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      Post-exposure prophylaxis vaccination rate and risk factors of human rabies in mainland China: a meta-analysis

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          Abstract

          Rabies is one of the major public health problems in China, and the mortality rate of rabies remains the highest among all notifiable infectious diseases. A meta-analysis was conducted to investigate the post-exposure prophylaxis (PEP) vaccination rate and risk factors for human rabies in mainland China. The PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical and Wanfang databases were searched for articles on rabies vaccination status (published between 2007 and 2017). In total, 10 174 human rabies cases from 136 studies were included in this meta-analysis. Approximately 97.2% (95% confidence interval (CI) 95.1–98.7%) of rabies cases occurred in rural areas and 72.6% (95% CI 70.0–75.1%) occurred in farmers. Overall, the vaccination rate in the reported human rabies cases was 15.4% (95% CI 13.7–17.4%). However, among vaccinated individuals, 85.5% (95% CI 79.8%–83.4%) did not complete the vaccination regimen. In a subgroup analysis, the PEP vaccination rate in the eastern region (18.8%, 95% CI 15.9–22.1%) was higher than that in the western region (13.3%, 95% CI 11.1–15.8%) and this rate decreased after 2007. Approximately 68.9% (95% CI 63.6–73.8%) of rabies cases experienced category-III exposures, but their PEP vaccination rate was 27.0% (95% CI 14.4–44.9%) and only 6.1% (95% CI 4.4–8.4%) received rabies immunoglobulin. Together, these results suggested that the PEP vaccination rate among human rabies cases was low in mainland China. Therefore, standardised treatment and vaccination programs of dog bites need to be further strengthened, particularly in rural areas.

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          Immunohaematological reference values in human immunodeficiency virus-negative adolescent and adults in rural northern Tanzania

          Background The amount of CD4 T cells is used for monitoring HIV progression and improvement, and to make decisions to start antiretroviral therapy and prophylactic drugs for opportunistic infections. The aim of this study was to determine normal reference values for CD4 T cells, lymphocytes, leucocytes and haemoglobin level in healthy, HIV negative adolescents and adults in rural northern Tanzania. Methods A cross sectional study was conducted from September 2006 to March 2007 in rural northern Tanzania. Participants were recruited from voluntary HIV counselling and testing clinics. Patients were counselled for HIV test and those who consented were tested for HIV. Clinical screening was done, and blood samples were collected for CD4 T cell counts and complete blood cell counts. Results We enrolled 102 participants, forty two (41.2%) males and 60 (58.8%) females. The mean age was 32.6 ± 95% CI 30.2–35.0. The mean absolute CD4 T cell count was 745.8 ± 95% CI 695.5–796.3, absolute CD8 T cells 504.6 ± 95% CI 461.7–547.5, absolute leukocyte count 5.1 ± 95% CI 4.8–5.4, absolute lymphocyte count 1.8 ± 95% CI 1.7–1.9, and haemoglobin level 13.2 ± 95% CI 12.7–13.7. Females had significantly higher mean absolute CD4 T cell count (p = 0.008), mean absolute CD8 T cell count (p = 0.009) and significantly lower mean haemoglobin level than males (p = 0.003) Conclusion Immunohaematological values found in this study were different from standard values for western countries. Females had significantly higher mean CD4 T cell counts and lower mean haemoglobin levels than males. This raises the issue of the appropriateness of the present reference values and guidelines for monitoring HIV/AIDS patients in Tanzania.
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            Potential economic benefits of eliminating canine rabies.

            Although canine rabies has been eliminated from industrialized countries, infected dogs remain the primary source of human and livestock exposures in Asia, Africa and much of South America. Human deaths are the most important direct economic impact of canine rabies, followed by livestock losses and the cost of PEP, while expenses associated with dog vaccination and control are major indirect impacts. The global burden of rabies disproportionately affects Asia, which experiences more than half of human rabies deaths and approximately 65% of livestock losses, and performs more than 90% of postexposure prophylaxis (PEP). Africa is second to Asia in terms of human deaths and livestock losses, but administers the least number of PEPs of the three regions. Recent experience in Latin America shows that efforts to reduce human deaths from rabies through expanded dog vaccination and improved access to PEP result in significant monetary savings. The elimination of canine rabies would lead to major economic benefits in developing countries that are often the least capable of dealing with the disease. This article forms part of a symposium in Antiviral Research on the elimination of canine rabies.
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              The Spatiotemporal Expansion of Human Rabies and Its Probable Explanation in Mainland China, 2004-2013

              Introduction Rabies is a viral zoonotic infection of the central nervous system caused by a lyssavirus, and its mortality rate is nearly 100% without proper post-exposure prophylaxis (PEP). As one of the most feared diseases throughout human history, rabies is widely distributed throughout the world with high mortality, leading to 55,000 human deaths each year [1]. China has the second highest rate of human rabies in Asia, where domestic dogs are the main source of infection and are the primary vector for human rabies. Towards the end of the last century, China encountered the third wave of human rabies since 1949 [2,3], and the reemerging disease was among the top three causes of human death due to infectious diseases in the country [4]. The rapid increase of domestic dog population and inadequate PEP for humans bitten by dogs were thought to be the important factors driving the high incidence of human rabies in mainland China [5–8]. However, data about the burden of canine rabies in China is limited given the lack of detailed data on the number of domestic dogs and comprehensive rabies surveillance among dogs in the country [9,10]. Although previous studies had revealed the number of human rabies cases slightly decreased since 2008, the rabies seemed to be gradually expanding to the low-incidence or non-epidemic areas due to human-related activities (i.e. human migration, pets keeping) [11,12], which would hinder the goal to eliminate rabies by year 2020 [13]. In order to control the burden of rabies expansion, a comprehensive understanding about the spatiotemporal feature and evolution dynamic of rabies is of great importance. However, the previous studies were limited, giving the hotspots and risk factors for the occurrence of human rabies over the years and the spread dynamic of rabies remain unclear. In this study, we conducted multidisciplinary analyses to characterize the spatiotemporal movement of human rabies cases, to describe the spread pattern and rabies evolution, to identify the risk factors for the occurrence of human rabies cases, which could provide evidence-based guidance for policy-makers and service providers to control and prevent the disease. Materials and Methods Data collection and management In China, human rabies is a class B notifiable infectious disease, and information regarding each laboratory-confirmed case must be reported to the Chinese CDC (CCDC) through the National Notifiable Disease Surveillance System (NNDSS) [14]. Data on human rabies cases, including age, gender, occupation and month of onset, from January 2004 to December 2013 in mainland China was obtained from the NNDSS. Demographic data, gross domestic product (GDP) per capita and education level specific to each county were obtained from the China Bureau of Statistics from the sixth national census in 2010. Average monthly temperature covering 700 surveillance stations in mainland China from 2004 to 2013 were collected from the China Meteorological Data Sharing Service System (http://cdc.cma.gov.cn). Monthly outbreaks of canine rabies at the province level were obtained from official veterinary bulletin from the ministry of agricultural of People’s Republic of China. For the phylodynamic analysis, the full sequences of the N gene of rabies with background information including isolation year, host, and province were retrieved from GenBank and literatures [6,15–19], accessed on April 15, 2014. Then we formed a data set including 219 N gene sequences from 19 provinces ranging from 1986 to 2012. According to the results of phylogenetic trees, we chose two main lineages named Clade I and Clade II for the discrete phylogeographic analysis. For all available sequence of the two main lineages, we excluded high homologous sequences with the same background information. Then we formed two datasets for the 141 Clade I and 62 Clade II sequences. The accession numbers and strains’ information used in this study are shown in S1 Table. Epidemiological features analysis The bar chart of monthly incidence was produced to check seasonality, and annual incidence curves were plotted to examine the overall temporal trend. Average annual incidences over the whole study period were compared across gender and age groups, and the proportions of human cases by occupation were calculated. To assess the spatiotemporal distribution of human rabies, map series were created to show the spatial distribution of annual incidence of each county. In addition, to better present the epidemic dynamic of the disease, the number of cases of each province was mapped from 2004 to 2013. Spatiotemporal hotspots analysis Hotspots are important characteristics that can be used to target interventions at most- needed places. The spatial movement of hotspots over time is useful not only in describing the disease spread dynamic but also in assessing the effectiveness of disease control and prevention programs. We evaluated the presence of space-time hotspots using Kulldorff’s spatiotemporal scan statistic implemented in SaTScan software (version 9.0) [20]. In order to find as many as possible spatially refined areas with reasonable LLR values, a discrete Poisson model was fitted to identify space-time hotspots, and 90% of the study period and the areas with 10% of the total population size in mainland China were set as the upper search bounds, respectively. Hotspots were detected using the log likelihood ratio (LLR) test statistic whose significance was evaluated with 999 Monte Carlo samples. Spatiotemporal hotspots were then mapped at the county level, together with a map of diffused counties by year, to show the geographic movement of human rabies after 2004. Panel Poisson Regression analysis To explore potential factors related to spatiotemporal heterogeneity of human rabies, a panel Poisson regression was fitted using STATA software (Version 10.0, StataCorp LP, Texas, USA) for the 2004–2013 period. The monthly number of human rabies for each county was set as the outcome variable, and population number was included as the offset variable. Potential risk factors at the county scale, such as temperature, average education level and GDP per capita, were included as covariates in the analysis. Because the incubation of rabies was average 1 to 3 month and the temperature was of lag effect, we explored the time lags of 0 to 4 months for the number of canine rabies outbreaks and 0 to 2 months for temperature. Univariate analysis was performed to examine the effects of individual variables. Multivariate analysis was performed using the variables with a P-value 0.5), while only two main lineages, Clade I and Clade II, contributed to rabies epidemic in mainland China from 2004 to 2013 (Fig. 5). In addition, seven sub-clades with high posterior value were identified in Clade I, and six in Clade II. Interestingly, the sequences from 2009 to 2012 were mostly clustered in Clade I (colored red in Fig. 5), indicating the dominant role of Clade I in recent rabies epidemics. The genetic diversities of Clade I and Clade II were mapped at the provincial level in Fig. 4C and 4D. The southern and southwestern provinces, in particular Hunan and Yunnan, had more genetic diversities than the northern and eastern provinces, such as Shanxi, Hebei, Beijing, Shanghai, Zhejiang and Fujian, which were mostly associated with Clade I-G. The abundant genetic diversity of rabies in Guangxi and Hunan province (Fig. 4C and 4D) suggested they might be the center for rabies circulation and evolution. Fig. 5 and 4C imply possible diffusion of Clade I-G from eastern region (e.g., Shanghai, Zhejiang) to southwestern (Sichuan) and northern (Shaanxi) regions and of Clade I-B from Henan to Anhui and Yunnan in recent years. It remains to be verified whether these two clades have gained enhanced fitness or transmissibility. 10.1371/journal.pntd.0003502.g005 Fig 5 Maximum Clade Credibility tree of N Genes of Rabies in mainland China. To further explore the diffusion pattern implied by genetic linkage while accounting for phylogenetic uncertainty, we summarized rates yielding a Bayes factor >3 in Figs. 4C and 4D and S3 Table, which reveal more spread events of Clade I than that of Clade II. Interestingly, in Clade I, we found some rabies spread events that could be related to the spread of human rabies from the south towards the north and west. The migrations of Clade I-G between Shaanxi and Zhejiang and between Shaanxi and Yunnan were strongly supported with high Bayes factors 33.97 and 12.36. Shanxi and Shaanxi, which have latest hotspots of human rabies, were involved in two and three migration pairs with Bayes factor >3 for Clade I-G (Fig. 4B). Additionally, spread events could have also occurred between southwestern provinces (Sichuan, Yunnan) and central, eastern and southern provinces (Henan, Anhui, Zhejiang and Guizhou). Discussion Rabies is considered one of the most dangerous but neglected diseases in developing countries, with the greatest burden in the poorest rural communities where 15 million people need PEP every year [28]. In China, rabies is thought to be under-reported or under-recognized, resulting in an under-estimation of the true disease burden [7].The State Council issued official notices in 2009 and 2012 underlining rabies control as a priority with control objectives between 2015 and 2020 [29,30]. Our study highlighted both the strengths and gaps in the rabies control efforts in China. Despite the decline in human rabies cases at the national level since 2008, especially successful control in historically high-incidence provinces, China has to face a new complication that rabies started to spread from high-incidence regions towards low-incidence regions, as evidenced in our statistical and phylogeographic analyses. Our findings reveal that the higher temperature, the higher risk of human rabies, which is consistent with the observed peak season in Summer and Autumn. Such seasonality is not surprising, as people tend to wear less and have more outdoor activities (in the absence of indoor air-conditioning in rural areas) in warm and hot weather, and hence have more frequent contact with canines, irascibility of which is sensitive to high temperatures. It also seems reasonable that the male incidence is far higher than the female incidence, as in rural China men tend to have more outdoor activities than women due to cultural factors [31]. The newly-established endemic counties or hotspots mostly occurred in the west or north to the previous endemic areas and represented a trend of spreading of the virus from the southern and eastern regions to the northern and western regions (Fig. 3, 4). Such movement might be explained by the fact that interventions were implemented in baseline high-incidence regions over the years [32] whereas the baseline low-incidence regions started to suffer the increasing burden of rabies in the absence of interventions. Our analyses revealed the importance of improving the education level and economic status in reducing human rabies incidence in mainland China, and partially explained why farmers, students, and pre-school children are the high risk groups [11]. It is believed that the unawareness of rabies risk and the high price of the rabies PEP are the main reasons for the high incidence in the population with low education and low income [8].The decreasing incidence in rural areas of high-incidence provinces might be partially due to recent efforts in educational campaign about rabies and the introduction of new rural cooperative medical subsidies for PEP costs [32]. In addition, the health services and medical standards for rabies diagnosis and treatment are believed to be other key factors affecting human rabies incidence. For example, the country’s investment in training health professionals on PEP and increasing access to PEP in the countryside likely contributed to the decrease in human rabies cases after 2007 [7,32]. In this study, however, we were not able to quantify the contribution of any intervention due to the lack of data. However, we urge relevant agencies and organizations to extend these intervention programs to rural areas with historical low incidences, in particular around the hotspots we identified. The rapid economic development in China has greatly encouraged the ownership and transportation of domestic dogs, yet the vaccination of dogs is left far behind [11,32], facilitating the rabies spread. With the help of phylogeographic analysis, some long-distance spread events were detected and support the geographic dispersion pattern found in our epidemiological investigation. Clade I of rabies, especially Clade I-G, was found to dominate recent spread across provinces. These results suggest that the movement of hotspots of human rabies may be a consequence of long distance instead of cross-border migration of hosts. However, interpretation of these results should be cautious as potential sampling bias of sequences could distort the underlying truth. Additionally, although having contributed to most rabies epidemics in the past decade, Clade II was playing a less significant role in the epidemic since 2009. The emergence of the Clade I and the gradual displacement of Clade II are also obvious in recent studies [3,6,33,34]. Our phylodynamic analyses highlight the importance of closely monitoring Clade I in the future and the need to strengthen canine rabies surveillance, to regulate interprovincial animal trade, and to intervene promptly upon detection of canine rabies outbreaks. The usefulness of efficient surveillance on canine rabies is also evidenced by our identification of the positive association of human rabies outbreaks with the canine counterparts at a two-month lag. While some developed countries, such as the United States and Western European countries had achieved their goal of eliminating human rabies cases, most developing countries, especially those in Africa and Asia, continue to suffer from the burden of rabies and account for 95% of global human cases [35,36]. The magnitudes and epidemiological patterns of rabies differ from country to country [37]. Taking countries bordering China for example, India has the highest rate of human rabies in the world, and its rabies incidence has been nearly constant for a decade. Thailand is moving towards low endemic status, and Indonesia sees increase in incidence and expansion in range. Despite these differences, these countries share some common risk factors, e.g., educational level, economic status and canine rabies [35,36]. A certain level of internationally coordinated efforts such as communication about successful control experiences may be helpful towards global elimination of human rabies [37]. Our study shares some similar limitations with previous studies. The data were collected from a passive surveillance system, which may underreport cases of human rabies especially in rural and remote areas. If underreporting is truly more severe in rural and remote areas where socioeconomic and educational levels are usually lower, the magnitude of the impact of GDP and education levels might have been underestimated. However, this underreporting should have small influence on our results for clustering and expansion of the epidemics, as the hotspots identified in this study are of large scale and encompass both developed and underdeveloped areas. The lack of some highly relevant data such as dog density and dog vaccine coverage also limited our understanding of the true effects of the available risk factors and the driving reason for the declining trend of the overall epidemic. Additionally, GDP per capita and average education years used in our panel Poisson regression were from a single year instead of all the study years. Nevertheless, these data were usually relatively stable over a few years, and spatial heterogeneity generally dominates over temporal changes. Moreover, Bayesian CAR could be used in the panel Poisson model to account for spatial and temporal correlations due to similarity in unmeasured risk factors, which is subject to future research [38]. Finally, despite the large geographic coverage of the sequences used in our phylogeographic analysis, the lack of a sufficient number of sequences at some high-incidence locations such as Guangdong may have led to an incomplete picture of the genotypic distribution and spread of rabies in mainland China. Overall, we outlined a clear picture of the epidemic patterns of human rabies in China using a multi-disciplinary spatiotemporal analytical approach, and this approach is an integral part in the design of effective elimination strategies for human rabies [35]. We reiterate that control efforts should focus on not only the high-incidence areas but also the low-incidence and emerging areas in order to achieve the goal of rabies elimination by 2020 [13]. The enhanced surveillance of human rabies cases, effective intervention programs, and efficient cooperation among relevant agencies have worked together to achieve the success in rabies control in high-incidence areas since 2007 [32,39,40]. Elimination of rabies is feasible and can be cost effective [41,42]. However, the new challenge of geographic expansion of the rabies epidemic needs to be addressed together with traditional challenges, e.g., the canine immunization coverage may be far below 70%, a critical threshold for interrupting rabies virus circulation in the dog population [1]. We recommend supplementing current control strategies with the allocation of appropriate amount of intervention resources to low-incidence areas, especially areas with limited access to educational and economic development. Conclusions The reduction of human case reports has been observed in mainland China but was accompanied with geographic expansion towards the north and the west. Our multidisciplinary study identified this new challenge with both epidemiological and phylogenetic evidence, and provided new insights on risk factors and control strategies for the disease spread. Supporting Information S1 Table The strains’ information used in this study. (DOCX) Click here for additional data file. S2 Table Parameter settings for phylodynamic analysis. (DOCX) Click here for additional data file. S3 Table Bayes factors value between two provinces. (DOCX) Click here for additional data file. S1 Checklist STROBE Checklist. (DOC) Click here for additional data file.
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                Author and article information

                Journal
                Epidemiol Infect
                Epidemiol. Infect
                HYG
                Epidemiology and Infection
                Cambridge University Press (Cambridge, UK )
                0950-2688
                1469-4409
                2019
                4 December 2018
                : 147
                : e64
                Affiliations
                [1 ]Department of Epidemiology and Health Statistics, School of Public Health, Southeast University , Nanjing (210009), China
                [2 ]Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University , Nanjing (210009), China
                [3 ]Jiangsu Provincial Center for Disease Control and Prevention , China
                Author notes
                Author for correspondence: H. Jin, E-mail: jinhui_hld@ 123456163.com
                Author information
                https://orcid.org/0000-0002-5888-7439
                https://orcid.org/0000-0002-2023-1733
                Article
                S0950268818003175 00317
                10.1017/S0950268818003175
                6518593
                30511609
                783b3e51-e55e-4dca-bff4-a2ff2a382ce3
                © The Author(s) 2018

                This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 April 2018
                : 24 October 2018
                : 01 November 2018
                Page count
                Figures: 2, Tables: 1, References: 25, Pages: 6
                Categories
                Original Paper

                Public health
                meta-analysis,pep vaccination rate,rabies,risk factors
                Public health
                meta-analysis, pep vaccination rate, rabies, risk factors

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