Background
Tuberculosis (TB) is caused by inhalation of the bacterium
Mycobacterium tuberculosis [
1], and is the leading cause of death from a single infectious agent, ranking above HIV/AIDS, and as the tenth most common cause of death worldwide [
2]. Pulmonary tuberculosis (PTB) contributed 85% of all notified TB cases worldwide, and 88% of TB deaths [
2,
3]. Globally, China had the second largest number of new TB cases in 2017, accounting for 8.9% of all new cases worldwide [
2]. The spatial distribution of PTB in the country is heterogeneous: incidence rates are higher in poorer, inland and western regions, and lower in more developed coastal regions [
4‐
6]. Among the major foci of ongoing transmission in China, the southwestern province Sichuan has, until recently, experienced a very high TB burden, with estimated prevalence of active and smear-positive PTB of 598 and 104 cases per 100,000 persons in 2010, respectively—substantially higher than the corresponding national averages of 442 and 59 cases per 100,000 persons [
7,
8]. With a population of more than 80 million people, the province accounts for 6.9 and 5.5% of China’s total PTB incidence and mortality [
9].
Despite the high burden of PTB and a population of more than 80 million people, there is a limited understanding of the demographic and spatiotemporal distributions of PTB in the region, and thus information is limited on whether there are areas within the province that have seen limited reductions, or even increases, in transmission [
10‐
12]. Here, we estimate annual PTB notification rates and the spatiotemporal distribution of PTB incidence in the region based on data from the National Infectious Disease Reporting System (NIDRS)—China’s real-time, high-coverage electronic disease notification system. We detail the demographic, temporal, and spatial distributions of reported active and smear-positive PTB cases from 2005 to 2017, and apply spatiotemporal scan statistics to detect areas with unusually high incidence rates in order to identify key areas where future control and prevention measures might be targeted.
Discussion
We investigated demographic and spatiotemporal trends in active and smear-positive PTB cases across 13 years of passive surveillance data in a region with a large population-at-risk. We found that the overall reported incidence rate of PTB has decreased in the region, but that there is both spatial and temporal heterogeneity in incidence rates across counties over the study period. We identified persistent clusters of ongoing transmission, including counties where the incidence rate is increasing, particularly in areas with high HIV incidence and those with substantial ethnic minority populations (Additional file
1: Figure S4). The clusters were generally consistent with the results of previous research [
11,
12], and may be explained by the limited access to healthcare or presence of major transportation hubs in these regions. We observed modest seasonality for PTB in the study region during the study period, with more cases being reported in March and April, and fewer cases in January and February.
Our results indicated that the incidence rate of PTB was extremely low in those age < 14, and that the median age of reported PTB cases was increasing, suggesting that the current TB prevention and control measures in China are generally succeeding in the region. The Bacillus Calmette–Guérin (BCG) vaccine has been mandatory in China since 1954 [
34,
35], and the proportion of patients detected at hospitals undergoing treatment in TB control institutions increased from 63.6% in 2006 to 93.5% in 2010 [
36]. Further evidence suggesting that the transmission rate of PTB has decreased over the past decade comes from comparing our results to other findings: a 2008 study examining the incidence of PTB among 5-year age groups from 2000 to 2006 found the highest incidence for the 20–24, 40–45, and 65–74 year-old groups [
10], while the age groups with the highest incidence for our study period were the 25–30, 50–55, and 70–75 year old groups.
We observed modest seasonal trends for PTB, with a higher number of cases in the spring and summer, which is consistent with patterns observed elsewhere in the world. High numbers of PTB cases in March and April have been reported throughout the northern hemisphere, including in other regions of China [
37‐
39], Mongolia [
40], the United States [
41], and Peru [
42], but at the same time there are exceptions to these patterns [
43‐
46]. Indeed, the drivers of the seasonality of PTB remain poorly understood. Given the long time period between the exposure and the onset of TB, one possible explanation for the excessive number of reported cases in spring and summer is increased transmission during winter, because both low temperature and high PM
2.5 level may increase the time spent indoors with poor ventilation [
39,
47,
48]. Another possible explanation is the weakened host immunity during winter, which is associated with the high prevalence of other respiratory infectious diseases, vitamin D deficiency due to insufficient ultraviolet radiation exposure, and high PM
2.5 level, which can impair respiratory system immune response [
17,
39,
48].
The spatial distribution of annual mean incidence rates of reported active PTB cases reported here is generally consistent with the results of previous research [
11,
12]. Clusters of both active and smear-positive PTB were detected in eastern Sichuan, possible owing to its early economic stage of development (see Additional file
1: Figure S7 for county-level GDP per capita in 2016), limited access to healthcare in the region, and the presence of major transportation hubs, which are associated with increased contact rates between travelers and local residents [
49,
50]. An emerging cluster of active PTB was found in the Ganzi and western Aba prefectures from 2011 to 2017, which are also exhibiting increasing growth rates of reported PTB incidence rates. These prefectures are also at an early stage of economic development (see Additional file
1: Figure S7), and importantly, ethnic minorities in these regions—especially Tibetan people—may be at higher risk of active PTB as compared with other ethnic groups, possibly due to genetic susceptibility [
51], nomadic lifestyle [
52], and particularly low socioeconomic status [
53]. This emerging cluster was detectable among active cases, but not smear-positive, which might be a consequence of the low laboratory capacity in these areas.
Among the important limitations of this study, the reliance on a passive surveillance system can yield estimated incidence rates that may be affected by individuals’ healthcare seeking behavior, diagnostic performance, and facility compliance, and key reporting biases may differ across demographic groups or counties. We attempted to control for variable reporting effort by using reporting facility density as a proxy variable, and found no relation with changes in PTB incidence. However, this approach has significant limitations in the assumption that all reporting facilities perform equally. Another challenge in relying on NIDRS data arises from the reporting guidelines and procedures, which have evolved substantially since the system was initiated, leading to possible inconsistencies in case definitions, reporting infrastructures, and data accuracy over time. To mitigate the influence of dramatically increasing case detection rate on the results, we excluded the data for 2004, the year when NIDRS was established, from the analyses. According to WHO’s estimation, case detection rate of TB increased 10% (64% to 74%) from 2003 to 2004 alone, and another 13% from 2005 to 2017 [
46]. Finally, compared to the diagnostic methods of many acute infectious diseases, diagnostic methods for PTB can be ambiguous and inconclusive [
1], which can contribute bias associated with misclassification of outcome. Although suspected cases were excluded in the analyses, misdiagnosis and under-ascertainment may still exist.
Conclusions
The present study suggests that the overall reported incidence rate of PTB is decreasing at the province-level, but progress has not been equally distributed. Achieving the goal of reducing the incidence rate to below 58 per 100,000 people by 2020 [
54] will require additional resources and control efforts directed at western Sichuan, where HIV prevalence is high, the reported incidence rate of PTB is increasing, and the laboratory capacity is low. Future research should focus on achieving a greater understanding of the environmental and socioeconomic drivers of PTB in this region—including temperature, sunlight exposure, PM
2.5 level, GDP, prevalence of other respiratory infectious diseases and HIV/AIDS—in order to better understand the observed spatiotemporal pattern and to inform targeted interventions.
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