key: cord-0846867-1xjbg0sn
authors: Shen, Li; Sun, Minghao; Song, Shuxuan; Hu, Qingwu; Wang, Nuoya; Ou, Guangyu; Guo, Zhaohui; Du, Jing; Shao, Zhongjun; Bai, Yao; Liu, Kun
title: The impact of anti‐COVID‐19 nonpharmaceutical interventions on hand, foot, and mouth disease—A spatiotemporal perspective in Xi'an, northwestern China
date: 2022-03-22
journal: J Med Virol
DOI: 10.1002/jmv.27715
sha: 26d4af6e7c93958a16b02b5323f7710386bdc98c
doc_id: 846867
cord_uid: 1xjbg0sn

Growing evidence has shown that anti‐COVID‐19 nonpharmaceutical interventions (NPIs) can support prevention and control of various infectious diseases, including intestinal diseases. However, most studies focused on the short‐term mitigating impact and neglected the dynamic impact over time. This study is aimed to investigate the dynamic impact of anti‐COVID‐19 NPIs on hand, foot, and mouth disease (HFMD) over time in Xi'an City, northwestern China. Based on the surveillance data of HFMD, meteorological and web search data, Bayesian Structural Time Series model and interrupted time series analysis were performed to quantitatively measure the impact of NPIs in sequent phases with different intensities and to predict the counterfactual number of HFMD cases. From 2013 to 2021, a total number of 172,898 HFMD cases were reported in Xi'an. In 2020, there appeared a significant decrease in HFMD incidence (−94.52%, 95% CI: −97.54% to −81.95%) in the first half of the year and the peak period shifted from June to October by a small margin of 6.74% compared to the previous years of 2013 to 2019. In 2021, the seasonality of HFMD incidence gradually returned to the bimodal temporal variation pattern with a significant average decline of 61.09%. In particular, the impact of NPIs on HFMD was more evident among young children (0–3 years), and the HFMD incidence reported in industrial areas had an unexpected increase of 51.71% in 2020 autumn and winter. Results suggested that both direct and indirect NPIs should be implemented as effective public health measures to reduce infectious disease and improve surveillance strategies, and HFMD incidence in Xi'an experienced a significant rebound to the previous seasonality after a prominent decline influenced by the anti‐COVID‐19 NPIs.

Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by more than 20 enteroviruses pathogens that mainly involve Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) serotypes. 1 HFMD is characterized by a sudden onset of fever with vesicular rashes on hands, feet, and buttocks and ulcers in the oral mucosa. Most patients infected with HFMD via close contact, respiratory droplets, or fecal-oral route could recover spontaneously within a week; however, in a few severe cases, cardiopulmonary complications can result in death. 2, 3 The susceptibility and severity of HFMD are closely associated with age, and children under 5 years are identified as the most susceptible targets, especially in densely populated urban areas. 4 Since 1997, the Asia-Pacific region has become the most vulnerable area to HFMD worldwide with China as the worst affected country. 2 In China, HFMD accounted for the largest percentage of notifiable infectious diseases from 2013 to 2018, and 2,353,310 cases were reported in 2018 (http://www.nhc.gov.cn/jkj/). To restrain the continuous prevalence of HFMD, the Chinese government has adopted a series of prevention and control measures, including vaccines, health education, and hand hygiene. 5 Vaccination has been proven to be an effective measure to reduce the incidence of HFMD, and in recent years, EV71-related HFMD incidence steadily decreased due to the advent of inactivated monovalent EV71 vaccines and an extensively developed three-level surveillance laboratory network. 2, 6 Nevertheless, there has been a growing number of Coxsackievirus-relative HFMD cases after 2017, 6, 7 which could engender a possible resurgence of the HFMD epidemic in the absence of targeted measures.

Effectively reducing the incidence of HFMD is still a critical issue among researchers and public health administrators. At the moment, lessons from measures against coronavirus disease 2019 (COVID-19) might provide a way. In 2020, the COVID-19 pandemic spread globally and led to disastrous and unforeseen consequences in most aspects of human society. To overcome the COVID-19 crisis, governments worldwide implemented a series of corresponding measures using nonpharmaceutical interventions (NPIs) (e.g., home quarantine, reducing social distancing, travel restrictions, and masking), which have mitigated the magnitude and geographical scope of COVID-19 propagation. 8, 9 Surprisingly, studies revealed that not only respiratory infectious diseases but also intestinal infectious diseases cases dramatically decreased in multiple regions during the COVID-19 pandemic. [10] [11] [12] This indicated that the positive effects of anti-COVID-19 measures extended to several other communicable diseases, [13] [14] [15] and were also confirmed in China. 16 Specifically, there was a more dramatic decline in HFMD incidence than in other intestinal infectious diseases in 2020. 17 In addition, due to the large-scale school closure, the reported cases of HFMD decreased more rapidly in children compared to other population groups, and strikingly, the number of local HFMD cases also varied between cities. 16, 18 This heterogeneous impact of NPIs could be attributed to differences in population mobility, geographical locations, and sociodemographic characteristics, which should require relevant specific policies for each region. 19, 20 While anti-COVID-19 NPIs have been proven effective in HFMD, the intensity of NPIs adopted by the Chinese government has changed in distinct epidemic stages to revive the economy-as opposed to remaining high at all times.

Accordingly, the role of NPIs in altering short-term (i.e., the early emergency response with strict anti-COVID-19 measures) and potential long-term (i.e., the stage of normalization of epidemic prevention and control) dynamics of HFMD must be quantified to develop more targeted measures. These insights can be simultaneously drawn from the fight against the COVID-19 pandemic and emphatically implemented to prevent and control HFMD in the postpandemic era. However, few studies have investigated the impacts of anti-COVID-19 NPIs on HFMD from a long-term perspective. Moreover, considering the geographical heterogeneity, the influence of NPIs during the COVID-19 pandemic on the spatial patterns of HFMD incidence in high-risk areas of China is also uncertain. Therefore, we conducted a retrospective epidemiological case study of 9-year HFMD surveillance in Xi'an, the largest regional central city in northwestern China with a serious prevalence of HFMD. 21 The main aims were to investigate how anti-COVID-19

NPIs can affect the HFMD epidemic in a large city with a population of over 12 million and to quantitatively assess the short-term and potential long-term impacts of NPIs in the postepidemic era. Furthermore, based on different mathematical models we also examined the geographical and populational heterogeneity of the detected impacts. Research into these problems will contribute to the formulation of HFMD prevention and control measures in large cities.

As the largest city in Northwest China, Xi'an (105°29'−115°15' E, 31°42'−39°35' N) has a total area of 10,752 km 2 , consisting of 13 districts and counties ( Figure S1 ). The total population in 2021 was 12.95 million (http://www.xa.gov.cn/). Xi'an is surrounded by Qinling Mountains in the south and experiences four distinct seasons with a subhumid warm temperate continental monsoon climate. Annually, the city typically receives 528.3-716.5 mm of precipitation with an average temperature of 13.1-14.3°C. The seasonality of HFMD differs geographically which shows a bimodal seasonality of May and October in certain cities in southern China, and a unimodal peak in June in northern China. 22 Two peak times for HFMD incidence are recognized in Xi'an with the larger in May and the second in October, which is significantly different from those observed in other areas of northern China. 21 Concomitant with rapid urban development, Xi'an has grown as a tourist city characterized by a high population density and mobility, which has posed great pressure on the epidemic prevention and control of the city. Although the number of HFMD cases in Xi'an initially declined after the outbreak of COVID-19, it has rapidly rebounded as schools resumed classes (http://jyt.shaanxi.gov.cn/). Thus, it is of great necessity to conduct this retrospective epidemiological study in such an important and representative study area.

The first confirmed case of COVID-19 in Xi'an was reported on January 23, 2020 and the local government immediately implemen- Table S1 were collected from the National Meteorological Information Centre for Xi'an (http://data.cma.cn/). In addition, web search data were used as an effective tool for obtaining information on infectious diseases complementary to the traditional monitoring systems. Previously, Baidu Search Index (BSI), which helps track disease-related trends based on the search behaviors of online users on a specific search engine, has been successfully applied to improve the accuracy of HFMD prediction. 3 Thus, we selected five indexes using the keywords of HFMD from the shared platform of the BSI (https://index.baidu.com/) with detailed descriptions of these indexes in Table S1 . After data cleaning and classification, we 

To compare the dynamic prevalence of HFMD in Xi'an, we calculated the differences between the weekly HFMD cases of The first step was to identify the change points of the HFMD time series for the whole research period, which can be used to further define distinct epidemic periods by combining the implementation of antipandemic regulations in Xi'an. The Bayesian model averaging scheme is a promising method to capture rich variations in trend, seasonality, and change points since it has been improved by integrating numerous optimization models in time-series decomposition. 23 Specifically, the superior model BEAST can manage the uncertainty by selecting the optimal candidate model and simultaneously relating the change, seasonality, and trend. 24 Moreover, the probability that a disturbance occurs at any specific time point can also be estimated to identify the potential changes in the time series. The BEAST modeling of the weekly and monthly HFMD time series was performed using the package "Rbeast" v0.2.2 (https://CRAN.R-project.org/ package=Rbeast) in R v4.0.4.

The time-series model used to predict the expected number of HFMD cases is the BSTS which is capable of separately extracting the trend, seasonal, and regression components based on stochastic state-space. 25 The BSTS model can be described by Equations 

where y t is the observation in week t of the HFMD time series and follows a Poisson distribution; μ t denotes the latent state evolving BSTS models finally yielded the expected HFMD cases with two types of covariates as the input for further regression analysis. More applicable models specific to different counties and age groups were also developed with meteorological factors because of deficient corresponding BSIs. Next, we calculated the symmetric mean absolute percentage error (SMAPE) and root mean square error (RMSE) of different models to test the prediction accuracy. 27 The aforementioned analyses were performed in R v4.0.4 using the package "bsts" v0.9.7 (https://cran.r-project.org/web/packages/bsts/ index.html).

Most studies commonly adopt the ITSA method when examining the effectiveness of an intervention on public health problems. 28 ITSA has been identified as a feasible and effective way to capture the potential association between the results and its influential NPI strategies at the population level over a clearly defined period. 29 Given that ITSA is often designed based on regression methods, we adopted the regression components obtained by the BSTS model to conduct ITSA with properly controlled variables for the autocorrelation effect.

As three critical anti-COVID 19 regulations were implemented in Xi'an, we set three interrupted points in the HFMD time-series, while also dividing the forecast period (i.e., postintervention period) into three corresponding stages. The first stage is from the 5th week week in 2021. According to these three stages with different intervention intensities, the ITSA segmented regression model can be described by Equation (4) as follows:

where Y t is the observation in week t; T is the timing sequence counting from 0 (with T 1 -T 3 as the interrupted points); X 1 , X 2 , and Particularly, the rebounded secondary peak in 2020 was more significant for the age groups 3-6 years and >6 years, demonstrating a much higher value compared to both the first and secondary peaks in 2013 to 2019. The relative reduction of the number of HFMD cases was over 90% from the 1st to 36th week in 2020 and less than 75% in 2021 for all gender and age groups (Table S2) . From the 37th

week to the 52nd week in 2020, it is clear that the relative increments of the number of HFMD cases for both males and females were similar to the overall tendency in Xi'an; however, the incidence growth for the three age groups varied with the high age group

showing the most dramatic change. In addition, the occurrence of HFMD demonstrated spatially dynamic distribution across the 13 counties within Xi'an ( Figure S2 ) with the normal primary peak disappearing and the secondary one rising in 2020. According to the overall variations in weekly HFMD incidence for 2020 (Table S2) Xi'an effectively met the strict requirements of governments which caused the reported number of reported HFMD cases to decline to near 0 ( Figure 5A ). In contrast, the predicted value gradually increased to a peak at the transitory stage between Phase 1 and Phase 2 which is also recognized as the main peak of HFMD incidence in previous years. As BSI covariates already contain the effect of policy-related human factors, we adopted the simulated result with meteorological factors as the only predictor to calculate the absolute and relative difference between the predicted and observed values. Table 1 shows a mean cumulative reduction of more than 4837 in Phase 1. In Phase 2, there was a steep rise in the observed number of HFMD cases while the predicted number reached the secondary peak slightly lower than that of the observed with a small relative increase (0.07). The relative reduction in Phase 3 (0.61) was lower than Phase 1 (0.95) despite a low-incidence period at the early time ( Figure 5A ).

Concerning the analysis for the three clustered classes and three age groups, Figure 6 shows the model results and their cumulative difference compared to the observed value in Table 1 .

It indicates that the seasonal trends of the predicted number of and hence presents a positive mean relative difference compared to Class 2 and Class 3. In addition, the mean relative difference between the observed and predicted number of HFMD cases for the 0-3 years age group was negative in Phase 2 ranging from −0.73 to 4.13 with a mean of −0.08, whereas the changes for the other two high-age groups showed relative growth (Table 1) . This inconsistency may be attributed to children younger than 3-yearold occupying the greatest proportion of the total HFMD cases in Xi'an. 22 Table 2 Table 2 also clearly indicate that the association of NPIs and HFMD incidence gradually diminished in both Phases 2 and 3.

As an interdisciplinary study, the present research was designed to investigate how HFMD transmission changes during the COVID-19 pandemic period in Xi'an and quantitatively evaluate the impacts of local governmental NPIs on HFMD incidence. Foremost, the results revealed that the impact of anti-COVID-19 NPIs on HFMD incidence varied between different age groups and spatial locations. Since the pandemic prevention and control have become routine, the risk of infection for young children under 3 years old was lower than for other age groups, whereas preschoolers between 3 and 6 years old and people older than 6 that needed to attend school or work were exposed to a higher risk of infection after resuming classes and production. This phenomenon can be attributed to the difference in behavioral and health monitoring between adults and children, but the deviation caused by their proportions of the total HFMD cases cannot be neglected. In addition, we also explored the associations between HFMD incidence and its relevant factors for three classes of counties. The results revealed that factors related to socioeconomic development exert a stronger influence on HFMD incidence in counties of Class 3, whereas explaining the exact effect mechanism beyond linear correlation is still a challenging task. However, to address this question, more attention should be focused on the differences caused by regional policies and community management that influence epidemic prevention and control. The spatial heterogeneity and inconsistency of HFMD incidence for the 13 counties in

Xi'an may be a consequence of the distinct NPIs proposed and implemented for each county. Moreover, the rezoning of the areas on Furthermore, the study also identified the characteristic tendency of how patients with HFMD select the most suitable medical institutions for healthcare service and help. Serious attention should be given to the evident changes in the proportion of HFMD incidence reported by the maternal and child healthcare hospital as well as T A B L E 1 Cumulative differences between the observed and simulated weekly number of HFMD cases in three prediction phases for 2020--2021. Notwithstanding these limitations, this study provides a preliminary effort in revealing how NPIs specific to COVID-19 acted on the changes of HFMD incidence in Xi'an, which can be extended to other national and international large cities as a reference in synergistic prevention and control of multiple epidemic diseases.

Simultaneously, results obtained in this study can also serve as supporting information to link policy-makers with the academic community in reducing diseases and promoting public health.

This study quantitatively assessed the positive impacts of NPIs on the reduction of HFMD incidence during the COVID-19 pandemic in

Xi'an, of which spatial-temporal characteristics varied in different age 

The authors were grateful and extended their appreciation to anonymous reviewers whose suggestions helped in the preparation of this paper. This study was funded by National Natural Science 

The authors declare no conflicts of interest.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.

In China, the collection of data from HFMD cases is part of routine public health surveillance, and such data collection is exempt from institutional review board assessment. Ethical approval for this study was not required in accordance with local legislation and national guidelines.

http://orcid.org/0000-0003-1847-8208

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