of rainfall (ERR = 3.46, 95% CI: 2.05, 4.88). We also found significant heterogeneity in the rainfall-HFMD relationships (I2 = 52.75%, P < 0.001). By incorporating the city-specific characteristics into the meta-regression model, temperature and student density can explain a substantial proportion of spatial heterogeneity with I2 statistics that decreased by 5.29 and 6.80% at most, respectively. CONCLUSIONS: Our findings verified the nonlinear association between rainfall and HFMD. The rainfall-HFMD relationship also varies depending on locations. Therefore, the estimation of the rain-HFMD relationship of one location should not be generalized to another location.

An alternative comprehensive index to quantify the interactive effect of temperature and relative humidity on hand, foot and mouth disease: A two-stage time series study including 143 cities in mainland China.

BACKGROUND: Comprehensive indices have been used to quantify the interactive effect of temperature and humidity on hand, foot and mouth disease (HFMD). The majority of them reflect how weather feels to humans. In this study, we propose an alternative index aiming to reflect the impacts of weather on HFMD and compare its performance with that of previous indices. METHODS: We proposed an index defined as the product of temperature and a weight parameter raised to the rescaled relative humidity, denoted by THIa. We then compared its model fit and heterogeneity with those of previous indices (including the humidex, heat index and temperature) by a multicity two-stage time series analysis. We first built a common distributed lag nonlinear model to estimate the associations between different indices and HFMD for each city separately. We then pooled the city-specific estimates and compared the average model fit (measured by the QAIC) and heterogeneity (measured by I2) among the different indices. RESULTS: We included the time series of HFMD and meteorological variables from 143 cities in mainland China from 2009 to 2014. By varying the weight parameter of THIa, the results suggested that 100% relative humidity can amplify the effects of temperature on HFMD 1.6-fold compared to 50% relative humidity. By comparing different candidate indices, THIa performed the best in terms of the average of the model fits (QAIC = 9449.37), followed by humidex, heat index and temperature. In addition, the estimated exposure-response curves between THIa and HFMD were consistent across climate regions with minimum heterogeneity (I2 = 65.90), whereas the others varied across climate regions. CONCLUSIONS: This study proposed an alternative comprehensive index to characterize the interactive effects of temperature and humidity on HFMD. In addition, the results also imply that previous human-based indices might not be sufficient to reflect the complicated associations between weather and HFMD.

The temporal characteristics of the lag-response relationship and related key time points between ambient temperature and hand, foot and mouth disease: A multicity study from mainland China.

BACKGROUND: Previous studies have thoroughly elucidated the exposure-response relationship between ambient temperature and hand, foot, and mouth disease (HFMD), whereas very little concern has been to the lag-response relationship and related key time points. OBJECTIVES: We aimed to clarify the temporal characteristics of the lag-response relationship between ambient temperature and HFMD and how they may vary spatially. METHODS: We retrieved the daily time series of meteorological variables and HFMD counts for 143 cities in mainland China between 2009 and 2014. We estimated the city-specific lag-response curve between ambient temperature and HFMD and related key time points by applying common distributed lag nonlinear models (DLNM) and Monte Carlo simulation methods. Then, we pooled the city-specific estimates by performing a meta-regression with the city-specific characteristics as meta-predictors to explain the potential spatial heterogeneity. RESULTS: We found a robust lag pattern between temperature and HFMD for different levels of temperatures. The temporal change of risk obtained its maximum value on the current day but dropped sharply thereafter and then rebounded to a secondary peak, which implied the presence of a harvesting effect. By contrast, the estimation of key time points showed substantial heterogeneity, especially at high temperature (the I2 statistics ranged from 47% to 80%). With one unit increase in the geographic index, the secondary peak would arrive 0.37 (0.02, 0.71) days later. With one unit increase in the economic index and climatic index, the duration time of the lag-response curve would be lengthened by 0.36 (0.1, 0.62) and 0.92 (0.54, 1.29) days, respectively. CONCLUSION: Our study examined the lag pattern and spatial heterogeneity of the lag-response relationship between temperature and HFMD. Those findings gave us new insights into the complex association and the related mechanisms between weather and HFMD and important information for weather-based disease early warning systems.