Epidemiological shift and geographical heterogeneity in the burden of leptospirosis in China

Epidemiological shift and geographical heterogeneity in the burden of leptospirosis in China Background: Leptospirosis morbidity and mortality rates in China have decreased since the 2000s. Further analyses of the spatiotemporal and demographic changes occurring in the last decade and its implication on estimates of disease burden are required to inform intervention strategies. In this study, we quantified the epidemiological shift and geographical heterogeneity in the burden of leptospirosis during 2005–2015 in China. Methods: We used reported leptospirosis case data from 1st January 2005 to 31st of December 2015 that routinely collected by the China Information System for Disease Control and Prevention (CISDCP) to analyze the epidemiological trend and estimate the burden in terms of disability-adjusted life-years (DALYs) over space, time, and demographical groups. Results: A total of 7763 cases were reported during 2005–2015. Of which, 2403 (31%) cases were the laboratory- confirmed case. Since 2005, the notified incidence rate was gradually decreased (P < 0.05) and it was relatively stable during 2011–2015 (P > 0.05). During 2005–2015, we estimated a total of 10 313 DALYs were lost due to leptospirosis comprising a total of 1804 years-lived with disability (YLDs) and 8509 years-life lost (YLLs). Males had the highest burden of disease (7149 DALYs) compared to females (3164 DALYs). The highest burden estimate was attributed to younger individuals aged 10–19 years who lived in southern provinces of China. During 2005–2015, this age group contributed to approximately 3078 DALYs corresponding to 30% of the total DALYs lost in China. Yet, our analysis indicated a declining trend in burden estimates (P < 0.001) since 2005 and remained relatively low during 2011–2015. Low burden estimates have been identified in the endemic regions where infections principally distributed. Most of the changes in DALY estimates were driven by changes in YLLs. Conclusions: In the last 11-years, the burden estimates of leptospirosis have shown a declining trend across the country; however, leptospirosis should not be neglected as it remains an important zoonotic disease and potentially affecting the young and productive population in economically less-developed provinces in southern of China. In addition, while in the last five years the incidence has been reported at very low-level, this might not reflect the true incidence of leptospirosis. Strengthened surveillance in the endemic regions is, hence, substantially required to capture the actual prevalence to better control leptospirosis in China. Keywords: Leptospirosis, Epidemiology, Burden, China, DALY, Spatiotemporal trends * Correspondence: p.dhewantara@uq.edu.au; zwy0419@126.com Spatial Epidemiology Laboratory, School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia Center for Disease Surveillance and Research, Institute of Disease Control and Prevention of PLA, Beijing 100071, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 2 of 14 Multilingual abstract notified morbidity and mortality of leptospirosis and to Please see Additional file 1 for translations of the abstract quantify the demographical, temporal and geographical het- into five official working languages of the United Nations. erogeneity of the burden during 2005–2015. The findings of this study provide evidence to inform policy to allocate Background effective targeted intervention strategies for better leptospir- Leptospirosis is a zoonotic disease of global public health osis control programmes in China. importance caused by pathogenic spirochetes belong to the genus Leptospira [1]. It has caused more than one mil- lion cases and 58 900 deaths per year [2], and it has been Methods estimated approximately 2.90 million disability-adjusted Data sources life-years (DALYs) lost due to leptospirosis worldwide [3]. In China, leptospirosis is one of 39 notifiable infectious Leptospirosis is acquired mainly through contact with diseases that must be reported within 24-h (Category B contaminated water or soil containing Leptospira.In some disease) [14]. To illustrate, infectious diseases surveillance cases, infections may also occur through direct contact data, including leptospirosis, is analyzed by the Center for with infected animals [4]. Due to non-specific clinical Disease Control and Prevention (CDC) at various level: characteristics, leptospirosis often challenging to diagnose county, prefecture, provincial, and national level. Case leading to underreported incidence which in turn may information is entered by all healthcare providers at all limit the effectiveness of control programme [5, 6]. level via a nationally-standard form into a web-based Leptospirosis is an important zoonotic disease in China. Notifiable Infectious Diseases Reporting Information Sys- It was firstly reported in 1934 and it becomes a mandatory tem (NIDRIS). In addition, a national system called China notifiable disease since 1955. To date, there were more than Infectious Disease Automated-alert and Response System 2.5 million cases and 20 000 deaths have been reported; (CIDARS) have been developed since 2005 to provide more than 80% of the total provinces (34 provinces) have real-time outbreak notifications [15, 16]. In term of diag- reported leptospirosis cases [7, 8]. Leptospirosis remains a nosis, the provincial branches are responsible for testing significant public health problem in the country where a suspected human patient and animal sera, collecting broad range of potential reservoirs and serovars are still infected animals and identifying infectious isolates by cul- circulating in the country. Furthermore, rapid population ture and microscopic agglutination test (MAT) according growth, poverty, and industrialization have led to excessive to the national diagnostic criteria for leptospirosis issued urbanization and environmental changes such as deforest- by the National Health and Family Planning Commission ationand urbanexpansion[9–13], which might influence (NHFPC) [17]. Results are then verified by the national- disease nidality through direct impacts on the natural habi- level CDC and finally reported to NHFPC. tat of reservoirs and affects the spillover of infection In this study, we used reported leptospirosis case between wildlife animals, domestic animals, and humans. data from 1st January 2005 to 31st of December Also, extreme weather events such as flooding following 2015. These data included information about age, typhoons may significantly impact impoverish communities gender, occupation, date of onset of illness, diagnosis with lack of access to safe water and sanitation and health and death, place of residence (i.e., county and services [6], leading to an increased risk of Leptospira province) and case classification (suspect, clinical, and exposures. confirmed). Yearly demographic data including popu- Using notified leptospirosis morbidity and mortality lation data by age, sex, and occupation was collected data from the 1970s, a study has estimated that there from the National Bureau of Statistics of China for were approximately 301 688 DALYs lost annually due to each province from 2005 to 2015 [18]. leptospirosis in China [3]. Nevertheless, in the last two decades, leptospirosis incidence has been reported to Human leptospirosis case definition reduce from 10.73 cases per 100 000 people in the 1960s Based on NHFPC diagnostic criteria for leptospirosis to 0.59 cases per 100 000 people in the 2000s [8, 10]. In [17], leptospirosis cases are defined into three categories: the light of changes in socioeconomic and environmen- suspected, clinical, and confirmed case. Suspected cases tal conditions that have been undergone in China for the are defined as an individual with: a) one of the following last two decades, there is a need to re-estimate the clinical symptoms such as acute fever (up to 39 °C) burden of leptospirosis and to identify residual pockets which may be accompanied by chills, myalgia, or malaise of transmission. To date, there is no single study have and; b) history of exposure within a month prior to the estimated the changes in burden in terms of DALYs onset of illness to the following risk factors: epidemic across China over time. season, reside in epidemic area, either direct or indir- Using available passive surveillance data on human lepto- ectly contacted with suspected animals and their urine spirosis in China, we aimed to investigate the changes on or faeces or contaminated water and soil. Clinical Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 3 of 14 (probable) cases are defined as suspected cases with at examine seasonality of leptospirosis incidence. Changes in least one of the following clinical manifestations: conjunc- the spatial distribution of incidence and burden during tival hyperemia, gastrocnemius tenderness, or enlarge- two periods were mapped using ArcGIS 10.5 (ESRI Inc., ment of the lymph nodes. Confirmed case is defined as Redlands, CA, USA). All other statistical analysis was suspected case with one or more any of the following la- conducted using STATA version 13.0 (Stata Corp., College boratory criteria: 1) positive culture of Leptospires from Station, TX, USA). blood, urine, tissues, or cerebrospinal fluid (CSF); 2) Microscopic Agglutination Test (MAT) titre of ≥400 in DALYs estimation single or paired serum samples; 3) a fourfold or greater Based on total cases, we estimated the burden in terms rise in MAT titers between acute and convalescent-phase of age-, sex- and province-specific DALYs during the samples; 4) presence of pathogenic Leptospira spp. de- period of study. We estimated the DALYs for each year tected by polymerase chain reaction (PCR); 5) presence of by adding the number of Years of Life Lost due to death IgM antibodies by enzyme-linked immunosorbent assay in the population (YLLs) and the number of Years Lived (ELISA). with Disability (YLDs) due to the disease [19]. The estimate of YLLs was obtained by multiplying number of cases per year and the standard life expectancy at the Data analysis age of death in years. To estimate life expectancy at the For our analyses, we divided China into four regions age of death, we used a standard life table used for the (Region A, B, C, and D) as previously described by Zhang estimation of Global Burden of Disease 2010 [20]. YLDs et al. [7] and investigated the temporal distribution of were calculated by multiplying incidence, disability notified leptospirosis incidence and mortality across the weight (DW), and duration of the illness. The disability four regions. The proportion of deaths (case-fatality-rates, weight used for the estimation of YLDs was the same CFR) due to leptospirosis infection was calculated. As we that used in a study elsewhere [3]. In brief, all death observed that there were different trends during 2005– cases were defined as fatal cases. Thus, we were given a 2015, we then divided the dataset into two temporal DW of 0.573 for one month as it was assumed that they subgroups: 2005–2010 and 2011–2015 to investigate had dialysis before death. For non-fatal cases, we epidemiological changes between these two periods. We assumed that there were 70% acute cases and 30% had used yearly population data as the denominator to calcu- chronic sequelae. Of those acute cases, 50% is mild late age-, gender-, and occupation-specific incidence and (given a DW 0.053 for 2 months), 40% is moderate (DW mortality rates over time. 0.21–2 months), and 10% severe (DW 0.562 for 2 weeks, A temporal analysis of morbidity and mortality of 0.51 for 2 weeks, and 0.21 for 1 month). Of those leptospirosis was conducted by gender, age groups, occu- chronic cases, a DW of 0.245 for two months to three pation, regions and case classification. We classified years was given. In our DALYs calculation, we did not occupational group into three main categories based on consider age-weighting and discounting. the type of industry: primary, secondary, and tertiary workforces. Farmers, plant growers, herdsman, seaman, and fishers were categorized as primary (agricultural-re- Results lated) workforces. The secondary industry was defined Descriptive analysis as manufacture-related work. The tertiary workforce was A total of 7763 leptospirosis cases were reported during defined for those individuals who work in services (e.g., 2005–2015 (Table 1). Of these, 2403 cases (31%) were teachers, doctors, nurses, students). The occupation recorded as confirmed cases, 4588 (59%) of cases as classified as “others” include individuals who retired/not clinical cases, and 772 (10%) cases were reported as working, including children and undefined profession. suspected cases. The proportion of confirmed cases A simple linear regression model was used to detect a towards the total cases was increased over time from trend in reported incidence, mortality, and burden 8.2% (120/1465) in 2005 to 56.7% (233/411) in 2015. estimates during 2005–2015, with the independent The proportion of reported laboratory-confirmed case variable being the year and the dependent variable being during 2005–2015 was varied across 26 provinces in a number of the case or disease rate. A chi-square (χ ) China (Additional file 2: Table S1). test was performed to determine the difference in By gender, a total of 5356 (69%) males and 2407 (31%) incidence, mortality rate and burden by age, sex, and females were observed. The annual incidence rate (IR) was occupation in different time periods. P-value < 0.05 higher in males (0.08 cases per 100 000 people) compared were considered statistically significant. A multiplicative to females (0.03/100 000 people) (χ = 22.50, P = 0.013, seasonal decomposition analysis was conducted using Table 1). Our results indicate that incidence differed SPSS version 24 (IBM Corp., Armonk, NY, USA) to significantly by age group (χ = 624.57, P < 0.001) with most Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 4 of 14 Table 1 Annual number of notified leptospirosis and incidence rate by sex, age and occupation and the proportion of case in China, 2005–2015 Characteristics Number of cases (per 100 000 people) Total IR 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Sex Female 439 (0.07) 217 (0.04) 300 (0.05) 254 (0.04) 197 (0.03) 218 (0.04) 134 (0.02) 154 (0.03) 156 (0.03) 207 (0.04) 131 (0.02) 2407 0.03 Male 1026 (0.16) 500 (0.08) 658 (0.10) 675 (0.11) 462 (0.08) 500 (0.08) 289 (0.05) 337 (0.06) 280 (0.05) 349 (0.06) 280 (0.04) 5356 0.08 Age 0–9 41 (0.03) 28 (0.02) 34 (0.03) 20 (0.02) 18 (0.01) 10 (0.00) 8 (0.01) 4 (0.00) 5 (0.00) 6 (0.00) 3 (0.00) 177 0.01 10–19 283 (0.13) 116 (0.06) 137 (0.07) 99 (0.06) 83 (0.05) 52 (0.03) 33 (0.02) 34 (0.03) 15 (0.01) 24 (0.02) 22 (0.01) 898 0.05 20–29 236 (0.14) 86 (0.06) 107 (0.07) 120 (0.08) 70 (0.04) 62 (0.04) 40 (0.02) 47 (0.02) 48 (0.03) 71 (0.04) 45 (0.02) 932 0.05 30–39 347 (0.14) 140 (0.07) 174 (0.09) 174 (0.09) 112 (0.06) 131 (0.07) 66 (0.04) 67 (0.04) 53 (0.03) 89 (0.05) 63 (0.03) 1416 0.07 40–49 228 (0.12) 140 (0.07) 202 (0.10) 180 (0.09) 126 (0.06) 159 (0.08) 99 (0.05) 126 (0.06) 106 (0.05) 142 (0.07) 83 (0.03) 1591 0.07 50–59 217 (0.15) 130 (0.08) 205 (0.12) 210 (0.12) 137 (0.08) 167 (0.10) 101 (0.08) 97 (0.07) 92 (0.07) 111 (0.08) 95 (0.05) 1562 0.09 60–69 87 (0.09) 53 (0.06) 75 (0.08) 93 (0.10) 92 (0.09) 112 (0.12) 55 (0.06) 84 (0.09) 83 (0.09) 84 (0.09) 83 (0.06) 901 0.08 70–79 16 (0.03) 15 (0.03) 23 (0.04) 30 (0.05) 20 (0.04) 27 (0.05) 20 (0.04) 32 (0.06) 23 (0.05) 22 (0.04) 25 (0.04) 253 0.04 80–89 1 (0.00) 0.00 6 (0.04) 4 (0.02) 1 (0.00) 0.00 3 (0.02) 3 (0.02) 4 (0.02) 5 (0.03) 3 (0.01) 30 0.02 90+ 0.00 0.00 1 (0.07) 0.00 0.00 0.00 0.00 0.00 1 (0.05) 0.00 1 (0.05) 3 0.02 Occupation Agriculture 1119 (0.32) 500 (0.15) 721 (0.22) 726 (0.24) 526 (0.18) 571 (0.22) 312 (0.11) 387 (0.14) 312 (0.12) 466 (0.19) 305 (0.13) 5944 0.18 Services 263 (0.11) 125 (0.05) 148 (0.06) 110 (0.03) 90 (0.02) 63 (0.02) 54 (0.02) 39 (0.01) 54 (0.02) 56 (0.02) 56 (0.02) 1058 0.04 Case Confirmed 120 227 267 249 158 229 178 182 239 321 233 2403 classification Clinical 1271 415 594 600 406 436 212 247 123 171 113 4588 Suspected 74 75 97 80 95 53 33 58 78 64 65 772 mean annual reported incidence rate of the cases (21%) reported in the 40–49 years old age leptospirosis cases were reported from Region B, where group. The higher incidence rate was identified in the older 6514 cases (84%) were reported during 2005–2015. The age groups of 50–59 (0.09/100 000 people) and 60–69 number of counties that reported cases demonstrated a (0.08/100 000 people). However, leptospirosis in younger significant reduction in 2005–2015 (P < 0.001). Overall, individuals under 20 years-old was also reported, which there was a significant declining trend in leptospirosis inci- accounted for a total of 1075 cases (14%) with reported dence from 0.11/100 000 people in 2005 to 0.03/100 000 incidence rates ranging from 0.01–0.05/100 000 people. people in 2015 (R = 0.646; P < 0.05). Among provinces, Based on patients’ occupation, we could only identify two both Sichuan and Yunnan had the highest reported main occupational type: primary (agriculture) and tertiary incidence rate (0.26/100 000 people) in the country. (services). Of 761 records were classified as ‘Other’ Similarly, the case-fatality rates (CFR) also showed a including who did not work, children, and retired people downturn trend from 3.29% in 2005 to 0.24% in 2015 (Additional file 2: Table S2). Leptospirosis incidence (R =0.815, P < 0.001). The highest CFR was recorded in rate was higher in primary sector (0.18/100 000 people) Guizhou (13.41%) compared to other provinces. Detailed compared to the group of tertiary workforces (0.04/100 000 temporal distribution of leptospirosis incidence and CFR people) (χ = 47.15; P < 0.001). Furthermore, among the for each province during 2005–2015 is provided (see primary workforces, of 298 (5%) cases were attributed Additional file 2:S1Table,S3Table). to young farmers aged under 20 years old. Whereas, In addition, during 2005–2015, a total of 168 deaths among the tertiary workforces, most cases (43%) was attributed to leptospirosis reported in China. Of which, predominantly attributed to students aged under 20 years. 71% (120/168) of reported deaths were attributed to Leptospirosis was reported from all four regions in males. High mortality rate was observed attributed to China; the highest reported incidence rate was primarily group 50–59 years (0.20 per 100 000 people) followed by observed in the Region A and B (Fig. 1). Based on the a group of age 10–19 years (0.18 per 100 000 people). A seasonal decomposition analysis, leptospirosis incidence high number of death (125 out of 168) were attributed increased from April to September and reached a peak to patients who worked in the primary sector as a on August/September and then diminished from October farmer. A high number of death reported from Region B thereafter. The lowest number of cases was consistently (74%), particularly in Guizhou, Sichuan, Hunan, Hubei, observed in February (Fig. 2). and Jiangxi (Additional file 2: Table S4). There was a In total, leptospirosis cases were reported from a total decrease in reported mortality rate since 2005 and it of 782 counties in 26 provinces in China (Table 2). Most reached a very low level from 2011 thereafter. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 5 of 14 Fig. 1 Annual average incidence map of leptospirosis in China, 2005–2015. It is divided into four regions (Region A, B, C, D) refer to Zhang et al. [7] Demographic and geographical changes in morbidity and notified incidence remained high in males and primary mortality between 2005 and 2010 and 2011–2015 workforces during both periods (P < 0.001). The trend in reported incidence and mortality was different Of total 168 deaths reported, most deaths were ob- between 2005-2010 and 2011–2015 (Fig. 3). A total of 5439 served (87%, 146/168) during 2005–2010 (Table 3). Few cases were reported in 2005–2010. Subsequently, there deaths (22 deaths) was recorded during 2011–2015. were only 2324 cases reported in 2011–2015 (annual IR = However, we noted a significant difference in the mortality 0.03/100 000 people), which was more than 50% lower than rate (P < 0.001) between 2005 and 2010 and 2011–2015. the preceding period (P < 0.001, Table 3). A slight The mortality rate fluctuated during 2005–2010; where decreasing trend in reported incidence was identified from two peaks were observed in 2005 and 2007. In contrast, a 2005 to 2010 (R = 0.480), while no trend in reported relatively stable and low mortality rates was observed dur- incidence has been observed during 2011–2015 (P > 0.05). ing 2011–2015. Statistically, there was a significant difference in reported Despite the significant drop in notified incidence and incidence between age groups during period 2005–2010 number of counties that reported leptospirosis, our analysis (z = 258.51; P < 0.001) and period 2011–2015 (z = 50.83; indicates 112 new counties were notified leptospirosis infec- P = 0.052). The highest reported incidence rate was tions in 2011–2015 (Additional file 2: Table S5). During this observed in the 50–59 age group (0.11/100 000 people). second period, we observed that leptospirosis infection had Moreover, there was no significant changes in gender and been reported in new four provinces including Hebei, Inner occupation-specific incidence since 2005 to 2015; the Mongolia, Jilin, and Gansu (Region C and D). Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 6 of 14 Fig. 2 Seasonal decomposition plot of leptospirosis cases in China Impact of changes in incidence and mortality on the DALYs). During 2005–2010, the total burden of lepto- burden of leptospirosis during 2005–2015 spirosis was estimated at approximately 8636 DALYs It is estimated that during 2005–2015 a total of 10 313 (1439 DALYs per annum). This consisted of 7379 YLLs DALYs were lost due to leptospirosis or approximately 937 and 1257 YLDs. It was much higher than the period of DALYs per annum (Table 4). Males are the most affected 2011–2015, which accounted for approximately 1600 group with an estimated 7149 DALYs or approximately DALYs or a decrease of 80% from the previous period 70% of the total burden. The highest burden estimate was (Additional file 2: Table S6). attributed to a group of age 10–19 years, both males and Between 2005 and 2010 and 2011–2015, a decline in females, accounted for around 30% of the total DALYs. The DALY estimate was observed in almost all provinces highest burden estimate was identified in Region B (7990 (Fig. 4). In 2005–2010, high DALYs estimates were ob- DALYs), followed by Region A (2312 DALYs) (Table 5). served in Sichuan (1337 DALYs), Guizhou (1936 DALYs), Our results indicate a 95% decline in DALYs due to Hunan (1374 DALYs), and Guangxi (1293 DALYs). These leptospirosis from 2005 to 2015 (P < 0.001, Table 5). The four provinces had contributed to approximately 70% of highest burden was estimated in 2005 (2966 DALYs), the total DALYs of that period. However, a substantial including 2632 YLLs and 334 YLDs; whereas the lowest reduction (on average at 53%) in DALYs occurred in burden estimates were identified during 2015 (144 many areas, including in those four provinces during Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 7 of 14 Table 2 Annual reported cases, confirmed case, counties, Table 2 Annual reported cases, confirmed case, counties, incidence and fatality rate of leptospirosis in China, 2005–2015 incidence and fatality rate of leptospirosis in China, 2005–2015 (Continued) No. of % No. of Incidence CFR cases confirmed county per (%) No. of % No. of Incidence CFR reported case reported 100 000 cases confirmed county per (%) (n = 7763) (n = 2403) (n = 782) people reported case reported 100 000 (n = 7763) (n = 2403) (n = 782) people Year Region D 2005 1465 8.2 307 0.11 3.29 Gansu 1 100 1 0.00 0.00 2006 717 31.7 265 0.05 2.66 Qinghai 1 0 1 0.00 0.00 2007 958 27.9 299 0.07 3.86 Xinjiang 2 0 2 0.00 0.00 2008 929 26.8 278 0.07 2.04 2009 659 24 222 0.05 1.82 2011–2015 (P < 0.05). Although there was a significant 2010 718 31.9 239 0.05 1.53 reduction in DALYs, we identify that higher estimates 2011 423 42.1 182 0.03 1.17 of the burden remain observed in young individuals at 2012 491 37.4 180 0.04 1.02 the age of 10–19, both sexes (P <0.05, Fig. 5). The 2013 436 54.3 165 0.03 1.16 burden estimates remained high among males (1316.8 2014 556 57.7 173 0.04 1.07 DALYs) compared to females (360.3 DALYs) during 2015 411 56.7 163 0.03 0.24 2011–2015 (P < 0.05). A larger quantity of annual YLLs estimates were lost dur- Region A ing 2005–2010 (1229 YLLs) compared to the 2011–2015 Guangdong 619 53.3 100 0.06 2.28 period (225 YLLs) (P < 0.05). Leptospirosis resulted in Guangxi 543 40.1 92 0.10 1.16 approximately 5689 YLLs during 2005–2007, and it has Hainan 47 10.6 15 0.05 0.00 contributed 55% of the total DALYs. A three-fold reduction Region B in the number of YLLs was observed in 2005–2006, but a Jiangsu 37 54.1 25 0.00 1.30 slight increase observed in 2007. Moreover, we found Zhejiang 138 42.8 28 0.02 1.31 higher YLLs estimates were contributed by economically less-developed provinces such as Sichuan, Guizhou, Hunan, Anhui 310 8.4 31 0.05 1.03 and Guangxi. The highest YLLs estimate was attributed to Fujian 502 47 62 0.12 0.74 the younger individual age of 10–19 years. Similarly, YLDs Jiangxi 421 5.5 52 0.09 1.62 estimates declined over time (P < 0.001) and a significant Henan 3 0 3 0.00 0.00 difference on annual YLDs was observed between the two Hubei 296 10.8 31 0.05 2.96 periods (P < 0.001). An extended analysis was provided (see Hunan 656 15.9 98 0.09 3.10 Additional file 2:Table S7–Table S10; Additional file 3). Chongqing 200 10 33 0.06 0.49 In terms of YLLs, Guizhou had the highest estimates on YLLs which account for 2300 YLLs or 27% of the Sichuan 2352 6.3 97 0.26 1.10 total YLLs during 2005–2015, followed by Hunan, Guizhou 291 11.7 45 0.07 13.41 Guangxi, and Sichuan (Fig. 6). In Guizhou, the highest Yunnan 1308 86.2 36 0.26 0.15 YLLs estimates were observed during 2005–2010 (1800 Region C YLLs). During 2011–2015, a dramatic change in YLLs Beijing 2 50 2 0.00 0.00 estimates was observed in most provinces. However, the Shandong 20 65 14 0.00 0.00 YLLs consistently remained relatively high in Guizhou. In terms of YLDs, Sichuan and Yunnan have higher esti- Hebei 3 33.3 3 0.00 0.00 mates during both periods. Shanxi 3 33.3 3 0.00 0.00 Inner Mongolia 1 100 1 0.00 0.00 Discussion Liaoning 1 0 1 0.00 0.00 Our study quantified the remarkable decrease in leptospir- Jilin 2 100 2 0.00 0.00 osis incidence and mortality in China during 2005–2015, Shaanxi 4 25 4 0.00 0.00 which was accompanied by substantial changes in the demographic and geographic pattern in disease burden estimates. We observed a remarkable decline in reported incidence and mortality in all provinces especially in region A and B where leptospirosis is principally most prevalent, such as Sichuan and Yunnan. These findings Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 8 of 14 Fig. 3 Annual reported incidence and mortality (per 100 000 people) of leptospirosis in China, 2005–2015 are in line with previous county-level studies which also water and sanitation facilities, and strengthening healthcare reported a reduction in notified incidence while local out- and local surveillance systems. breaks still frequently reported in some areas [21–26]. Our study demonstrates an updated burden estimates in Our analysis indicates that following a steep downward terms of DALYs for leptospirosis in China. To the best of trend during 2005–2010, the reported incidence of our knowledge, this is the first study that attempted to leptospirosis in China remained quite low during the last quantify the spatiotemporal heterogeneity in the burden five years. This finding suggests that China might have of leptospirosis using time-series historical notification reached a low-level leptospirosis transmission similar to data, especially in China. From 2005 to 2015, it was esti- other developed countries [27] although this might not mated that more than 10 000 DALYs lost due to infections indicate a real epidemiological situation as evidenced by where the burden predominantly contributed by high the existence of persistent geographical foci of infection YLLs. However, our estimates are in stark contrast with that can potentially lead to future outbreaks in the coun- those reported by a study elsewhere [3]. Our smaller try. Also, we observed marked variation in fatality-rates DALYs estimates may reflect the sharp reduction in both across regions over time, which may be explained by the reported incidence and mortality that occurred during heterogeneity the level of awareness and knowledge among 2005 to 2015. populations towards leptospirosis, inadequate measures for The burden estimates provided by Torgerson et al. [3] early diagnosis and treatment especially during outbreaks, was mainly generated based on the morbidity and mortal- delay in seeking treatment, and severity of illness due to ity estimates developed by another study elsewhere [2] variation to Leptospira exposure and localized risk factors. that involved modelling on the morbidity and mortality Hence, more targeted control efforts are needed especially data by incorporating several variables, adjustments, and in those high-risk areas and economically less developed uncertainties. Their study was a global study and applied a areas by enhancing awareness, improving access to safe global model to each country. It is important to consider Table 3 Changes in notified incidence and mortality (per 100 000 people) due to leptospirosis in four regions in China during 2005–2010 and 2011–2015 Region 2005–2010 2011–2015 No. of cases Incidence Deaths Mortality No. of cases Incidence rate Deaths Mortality rate A 835 0.05–0.14 39 0.00–0.01 374 0.04–0.06 4 < 0.01 B 4593 0.00–0.38 107 0.00–0.01 1941 0.00–0.28 18 < 0.01 C 9 < 0.01 0 0 7 < 0.00 0 0 D 2 < 0.00 0 0 2 < 0.00 0 0 Total 5439 0.07 146 0.002 2324 0.03 22 < 0.01 included all cases (i.e., confirmed, clinical, and suspected) Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 9 of 14 Table 4 Age and gender-specific YLLs, YLDs, and DALYs estimates based on reported leptospirosis in China, 2005–2015 Age YLLs YLDs DALYs Female Male Total Female Male Total Female Male Total 0–9 79.31 237.92 317.23 9.50 31.59 41.09 88.81 269.51 358.32 10–19 1077.14 1796.61 2873.75 40.37 163.4 203.77 1117.51 1960.01 3077.52 20–29 566.89 1281.47 1848.36 62.94 151.28 214.22 629.83 1432.75 2062.58 30–39 256.71 824.46 1081.17 117.32 213.98 331.31 374.03 1038.44 1412.48 40–49 255.03 620.29 875.32 132.52 240.34 372.87 387.55 860.63 1248.19 50–59 277.2 695.33 972.53 119.70 244.38 364.08 396.9 939.71 1336.61 60–69 73.73 397.18 470.91 58.90 150.57 209.47 132.63 547.75 680.38 70–79 17.28 52.81 70.09 16.15 42.99 59.14 33.43 95.8 129.23 80–89 0 0 0 2.37 4.75 7.12 2.37 4.75 7.12 90+ 0 0 0 0.47 0.24 0.71 0.47 0.24 0.71 TOTAL 2603.29 5906.07 8509.36 560.25 1243.52 1803.77 3163.54 7149.59 10 313.13 that epidemiological conditions for leptospirosis transmis- previous studies. We also identified variation in the sur- sion and notifications are geographically non-stationary veillance system capacity, as evidenced by the difference and this approach might be inadequate to capture small- in laboratory-confirmed cases among provinces, which scale heterogeneities. Importantly, that study used pub- means that adjustments should be cautiously applied for lished data from 1970s, a period when leptospirosis was the whole country. Applying adjustments to the whole highly endemic and when China’ssurveillance systems country could be over/underestimated the actual inci- might be different compared to the period of the 2000s. dence and mortality rates. This study extends Torgersen’s[3] study in that we used Changes in incidence and burden can be partly associ- high-resolution, contemporaneous data based on recent ated with improvement in prevention and control mea- national Chinese disease surveillance systems that have sures including health promotion activities, sanitation, relatively good coverage across the country. This study and the application of leptospirosis vaccination was successfully demonstrated spatiotemporal heterogen- programme [10, 16, 26, 28, 29]. In terms of the surveil- eity in burden within China that was not captured by lance system, the development of NIDRIS and CIDARS Table 5 Temporal and geographical distribution of YLLs, YLDs, and DALYs of leptospirosis in China, 2005–2015 Years of life Years lived with Disability-adjusted DALYs/100 000 lost (YLLs) disability (YLDs) life years (DALYs) people Year 2005 2631.51 334.39 2965.90 0.22 2006 1066.17 163.63 1229.80 0.09 2007 1991.61 220.16 2211.77 0.16 2008 813.55 216.36 1029.91 0.08 2009 530.56 153.66 684.22 0.05 2010 345.99 168.38 514.37 0.04 2011 249.07 99.75 348.82 0.03 2012 303.1 116.14 419.24 0.03 2013 245.77 100.94 346.71 0.03 2014 287.34 130.15 417.49 0.03 2015 44.69 100.22 144.91 0.01 Region A 2035.89 276.92 2312.81 1.44 B 6473.47 1517.36 7990.83 1.11 C 0 8.55 8.55 < 0.01 D 0 0.95 0.95 < 0.01 Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 10 of 14 Fig. 4 Changes on notified incidence (top) and geographical distribution of the burden (bottom) of leptospirosis in China over two periods, 2005–2010 and 2011–2015 following outbreaks of the severe acute respiratory syn- and livestock husbandry, for instance, restriction on live- drome (SARS) in 2003 have helped efficiently improve stock herding, farming commercialization, and pigs or the timeliness, completeness, and coverage of the data livestock vaccination [10, 30] that happened in China across China as well as facilitates early detection of dis- could have impacted the transmission rate of leptospir- eases outbreaks [16]. However, it has been confirmed osis in China. Industrialization, for example, has led to that during 2005–2015, there has been no significant significant epidemiological shifts in rural areas change in the surveillance systems, specifically for lepto- through the introduction of agricultural technology spirosis. While, in terms of the vaccination programme, and mechanization which might reduce the rate of human leptospirosis vaccine has been developed since human exposure to the Leptospira-contaminated en- 1958 and until now it has been administered to high-risk vironment. Also, we had noticed that there were sig- populations in China during the epidemic seasons. A nificant anthropogenic ecological changes following multivalent inactivated vaccine is currently the only the development of the Three Gorges Dam and the available in China [29]. nationwide reforestation programme called “Grain for Changes in ecological and social conditions that have Green”, which probably had an effect of leptospirosis been underway in China in the past 20 years may also transmission. Water impoundment in many endemic have played an essential role in leptospirosis epidemi- areas has been known to have an impact on rodents’ ology. Changes in the landscape, agricultural practices habitat and population dynamics of the pathogen Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 11 of 14 Fig. 5 Temporal distribution of the burden estimates of leptospirosis by gender and age groups in China during 2005–2010 and 2011–2015 in those regions [31, 32]. These projects have also Product among provinces in China [18]. High burden esti- been reported to have had a substantial impact on mates in school-aged children may probably be associated another rodent- and water-borne diseases, such as with lack of parental supervision because of parental migra- hemorrhagic fever with renal syndrome and schisto- tion from rural to the cities that happened during the last somiasis [33–35]. However, the role of environmental three decades. Lack of parental supervision on preventing changes on space-time variation on leptospirosis their children from unhealthy behaviors and environment incidence and burden still needs to be explored. Also, may likely increase the risk of pathogenic exposure and chil- a substantial change in the quality of livestock hus- dren’s health [37]. Additionally, rural migration has shifted bandry in China (e.g., improved waste management labor allocation and participation in families in farming ac- and farm biosecurity) might also have contributed to tivities, where children, women, and elderly become more adecreaseintransmission rateinlivestock [10]. A re- active in farming [38, 39] and, therefore, they are more likely view of significant changes in the epidemiology of in- to be exposed to Leptospira-contaminated environments. It fectious diseases in China, including leptospirosis, has has been indicated in our findings that 5% of the total cases also been described elsewhere [14, 36]. among farmers were attributed to young farmers (aged Our results demonstrate that the highest DALY was under 20 years). Health education and awareness amongst attributed to younger individuals aged 10–19 years due to this population group, especially in rural communities is, higher mortality (YLLs) observed in this group. Interestingly, therefore essential to furtherreducethe risk in thisdemo- higher DALYs estimates were identified in economically graphic group. These findings highlight the importance of less-developed provinces in China including Guangxi in improving current local surveillance for leptospirosis and Region Aand Guizhouand SichuaninRegionB.Guangxi health care services for the high-risk populations living in and Guizhou are known to have low Gross Regional the high-risk areas identified in our study. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 12 of 14 Fig. 6 Changes in geographical distribution of years of life lost (YLL) and years-lived with disability (YLD) due to leptospirosis in China during 2005–2015 We also found that disease transmission might have However, our study has several limitations that need emerged in some counties located in temperate regions to be considered; which mainly associated with the data. to the north of the country although at the very low rate. First, as there was no information regarding with sero- This may partly be due to change in environmental vars in our data, we could not be able to analyze further conditions (i.e., climate variation and changes in land whether the observed change in incidence, mortality and use/land cover) or the translocation of potential reser- burden was also reflected a dynamic change in circulat- voirs from adjoining endemic regions. Climate variation ing serovars in the country during the period of study. notably the increase in temperatures may have driven Second, it should also be noted that our burden estimate the spread of Leptospira towards temperate regions in was based on passive surveillance and all cases reported China through its impact on rodent population growth during the period, which might not represent the actual in these areas [40]. Several outbreaks in China have been incidence and burden of disease. The number of reported thought to be associated with high rainfall intensity [26]. cases, the proportion of laboratory-confirmed cases, and However, we suggest that further investigation should be fatality-rates have shown markedly varied during the performed to determine whether the emerging incidence period of study and across provinces indicating a variation may correlate with changes in climate and other envir- in diagnostic techniques capacity across the province in onmental and social conditions (e.g., human migration). the country and therefore could bias our analysis. It Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 13 of 14 should be noted that the surveillance system in China is Additional files mainly a hospital-based, but their laboratory capacity to Additional file 1: Multilingual abstract in the five official working undertake diagnosis through MAT, ELISA, or PCR is also languages of the United Nations. (PDF 778 kb) vary across hospitals over the country. Also, since lepto- Additional file 2: Table S1. Temporal distribution of reported spirosis often presenting a broad spectrum of clinical leptospirosis incidence in four regions in China by province, 2005–2015. manifestations, more untreated cases or false-negative Table S2. Reported leptospirosis cases and the proportion of laboratory- confirmed case (in percent) by type of occupational group, China, 2005–2015. cases might occur and lead to a high number of underre- Table S3. Case fatality-rates (CFR) of leptospirosis by province in two regions ported and misdiagnosed cases, especially in resource- in China, 2005–2015. Table S4. Temporal distribution of notified mortality limited endemic areas. The recent finding indicated the rates due to leptospirosis in two regions in China, by province, 2005–2015. Table S5. Number of counties reported leptospirosis each year and new presence of leptospiral infection among patients with counties that reported leptospirosis during 2005–2010 and 2011–2015. Table undifferentiated fever in Hainan province [41], suggesting S6. Disability-adjusted life-years (DALYs) estimates of leptospirosis by gender, that the incidence and burden may be underestimated. by age and year, China. Table S7. Temporal trend of years of life lost (YLL) due to leptospirosis in China, by gender, by age and year. Table S8. Years of Thus, enhanced-surveillance prospective population- life lost (YLLs) estimates for leptospirosis in China, by region, gender, by age based studies may help to determine existing leptospirosis period of year. Table S9. Years-lived with disability (YLD) due to leptospirosis cases in China better. in China, by gender, by age and year. Table S10. Geographical distribution of years of life lost (YLL), years-lived with disability (YLD), and disability-adjusted Another drawback is that there was no detail data avail- life years (DALY) by region during both periods in China. (DOCX 64 kb) able on patient’s clinical presentations in our dataset that Additional file 3: The distribution of age-, sex-, and geographically-specific we used, so that it was not possible to determine the years of life lost (YLLs) estimates in China, 2005–2015. (XLSX 23 kb) severity of disease that may help to assess disability weight for DALY estimation as well as to explain the variation of Abbreviations fatality-rates across China. In addition, in this study, we CDC: Center for Disease Control and Prevention; CFR: Case fatality-rate; CIDARS: China Infectious Disease Automated-alert and Response System; used all categories of cases including suspect, clinical, and CISDCP: China Information System for Disease Control and Prevention; confirmed leptospirosis cases as defined by China health DALY: Disability-adjusted life-year; DW: Disability weight; ELISA: Enzyme- authority. It is necessary to acknowledge that there may linked immunosorbent assay; IR: Incidence rate; MAT: Microscopic agglutination test; MR: Mortality rate; NHFPC: National Health and Family also be a reporting bias that affects our analysis as Planning Commission; NIDRIS: Notifiable Infectious Diseases Reporting leptospirosis have overlapping clinical presentations with Information System; PCR: Polymerase chain reaction; SARS: Severe acute another disease (e.g., dengue) [5]. respiratory syndrome; WHO: World Health Organization; YLD: Years-lived with disability; YLL: Years of life-lost Lastly, the observed reduction in reported incidence and mortality from 2005 to 2015 may also a result of the Acknowledgements changes in social and environmental conditions in en- We are grateful to anonymous reviewers of this study for their thorough, demic areas as have been discussed above. In a subse- constructive, and helpful review, which led to substantial improvements of the manuscript. quent study we, therefore, will aim to understand the drivers of such reduction by focusing on high-risk areas Funding and quantify the attributable fraction of determinants PWD received support from Australia Awards Scholarships – Department of Foreign Affairs and Trade. WYZ received support from National Natural such as socioeconomic development, farming practices, Science Foundation of China (No. 11501339). The funder had no role in the and environmental changes. study design, data collection or analysis, the decision to publish, and the preparation of this manuscript. The findings and conclusions of this study are those of the authors and do not necessarily represent the views of the funding agency. Conclusions In the last 11-years, the burden estimates of leptospir- Availability of data and materials osis indicated a declining trend across the country; The datasets used and/or analysed during the current study are protected by the China CDC and are unsuitable for public sharing. Interested parties however, leptospirosis should not be neglected as it can apply for the data by contacting the data center of China public health remains an important zoonotic disease and potentially science or email data@chinacic.cn. The metadata supporting the conclusions disproportionately affected the young and productive of this article are available in supplementary files. population group in China. In addition, while in the last Authors’ contributions five years the incidence has been reported at very low-level, PWD RJSM conceived and designed the study. WYZ provided the data. this might not reflect the actual incidence of leptospirosis. PWD RJSM analysed the data. PWD wrote the first draft, revisions and final manuscript. AAM WYZ WWY FD GH WH FC AIK RJSM reviewed and edited Active surveillance studies on acute febrile illnesses are ur- the manuscript. All authors read and approved the final manuscript. gently required. Finally, these findings may help to design targeted intervention strategies in China to reduce the Ethics approval and consent to participate burden of human leptospirosis. An evaluation of the role of The study was approved by the Medical Research Ethics Committee of the University of Queensland (No. 2016001608) and Beijing Institute of Disease environment and socioeconomic on the changing leptospir- Control and Prevention. Patient confidentiality was ensured throughout the osis epidemiology and burden should be considered in the analysis of the data through data de-identification and aggregation of data future works. records to the county-level. Dhewantara et al. 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Zhang L, Wilson DP. Trends in notifiable infectious diseases in China: among patients with fever in Hainan Province. China Chin J Zoonoses. implications for surveillance and population health policy. PLoS One. 2017;3:276–9. (in Chinese) 2012;7(2):e31076. 15. Vlieg WL, Fanoy EB, van Asten L, Liu X, Yang J, Pilot E, et al. Comparing national infectious disease surveillance systems: China and the Netherlands. BMC Public Health. 2017;17(1):415. 16. Yang W, Li Z, Lan Y, Wang J, Ma J, Jin L, et al. A nationwide web-based automated system for outbreak early detection and rapid response in China. Western Pac Surveill Response J. 2011;2(1):10–5. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Diseases of Poverty Springer Journals

Epidemiological shift and geographical heterogeneity in the burden of leptospirosis in China

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Abstract

Background: Leptospirosis morbidity and mortality rates in China have decreased since the 2000s. Further analyses of the spatiotemporal and demographic changes occurring in the last decade and its implication on estimates of disease burden are required to inform intervention strategies. In this study, we quantified the epidemiological shift and geographical heterogeneity in the burden of leptospirosis during 2005–2015 in China. Methods: We used reported leptospirosis case data from 1st January 2005 to 31st of December 2015 that routinely collected by the China Information System for Disease Control and Prevention (CISDCP) to analyze the epidemiological trend and estimate the burden in terms of disability-adjusted life-years (DALYs) over space, time, and demographical groups. Results: A total of 7763 cases were reported during 2005–2015. Of which, 2403 (31%) cases were the laboratory- confirmed case. Since 2005, the notified incidence rate was gradually decreased (P < 0.05) and it was relatively stable during 2011–2015 (P > 0.05). During 2005–2015, we estimated a total of 10 313 DALYs were lost due to leptospirosis comprising a total of 1804 years-lived with disability (YLDs) and 8509 years-life lost (YLLs). Males had the highest burden of disease (7149 DALYs) compared to females (3164 DALYs). The highest burden estimate was attributed to younger individuals aged 10–19 years who lived in southern provinces of China. During 2005–2015, this age group contributed to approximately 3078 DALYs corresponding to 30% of the total DALYs lost in China. Yet, our analysis indicated a declining trend in burden estimates (P < 0.001) since 2005 and remained relatively low during 2011–2015. Low burden estimates have been identified in the endemic regions where infections principally distributed. Most of the changes in DALY estimates were driven by changes in YLLs. Conclusions: In the last 11-years, the burden estimates of leptospirosis have shown a declining trend across the country; however, leptospirosis should not be neglected as it remains an important zoonotic disease and potentially affecting the young and productive population in economically less-developed provinces in southern of China. In addition, while in the last five years the incidence has been reported at very low-level, this might not reflect the true incidence of leptospirosis. Strengthened surveillance in the endemic regions is, hence, substantially required to capture the actual prevalence to better control leptospirosis in China. Keywords: Leptospirosis, Epidemiology, Burden, China, DALY, Spatiotemporal trends * Correspondence: p.dhewantara@uq.edu.au; zwy0419@126.com Spatial Epidemiology Laboratory, School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia Center for Disease Surveillance and Research, Institute of Disease Control and Prevention of PLA, Beijing 100071, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 2 of 14 Multilingual abstract notified morbidity and mortality of leptospirosis and to Please see Additional file 1 for translations of the abstract quantify the demographical, temporal and geographical het- into five official working languages of the United Nations. erogeneity of the burden during 2005–2015. The findings of this study provide evidence to inform policy to allocate Background effective targeted intervention strategies for better leptospir- Leptospirosis is a zoonotic disease of global public health osis control programmes in China. importance caused by pathogenic spirochetes belong to the genus Leptospira [1]. It has caused more than one mil- lion cases and 58 900 deaths per year [2], and it has been Methods estimated approximately 2.90 million disability-adjusted Data sources life-years (DALYs) lost due to leptospirosis worldwide [3]. In China, leptospirosis is one of 39 notifiable infectious Leptospirosis is acquired mainly through contact with diseases that must be reported within 24-h (Category B contaminated water or soil containing Leptospira.In some disease) [14]. To illustrate, infectious diseases surveillance cases, infections may also occur through direct contact data, including leptospirosis, is analyzed by the Center for with infected animals [4]. Due to non-specific clinical Disease Control and Prevention (CDC) at various level: characteristics, leptospirosis often challenging to diagnose county, prefecture, provincial, and national level. Case leading to underreported incidence which in turn may information is entered by all healthcare providers at all limit the effectiveness of control programme [5, 6]. level via a nationally-standard form into a web-based Leptospirosis is an important zoonotic disease in China. Notifiable Infectious Diseases Reporting Information Sys- It was firstly reported in 1934 and it becomes a mandatory tem (NIDRIS). In addition, a national system called China notifiable disease since 1955. To date, there were more than Infectious Disease Automated-alert and Response System 2.5 million cases and 20 000 deaths have been reported; (CIDARS) have been developed since 2005 to provide more than 80% of the total provinces (34 provinces) have real-time outbreak notifications [15, 16]. In term of diag- reported leptospirosis cases [7, 8]. Leptospirosis remains a nosis, the provincial branches are responsible for testing significant public health problem in the country where a suspected human patient and animal sera, collecting broad range of potential reservoirs and serovars are still infected animals and identifying infectious isolates by cul- circulating in the country. Furthermore, rapid population ture and microscopic agglutination test (MAT) according growth, poverty, and industrialization have led to excessive to the national diagnostic criteria for leptospirosis issued urbanization and environmental changes such as deforest- by the National Health and Family Planning Commission ationand urbanexpansion[9–13], which might influence (NHFPC) [17]. Results are then verified by the national- disease nidality through direct impacts on the natural habi- level CDC and finally reported to NHFPC. tat of reservoirs and affects the spillover of infection In this study, we used reported leptospirosis case between wildlife animals, domestic animals, and humans. data from 1st January 2005 to 31st of December Also, extreme weather events such as flooding following 2015. These data included information about age, typhoons may significantly impact impoverish communities gender, occupation, date of onset of illness, diagnosis with lack of access to safe water and sanitation and health and death, place of residence (i.e., county and services [6], leading to an increased risk of Leptospira province) and case classification (suspect, clinical, and exposures. confirmed). Yearly demographic data including popu- Using notified leptospirosis morbidity and mortality lation data by age, sex, and occupation was collected data from the 1970s, a study has estimated that there from the National Bureau of Statistics of China for were approximately 301 688 DALYs lost annually due to each province from 2005 to 2015 [18]. leptospirosis in China [3]. Nevertheless, in the last two decades, leptospirosis incidence has been reported to Human leptospirosis case definition reduce from 10.73 cases per 100 000 people in the 1960s Based on NHFPC diagnostic criteria for leptospirosis to 0.59 cases per 100 000 people in the 2000s [8, 10]. In [17], leptospirosis cases are defined into three categories: the light of changes in socioeconomic and environmen- suspected, clinical, and confirmed case. Suspected cases tal conditions that have been undergone in China for the are defined as an individual with: a) one of the following last two decades, there is a need to re-estimate the clinical symptoms such as acute fever (up to 39 °C) burden of leptospirosis and to identify residual pockets which may be accompanied by chills, myalgia, or malaise of transmission. To date, there is no single study have and; b) history of exposure within a month prior to the estimated the changes in burden in terms of DALYs onset of illness to the following risk factors: epidemic across China over time. season, reside in epidemic area, either direct or indir- Using available passive surveillance data on human lepto- ectly contacted with suspected animals and their urine spirosis in China, we aimed to investigate the changes on or faeces or contaminated water and soil. Clinical Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 3 of 14 (probable) cases are defined as suspected cases with at examine seasonality of leptospirosis incidence. Changes in least one of the following clinical manifestations: conjunc- the spatial distribution of incidence and burden during tival hyperemia, gastrocnemius tenderness, or enlarge- two periods were mapped using ArcGIS 10.5 (ESRI Inc., ment of the lymph nodes. Confirmed case is defined as Redlands, CA, USA). All other statistical analysis was suspected case with one or more any of the following la- conducted using STATA version 13.0 (Stata Corp., College boratory criteria: 1) positive culture of Leptospires from Station, TX, USA). blood, urine, tissues, or cerebrospinal fluid (CSF); 2) Microscopic Agglutination Test (MAT) titre of ≥400 in DALYs estimation single or paired serum samples; 3) a fourfold or greater Based on total cases, we estimated the burden in terms rise in MAT titers between acute and convalescent-phase of age-, sex- and province-specific DALYs during the samples; 4) presence of pathogenic Leptospira spp. de- period of study. We estimated the DALYs for each year tected by polymerase chain reaction (PCR); 5) presence of by adding the number of Years of Life Lost due to death IgM antibodies by enzyme-linked immunosorbent assay in the population (YLLs) and the number of Years Lived (ELISA). with Disability (YLDs) due to the disease [19]. The estimate of YLLs was obtained by multiplying number of cases per year and the standard life expectancy at the Data analysis age of death in years. To estimate life expectancy at the For our analyses, we divided China into four regions age of death, we used a standard life table used for the (Region A, B, C, and D) as previously described by Zhang estimation of Global Burden of Disease 2010 [20]. YLDs et al. [7] and investigated the temporal distribution of were calculated by multiplying incidence, disability notified leptospirosis incidence and mortality across the weight (DW), and duration of the illness. The disability four regions. The proportion of deaths (case-fatality-rates, weight used for the estimation of YLDs was the same CFR) due to leptospirosis infection was calculated. As we that used in a study elsewhere [3]. In brief, all death observed that there were different trends during 2005– cases were defined as fatal cases. Thus, we were given a 2015, we then divided the dataset into two temporal DW of 0.573 for one month as it was assumed that they subgroups: 2005–2010 and 2011–2015 to investigate had dialysis before death. For non-fatal cases, we epidemiological changes between these two periods. We assumed that there were 70% acute cases and 30% had used yearly population data as the denominator to calcu- chronic sequelae. Of those acute cases, 50% is mild late age-, gender-, and occupation-specific incidence and (given a DW 0.053 for 2 months), 40% is moderate (DW mortality rates over time. 0.21–2 months), and 10% severe (DW 0.562 for 2 weeks, A temporal analysis of morbidity and mortality of 0.51 for 2 weeks, and 0.21 for 1 month). Of those leptospirosis was conducted by gender, age groups, occu- chronic cases, a DW of 0.245 for two months to three pation, regions and case classification. We classified years was given. In our DALYs calculation, we did not occupational group into three main categories based on consider age-weighting and discounting. the type of industry: primary, secondary, and tertiary workforces. Farmers, plant growers, herdsman, seaman, and fishers were categorized as primary (agricultural-re- Results lated) workforces. The secondary industry was defined Descriptive analysis as manufacture-related work. The tertiary workforce was A total of 7763 leptospirosis cases were reported during defined for those individuals who work in services (e.g., 2005–2015 (Table 1). Of these, 2403 cases (31%) were teachers, doctors, nurses, students). The occupation recorded as confirmed cases, 4588 (59%) of cases as classified as “others” include individuals who retired/not clinical cases, and 772 (10%) cases were reported as working, including children and undefined profession. suspected cases. The proportion of confirmed cases A simple linear regression model was used to detect a towards the total cases was increased over time from trend in reported incidence, mortality, and burden 8.2% (120/1465) in 2005 to 56.7% (233/411) in 2015. estimates during 2005–2015, with the independent The proportion of reported laboratory-confirmed case variable being the year and the dependent variable being during 2005–2015 was varied across 26 provinces in a number of the case or disease rate. A chi-square (χ ) China (Additional file 2: Table S1). test was performed to determine the difference in By gender, a total of 5356 (69%) males and 2407 (31%) incidence, mortality rate and burden by age, sex, and females were observed. The annual incidence rate (IR) was occupation in different time periods. P-value < 0.05 higher in males (0.08 cases per 100 000 people) compared were considered statistically significant. A multiplicative to females (0.03/100 000 people) (χ = 22.50, P = 0.013, seasonal decomposition analysis was conducted using Table 1). Our results indicate that incidence differed SPSS version 24 (IBM Corp., Armonk, NY, USA) to significantly by age group (χ = 624.57, P < 0.001) with most Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 4 of 14 Table 1 Annual number of notified leptospirosis and incidence rate by sex, age and occupation and the proportion of case in China, 2005–2015 Characteristics Number of cases (per 100 000 people) Total IR 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Sex Female 439 (0.07) 217 (0.04) 300 (0.05) 254 (0.04) 197 (0.03) 218 (0.04) 134 (0.02) 154 (0.03) 156 (0.03) 207 (0.04) 131 (0.02) 2407 0.03 Male 1026 (0.16) 500 (0.08) 658 (0.10) 675 (0.11) 462 (0.08) 500 (0.08) 289 (0.05) 337 (0.06) 280 (0.05) 349 (0.06) 280 (0.04) 5356 0.08 Age 0–9 41 (0.03) 28 (0.02) 34 (0.03) 20 (0.02) 18 (0.01) 10 (0.00) 8 (0.01) 4 (0.00) 5 (0.00) 6 (0.00) 3 (0.00) 177 0.01 10–19 283 (0.13) 116 (0.06) 137 (0.07) 99 (0.06) 83 (0.05) 52 (0.03) 33 (0.02) 34 (0.03) 15 (0.01) 24 (0.02) 22 (0.01) 898 0.05 20–29 236 (0.14) 86 (0.06) 107 (0.07) 120 (0.08) 70 (0.04) 62 (0.04) 40 (0.02) 47 (0.02) 48 (0.03) 71 (0.04) 45 (0.02) 932 0.05 30–39 347 (0.14) 140 (0.07) 174 (0.09) 174 (0.09) 112 (0.06) 131 (0.07) 66 (0.04) 67 (0.04) 53 (0.03) 89 (0.05) 63 (0.03) 1416 0.07 40–49 228 (0.12) 140 (0.07) 202 (0.10) 180 (0.09) 126 (0.06) 159 (0.08) 99 (0.05) 126 (0.06) 106 (0.05) 142 (0.07) 83 (0.03) 1591 0.07 50–59 217 (0.15) 130 (0.08) 205 (0.12) 210 (0.12) 137 (0.08) 167 (0.10) 101 (0.08) 97 (0.07) 92 (0.07) 111 (0.08) 95 (0.05) 1562 0.09 60–69 87 (0.09) 53 (0.06) 75 (0.08) 93 (0.10) 92 (0.09) 112 (0.12) 55 (0.06) 84 (0.09) 83 (0.09) 84 (0.09) 83 (0.06) 901 0.08 70–79 16 (0.03) 15 (0.03) 23 (0.04) 30 (0.05) 20 (0.04) 27 (0.05) 20 (0.04) 32 (0.06) 23 (0.05) 22 (0.04) 25 (0.04) 253 0.04 80–89 1 (0.00) 0.00 6 (0.04) 4 (0.02) 1 (0.00) 0.00 3 (0.02) 3 (0.02) 4 (0.02) 5 (0.03) 3 (0.01) 30 0.02 90+ 0.00 0.00 1 (0.07) 0.00 0.00 0.00 0.00 0.00 1 (0.05) 0.00 1 (0.05) 3 0.02 Occupation Agriculture 1119 (0.32) 500 (0.15) 721 (0.22) 726 (0.24) 526 (0.18) 571 (0.22) 312 (0.11) 387 (0.14) 312 (0.12) 466 (0.19) 305 (0.13) 5944 0.18 Services 263 (0.11) 125 (0.05) 148 (0.06) 110 (0.03) 90 (0.02) 63 (0.02) 54 (0.02) 39 (0.01) 54 (0.02) 56 (0.02) 56 (0.02) 1058 0.04 Case Confirmed 120 227 267 249 158 229 178 182 239 321 233 2403 classification Clinical 1271 415 594 600 406 436 212 247 123 171 113 4588 Suspected 74 75 97 80 95 53 33 58 78 64 65 772 mean annual reported incidence rate of the cases (21%) reported in the 40–49 years old age leptospirosis cases were reported from Region B, where group. The higher incidence rate was identified in the older 6514 cases (84%) were reported during 2005–2015. The age groups of 50–59 (0.09/100 000 people) and 60–69 number of counties that reported cases demonstrated a (0.08/100 000 people). However, leptospirosis in younger significant reduction in 2005–2015 (P < 0.001). Overall, individuals under 20 years-old was also reported, which there was a significant declining trend in leptospirosis inci- accounted for a total of 1075 cases (14%) with reported dence from 0.11/100 000 people in 2005 to 0.03/100 000 incidence rates ranging from 0.01–0.05/100 000 people. people in 2015 (R = 0.646; P < 0.05). Among provinces, Based on patients’ occupation, we could only identify two both Sichuan and Yunnan had the highest reported main occupational type: primary (agriculture) and tertiary incidence rate (0.26/100 000 people) in the country. (services). Of 761 records were classified as ‘Other’ Similarly, the case-fatality rates (CFR) also showed a including who did not work, children, and retired people downturn trend from 3.29% in 2005 to 0.24% in 2015 (Additional file 2: Table S2). Leptospirosis incidence (R =0.815, P < 0.001). The highest CFR was recorded in rate was higher in primary sector (0.18/100 000 people) Guizhou (13.41%) compared to other provinces. Detailed compared to the group of tertiary workforces (0.04/100 000 temporal distribution of leptospirosis incidence and CFR people) (χ = 47.15; P < 0.001). Furthermore, among the for each province during 2005–2015 is provided (see primary workforces, of 298 (5%) cases were attributed Additional file 2:S1Table,S3Table). to young farmers aged under 20 years old. Whereas, In addition, during 2005–2015, a total of 168 deaths among the tertiary workforces, most cases (43%) was attributed to leptospirosis reported in China. Of which, predominantly attributed to students aged under 20 years. 71% (120/168) of reported deaths were attributed to Leptospirosis was reported from all four regions in males. High mortality rate was observed attributed to China; the highest reported incidence rate was primarily group 50–59 years (0.20 per 100 000 people) followed by observed in the Region A and B (Fig. 1). Based on the a group of age 10–19 years (0.18 per 100 000 people). A seasonal decomposition analysis, leptospirosis incidence high number of death (125 out of 168) were attributed increased from April to September and reached a peak to patients who worked in the primary sector as a on August/September and then diminished from October farmer. A high number of death reported from Region B thereafter. The lowest number of cases was consistently (74%), particularly in Guizhou, Sichuan, Hunan, Hubei, observed in February (Fig. 2). and Jiangxi (Additional file 2: Table S4). There was a In total, leptospirosis cases were reported from a total decrease in reported mortality rate since 2005 and it of 782 counties in 26 provinces in China (Table 2). Most reached a very low level from 2011 thereafter. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 5 of 14 Fig. 1 Annual average incidence map of leptospirosis in China, 2005–2015. It is divided into four regions (Region A, B, C, D) refer to Zhang et al. [7] Demographic and geographical changes in morbidity and notified incidence remained high in males and primary mortality between 2005 and 2010 and 2011–2015 workforces during both periods (P < 0.001). The trend in reported incidence and mortality was different Of total 168 deaths reported, most deaths were ob- between 2005-2010 and 2011–2015 (Fig. 3). A total of 5439 served (87%, 146/168) during 2005–2010 (Table 3). Few cases were reported in 2005–2010. Subsequently, there deaths (22 deaths) was recorded during 2011–2015. were only 2324 cases reported in 2011–2015 (annual IR = However, we noted a significant difference in the mortality 0.03/100 000 people), which was more than 50% lower than rate (P < 0.001) between 2005 and 2010 and 2011–2015. the preceding period (P < 0.001, Table 3). A slight The mortality rate fluctuated during 2005–2010; where decreasing trend in reported incidence was identified from two peaks were observed in 2005 and 2007. In contrast, a 2005 to 2010 (R = 0.480), while no trend in reported relatively stable and low mortality rates was observed dur- incidence has been observed during 2011–2015 (P > 0.05). ing 2011–2015. Statistically, there was a significant difference in reported Despite the significant drop in notified incidence and incidence between age groups during period 2005–2010 number of counties that reported leptospirosis, our analysis (z = 258.51; P < 0.001) and period 2011–2015 (z = 50.83; indicates 112 new counties were notified leptospirosis infec- P = 0.052). The highest reported incidence rate was tions in 2011–2015 (Additional file 2: Table S5). During this observed in the 50–59 age group (0.11/100 000 people). second period, we observed that leptospirosis infection had Moreover, there was no significant changes in gender and been reported in new four provinces including Hebei, Inner occupation-specific incidence since 2005 to 2015; the Mongolia, Jilin, and Gansu (Region C and D). Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 6 of 14 Fig. 2 Seasonal decomposition plot of leptospirosis cases in China Impact of changes in incidence and mortality on the DALYs). During 2005–2010, the total burden of lepto- burden of leptospirosis during 2005–2015 spirosis was estimated at approximately 8636 DALYs It is estimated that during 2005–2015 a total of 10 313 (1439 DALYs per annum). This consisted of 7379 YLLs DALYs were lost due to leptospirosis or approximately 937 and 1257 YLDs. It was much higher than the period of DALYs per annum (Table 4). Males are the most affected 2011–2015, which accounted for approximately 1600 group with an estimated 7149 DALYs or approximately DALYs or a decrease of 80% from the previous period 70% of the total burden. The highest burden estimate was (Additional file 2: Table S6). attributed to a group of age 10–19 years, both males and Between 2005 and 2010 and 2011–2015, a decline in females, accounted for around 30% of the total DALYs. The DALY estimate was observed in almost all provinces highest burden estimate was identified in Region B (7990 (Fig. 4). In 2005–2010, high DALYs estimates were ob- DALYs), followed by Region A (2312 DALYs) (Table 5). served in Sichuan (1337 DALYs), Guizhou (1936 DALYs), Our results indicate a 95% decline in DALYs due to Hunan (1374 DALYs), and Guangxi (1293 DALYs). These leptospirosis from 2005 to 2015 (P < 0.001, Table 5). The four provinces had contributed to approximately 70% of highest burden was estimated in 2005 (2966 DALYs), the total DALYs of that period. However, a substantial including 2632 YLLs and 334 YLDs; whereas the lowest reduction (on average at 53%) in DALYs occurred in burden estimates were identified during 2015 (144 many areas, including in those four provinces during Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 7 of 14 Table 2 Annual reported cases, confirmed case, counties, Table 2 Annual reported cases, confirmed case, counties, incidence and fatality rate of leptospirosis in China, 2005–2015 incidence and fatality rate of leptospirosis in China, 2005–2015 (Continued) No. of % No. of Incidence CFR cases confirmed county per (%) No. of % No. of Incidence CFR reported case reported 100 000 cases confirmed county per (%) (n = 7763) (n = 2403) (n = 782) people reported case reported 100 000 (n = 7763) (n = 2403) (n = 782) people Year Region D 2005 1465 8.2 307 0.11 3.29 Gansu 1 100 1 0.00 0.00 2006 717 31.7 265 0.05 2.66 Qinghai 1 0 1 0.00 0.00 2007 958 27.9 299 0.07 3.86 Xinjiang 2 0 2 0.00 0.00 2008 929 26.8 278 0.07 2.04 2009 659 24 222 0.05 1.82 2011–2015 (P < 0.05). Although there was a significant 2010 718 31.9 239 0.05 1.53 reduction in DALYs, we identify that higher estimates 2011 423 42.1 182 0.03 1.17 of the burden remain observed in young individuals at 2012 491 37.4 180 0.04 1.02 the age of 10–19, both sexes (P <0.05, Fig. 5). The 2013 436 54.3 165 0.03 1.16 burden estimates remained high among males (1316.8 2014 556 57.7 173 0.04 1.07 DALYs) compared to females (360.3 DALYs) during 2015 411 56.7 163 0.03 0.24 2011–2015 (P < 0.05). A larger quantity of annual YLLs estimates were lost dur- Region A ing 2005–2010 (1229 YLLs) compared to the 2011–2015 Guangdong 619 53.3 100 0.06 2.28 period (225 YLLs) (P < 0.05). Leptospirosis resulted in Guangxi 543 40.1 92 0.10 1.16 approximately 5689 YLLs during 2005–2007, and it has Hainan 47 10.6 15 0.05 0.00 contributed 55% of the total DALYs. A three-fold reduction Region B in the number of YLLs was observed in 2005–2006, but a Jiangsu 37 54.1 25 0.00 1.30 slight increase observed in 2007. Moreover, we found Zhejiang 138 42.8 28 0.02 1.31 higher YLLs estimates were contributed by economically less-developed provinces such as Sichuan, Guizhou, Hunan, Anhui 310 8.4 31 0.05 1.03 and Guangxi. The highest YLLs estimate was attributed to Fujian 502 47 62 0.12 0.74 the younger individual age of 10–19 years. Similarly, YLDs Jiangxi 421 5.5 52 0.09 1.62 estimates declined over time (P < 0.001) and a significant Henan 3 0 3 0.00 0.00 difference on annual YLDs was observed between the two Hubei 296 10.8 31 0.05 2.96 periods (P < 0.001). An extended analysis was provided (see Hunan 656 15.9 98 0.09 3.10 Additional file 2:Table S7–Table S10; Additional file 3). Chongqing 200 10 33 0.06 0.49 In terms of YLLs, Guizhou had the highest estimates on YLLs which account for 2300 YLLs or 27% of the Sichuan 2352 6.3 97 0.26 1.10 total YLLs during 2005–2015, followed by Hunan, Guizhou 291 11.7 45 0.07 13.41 Guangxi, and Sichuan (Fig. 6). In Guizhou, the highest Yunnan 1308 86.2 36 0.26 0.15 YLLs estimates were observed during 2005–2010 (1800 Region C YLLs). During 2011–2015, a dramatic change in YLLs Beijing 2 50 2 0.00 0.00 estimates was observed in most provinces. However, the Shandong 20 65 14 0.00 0.00 YLLs consistently remained relatively high in Guizhou. In terms of YLDs, Sichuan and Yunnan have higher esti- Hebei 3 33.3 3 0.00 0.00 mates during both periods. Shanxi 3 33.3 3 0.00 0.00 Inner Mongolia 1 100 1 0.00 0.00 Discussion Liaoning 1 0 1 0.00 0.00 Our study quantified the remarkable decrease in leptospir- Jilin 2 100 2 0.00 0.00 osis incidence and mortality in China during 2005–2015, Shaanxi 4 25 4 0.00 0.00 which was accompanied by substantial changes in the demographic and geographic pattern in disease burden estimates. We observed a remarkable decline in reported incidence and mortality in all provinces especially in region A and B where leptospirosis is principally most prevalent, such as Sichuan and Yunnan. These findings Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 8 of 14 Fig. 3 Annual reported incidence and mortality (per 100 000 people) of leptospirosis in China, 2005–2015 are in line with previous county-level studies which also water and sanitation facilities, and strengthening healthcare reported a reduction in notified incidence while local out- and local surveillance systems. breaks still frequently reported in some areas [21–26]. Our study demonstrates an updated burden estimates in Our analysis indicates that following a steep downward terms of DALYs for leptospirosis in China. To the best of trend during 2005–2010, the reported incidence of our knowledge, this is the first study that attempted to leptospirosis in China remained quite low during the last quantify the spatiotemporal heterogeneity in the burden five years. This finding suggests that China might have of leptospirosis using time-series historical notification reached a low-level leptospirosis transmission similar to data, especially in China. From 2005 to 2015, it was esti- other developed countries [27] although this might not mated that more than 10 000 DALYs lost due to infections indicate a real epidemiological situation as evidenced by where the burden predominantly contributed by high the existence of persistent geographical foci of infection YLLs. However, our estimates are in stark contrast with that can potentially lead to future outbreaks in the coun- those reported by a study elsewhere [3]. Our smaller try. Also, we observed marked variation in fatality-rates DALYs estimates may reflect the sharp reduction in both across regions over time, which may be explained by the reported incidence and mortality that occurred during heterogeneity the level of awareness and knowledge among 2005 to 2015. populations towards leptospirosis, inadequate measures for The burden estimates provided by Torgerson et al. [3] early diagnosis and treatment especially during outbreaks, was mainly generated based on the morbidity and mortal- delay in seeking treatment, and severity of illness due to ity estimates developed by another study elsewhere [2] variation to Leptospira exposure and localized risk factors. that involved modelling on the morbidity and mortality Hence, more targeted control efforts are needed especially data by incorporating several variables, adjustments, and in those high-risk areas and economically less developed uncertainties. Their study was a global study and applied a areas by enhancing awareness, improving access to safe global model to each country. It is important to consider Table 3 Changes in notified incidence and mortality (per 100 000 people) due to leptospirosis in four regions in China during 2005–2010 and 2011–2015 Region 2005–2010 2011–2015 No. of cases Incidence Deaths Mortality No. of cases Incidence rate Deaths Mortality rate A 835 0.05–0.14 39 0.00–0.01 374 0.04–0.06 4 < 0.01 B 4593 0.00–0.38 107 0.00–0.01 1941 0.00–0.28 18 < 0.01 C 9 < 0.01 0 0 7 < 0.00 0 0 D 2 < 0.00 0 0 2 < 0.00 0 0 Total 5439 0.07 146 0.002 2324 0.03 22 < 0.01 included all cases (i.e., confirmed, clinical, and suspected) Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 9 of 14 Table 4 Age and gender-specific YLLs, YLDs, and DALYs estimates based on reported leptospirosis in China, 2005–2015 Age YLLs YLDs DALYs Female Male Total Female Male Total Female Male Total 0–9 79.31 237.92 317.23 9.50 31.59 41.09 88.81 269.51 358.32 10–19 1077.14 1796.61 2873.75 40.37 163.4 203.77 1117.51 1960.01 3077.52 20–29 566.89 1281.47 1848.36 62.94 151.28 214.22 629.83 1432.75 2062.58 30–39 256.71 824.46 1081.17 117.32 213.98 331.31 374.03 1038.44 1412.48 40–49 255.03 620.29 875.32 132.52 240.34 372.87 387.55 860.63 1248.19 50–59 277.2 695.33 972.53 119.70 244.38 364.08 396.9 939.71 1336.61 60–69 73.73 397.18 470.91 58.90 150.57 209.47 132.63 547.75 680.38 70–79 17.28 52.81 70.09 16.15 42.99 59.14 33.43 95.8 129.23 80–89 0 0 0 2.37 4.75 7.12 2.37 4.75 7.12 90+ 0 0 0 0.47 0.24 0.71 0.47 0.24 0.71 TOTAL 2603.29 5906.07 8509.36 560.25 1243.52 1803.77 3163.54 7149.59 10 313.13 that epidemiological conditions for leptospirosis transmis- previous studies. We also identified variation in the sur- sion and notifications are geographically non-stationary veillance system capacity, as evidenced by the difference and this approach might be inadequate to capture small- in laboratory-confirmed cases among provinces, which scale heterogeneities. Importantly, that study used pub- means that adjustments should be cautiously applied for lished data from 1970s, a period when leptospirosis was the whole country. Applying adjustments to the whole highly endemic and when China’ssurveillance systems country could be over/underestimated the actual inci- might be different compared to the period of the 2000s. dence and mortality rates. This study extends Torgersen’s[3] study in that we used Changes in incidence and burden can be partly associ- high-resolution, contemporaneous data based on recent ated with improvement in prevention and control mea- national Chinese disease surveillance systems that have sures including health promotion activities, sanitation, relatively good coverage across the country. This study and the application of leptospirosis vaccination was successfully demonstrated spatiotemporal heterogen- programme [10, 16, 26, 28, 29]. In terms of the surveil- eity in burden within China that was not captured by lance system, the development of NIDRIS and CIDARS Table 5 Temporal and geographical distribution of YLLs, YLDs, and DALYs of leptospirosis in China, 2005–2015 Years of life Years lived with Disability-adjusted DALYs/100 000 lost (YLLs) disability (YLDs) life years (DALYs) people Year 2005 2631.51 334.39 2965.90 0.22 2006 1066.17 163.63 1229.80 0.09 2007 1991.61 220.16 2211.77 0.16 2008 813.55 216.36 1029.91 0.08 2009 530.56 153.66 684.22 0.05 2010 345.99 168.38 514.37 0.04 2011 249.07 99.75 348.82 0.03 2012 303.1 116.14 419.24 0.03 2013 245.77 100.94 346.71 0.03 2014 287.34 130.15 417.49 0.03 2015 44.69 100.22 144.91 0.01 Region A 2035.89 276.92 2312.81 1.44 B 6473.47 1517.36 7990.83 1.11 C 0 8.55 8.55 < 0.01 D 0 0.95 0.95 < 0.01 Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 10 of 14 Fig. 4 Changes on notified incidence (top) and geographical distribution of the burden (bottom) of leptospirosis in China over two periods, 2005–2010 and 2011–2015 following outbreaks of the severe acute respiratory syn- and livestock husbandry, for instance, restriction on live- drome (SARS) in 2003 have helped efficiently improve stock herding, farming commercialization, and pigs or the timeliness, completeness, and coverage of the data livestock vaccination [10, 30] that happened in China across China as well as facilitates early detection of dis- could have impacted the transmission rate of leptospir- eases outbreaks [16]. However, it has been confirmed osis in China. Industrialization, for example, has led to that during 2005–2015, there has been no significant significant epidemiological shifts in rural areas change in the surveillance systems, specifically for lepto- through the introduction of agricultural technology spirosis. While, in terms of the vaccination programme, and mechanization which might reduce the rate of human leptospirosis vaccine has been developed since human exposure to the Leptospira-contaminated en- 1958 and until now it has been administered to high-risk vironment. Also, we had noticed that there were sig- populations in China during the epidemic seasons. A nificant anthropogenic ecological changes following multivalent inactivated vaccine is currently the only the development of the Three Gorges Dam and the available in China [29]. nationwide reforestation programme called “Grain for Changes in ecological and social conditions that have Green”, which probably had an effect of leptospirosis been underway in China in the past 20 years may also transmission. Water impoundment in many endemic have played an essential role in leptospirosis epidemi- areas has been known to have an impact on rodents’ ology. Changes in the landscape, agricultural practices habitat and population dynamics of the pathogen Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 11 of 14 Fig. 5 Temporal distribution of the burden estimates of leptospirosis by gender and age groups in China during 2005–2010 and 2011–2015 in those regions [31, 32]. These projects have also Product among provinces in China [18]. High burden esti- been reported to have had a substantial impact on mates in school-aged children may probably be associated another rodent- and water-borne diseases, such as with lack of parental supervision because of parental migra- hemorrhagic fever with renal syndrome and schisto- tion from rural to the cities that happened during the last somiasis [33–35]. However, the role of environmental three decades. Lack of parental supervision on preventing changes on space-time variation on leptospirosis their children from unhealthy behaviors and environment incidence and burden still needs to be explored. Also, may likely increase the risk of pathogenic exposure and chil- a substantial change in the quality of livestock hus- dren’s health [37]. Additionally, rural migration has shifted bandry in China (e.g., improved waste management labor allocation and participation in families in farming ac- and farm biosecurity) might also have contributed to tivities, where children, women, and elderly become more adecreaseintransmission rateinlivestock [10]. A re- active in farming [38, 39] and, therefore, they are more likely view of significant changes in the epidemiology of in- to be exposed to Leptospira-contaminated environments. It fectious diseases in China, including leptospirosis, has has been indicated in our findings that 5% of the total cases also been described elsewhere [14, 36]. among farmers were attributed to young farmers (aged Our results demonstrate that the highest DALY was under 20 years). Health education and awareness amongst attributed to younger individuals aged 10–19 years due to this population group, especially in rural communities is, higher mortality (YLLs) observed in this group. Interestingly, therefore essential to furtherreducethe risk in thisdemo- higher DALYs estimates were identified in economically graphic group. These findings highlight the importance of less-developed provinces in China including Guangxi in improving current local surveillance for leptospirosis and Region Aand Guizhouand SichuaninRegionB.Guangxi health care services for the high-risk populations living in and Guizhou are known to have low Gross Regional the high-risk areas identified in our study. Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 12 of 14 Fig. 6 Changes in geographical distribution of years of life lost (YLL) and years-lived with disability (YLD) due to leptospirosis in China during 2005–2015 We also found that disease transmission might have However, our study has several limitations that need emerged in some counties located in temperate regions to be considered; which mainly associated with the data. to the north of the country although at the very low rate. First, as there was no information regarding with sero- This may partly be due to change in environmental vars in our data, we could not be able to analyze further conditions (i.e., climate variation and changes in land whether the observed change in incidence, mortality and use/land cover) or the translocation of potential reser- burden was also reflected a dynamic change in circulat- voirs from adjoining endemic regions. Climate variation ing serovars in the country during the period of study. notably the increase in temperatures may have driven Second, it should also be noted that our burden estimate the spread of Leptospira towards temperate regions in was based on passive surveillance and all cases reported China through its impact on rodent population growth during the period, which might not represent the actual in these areas [40]. Several outbreaks in China have been incidence and burden of disease. The number of reported thought to be associated with high rainfall intensity [26]. cases, the proportion of laboratory-confirmed cases, and However, we suggest that further investigation should be fatality-rates have shown markedly varied during the performed to determine whether the emerging incidence period of study and across provinces indicating a variation may correlate with changes in climate and other envir- in diagnostic techniques capacity across the province in onmental and social conditions (e.g., human migration). the country and therefore could bias our analysis. It Dhewantara et al. Infectious Diseases of Poverty (2018) 7:57 Page 13 of 14 should be noted that the surveillance system in China is Additional files mainly a hospital-based, but their laboratory capacity to Additional file 1: Multilingual abstract in the five official working undertake diagnosis through MAT, ELISA, or PCR is also languages of the United Nations. (PDF 778 kb) vary across hospitals over the country. Also, since lepto- Additional file 2: Table S1. Temporal distribution of reported spirosis often presenting a broad spectrum of clinical leptospirosis incidence in four regions in China by province, 2005–2015. manifestations, more untreated cases or false-negative Table S2. Reported leptospirosis cases and the proportion of laboratory- confirmed case (in percent) by type of occupational group, China, 2005–2015. cases might occur and lead to a high number of underre- Table S3. Case fatality-rates (CFR) of leptospirosis by province in two regions ported and misdiagnosed cases, especially in resource- in China, 2005–2015. Table S4. Temporal distribution of notified mortality limited endemic areas. The recent finding indicated the rates due to leptospirosis in two regions in China, by province, 2005–2015. Table S5. Number of counties reported leptospirosis each year and new presence of leptospiral infection among patients with counties that reported leptospirosis during 2005–2010 and 2011–2015. Table undifferentiated fever in Hainan province [41], suggesting S6. Disability-adjusted life-years (DALYs) estimates of leptospirosis by gender, that the incidence and burden may be underestimated. by age and year, China. Table S7. Temporal trend of years of life lost (YLL) due to leptospirosis in China, by gender, by age and year. Table S8. Years of Thus, enhanced-surveillance prospective population- life lost (YLLs) estimates for leptospirosis in China, by region, gender, by age based studies may help to determine existing leptospirosis period of year. Table S9. Years-lived with disability (YLD) due to leptospirosis cases in China better. in China, by gender, by age and year. Table S10. Geographical distribution of years of life lost (YLL), years-lived with disability (YLD), and disability-adjusted Another drawback is that there was no detail data avail- life years (DALY) by region during both periods in China. (DOCX 64 kb) able on patient’s clinical presentations in our dataset that Additional file 3: The distribution of age-, sex-, and geographically-specific we used, so that it was not possible to determine the years of life lost (YLLs) estimates in China, 2005–2015. (XLSX 23 kb) severity of disease that may help to assess disability weight for DALY estimation as well as to explain the variation of Abbreviations fatality-rates across China. In addition, in this study, we CDC: Center for Disease Control and Prevention; CFR: Case fatality-rate; CIDARS: China Infectious Disease Automated-alert and Response System; used all categories of cases including suspect, clinical, and CISDCP: China Information System for Disease Control and Prevention; confirmed leptospirosis cases as defined by China health DALY: Disability-adjusted life-year; DW: Disability weight; ELISA: Enzyme- authority. It is necessary to acknowledge that there may linked immunosorbent assay; IR: Incidence rate; MAT: Microscopic agglutination test; MR: Mortality rate; NHFPC: National Health and Family also be a reporting bias that affects our analysis as Planning Commission; NIDRIS: Notifiable Infectious Diseases Reporting leptospirosis have overlapping clinical presentations with Information System; PCR: Polymerase chain reaction; SARS: Severe acute another disease (e.g., dengue) [5]. respiratory syndrome; WHO: World Health Organization; YLD: Years-lived with disability; YLL: Years of life-lost Lastly, the observed reduction in reported incidence and mortality from 2005 to 2015 may also a result of the Acknowledgements changes in social and environmental conditions in en- We are grateful to anonymous reviewers of this study for their thorough, demic areas as have been discussed above. In a subse- constructive, and helpful review, which led to substantial improvements of the manuscript. quent study we, therefore, will aim to understand the drivers of such reduction by focusing on high-risk areas Funding and quantify the attributable fraction of determinants PWD received support from Australia Awards Scholarships – Department of Foreign Affairs and Trade. WYZ received support from National Natural such as socioeconomic development, farming practices, Science Foundation of China (No. 11501339). The funder had no role in the and environmental changes. study design, data collection or analysis, the decision to publish, and the preparation of this manuscript. The findings and conclusions of this study are those of the authors and do not necessarily represent the views of the funding agency. Conclusions In the last 11-years, the burden estimates of leptospir- Availability of data and materials osis indicated a declining trend across the country; The datasets used and/or analysed during the current study are protected by the China CDC and are unsuitable for public sharing. Interested parties however, leptospirosis should not be neglected as it can apply for the data by contacting the data center of China public health remains an important zoonotic disease and potentially science or email data@chinacic.cn. The metadata supporting the conclusions disproportionately affected the young and productive of this article are available in supplementary files. population group in China. In addition, while in the last Authors’ contributions five years the incidence has been reported at very low-level, PWD RJSM conceived and designed the study. WYZ provided the data. this might not reflect the actual incidence of leptospirosis. PWD RJSM analysed the data. PWD wrote the first draft, revisions and final manuscript. AAM WYZ WWY FD GH WH FC AIK RJSM reviewed and edited Active surveillance studies on acute febrile illnesses are ur- the manuscript. All authors read and approved the final manuscript. gently required. Finally, these findings may help to design targeted intervention strategies in China to reduce the Ethics approval and consent to participate burden of human leptospirosis. An evaluation of the role of The study was approved by the Medical Research Ethics Committee of the University of Queensland (No. 2016001608) and Beijing Institute of Disease environment and socioeconomic on the changing leptospir- Control and Prevention. Patient confidentiality was ensured throughout the osis epidemiology and burden should be considered in the analysis of the data through data de-identification and aggregation of data future works. records to the county-level. Dhewantara et al. 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Infectious Diseases of PovertySpringer Journals

Published: May 18, 2018

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