Co-endemicity Of Tuberculosis And Intestinal Parasitic Diseases In P. R. China

Tuberculosis (TB) and intestinal parasitic diseases are important infectious diseases in the People’s Republic of China (P. R. China), and both of diseases still affect millions of people every year. The national-scale estimation of prevalence risks and risk maps for pulmonary TB (PTB) and intestinal parasitic diseases as well as co-endemic maps of both diseases’prevalence are poorly understood, although many studies on spatial epidemiological survey for both diseases at the local-scale were conducted. It is essential to detect co-endemic areas because there are the high risk areas of both diseases’syndemics. The syndemic means that the negative health effects of any or all of the diseases are exacerbated under co-infection of Mycobacterium tuberculosis (MTB) and intestinal parasites. However, little is known about co-infection of MTB and intestinal parasites including protozoa and helminths in humans in P. R. China, which includes prevalence of co-infection and host’s immune response to co-infection. This study aims to fill these gaps in order to provide technical support to two national control programmes.First, we explored the ecological factors related to the spatial heterogeneity of PTB prevalence in P. R. China. The latent variables including PTB prevalence and ecological factors were identified by using the exploratory factor analysis from the observed variables during2001to2010that were obtained from four sources, i.e., the databases of the National TB Control Programme (NTP)(2001-2010) in P. R. China, the P. R. China Health Statistical Yearbook during2002-2011, the P. R. China Statistical Yearbook during2002-2011and the provincial government websites in2013. The partial least squares path modeling was chosen to construct the structural equation model to evaluate the causal relationship between PTB prevalence and ecological factors. Furthermore, the geographically weighted regression model was used to explore the local spatial heterogeneity in the causal relationships. We identified "TB prevalence" and eight ecological factors including "TB prevalence","TB investment","TB service","health investment","health level","economic level","air quality","climatic factor" and "geographic factor". With the exception of "TB service" and "health level", other ecological factors had explicit impacts on "TB prevalence" significantly at different levels. Among the remaining six ecological factors,"economic level" and "geographic factor" had stronger impacts on "TB prevalence" aside from "TB investment" and "health investment". Additionally, each ecological factor had different impacts on "TB prevalence" in different regions significantly. Ecological factors that were found predictive of PTB prevalence in P. R. China are essential to take into account in the formulation of locally comprehensive strategies and interventions aiming to tailor the TB control and prevention programme into local settings in each ecozone.Based on previous findings, we tried to accurately estimate the continuous spatial variations of PTB prevalence in2010, which is an importance in allocation of the limited resources of NTP to the different regions in P. R. China. An evaluation was performed to decide which ordinary kriging and cokriging methods along with different combinations of types of detrending, semivariogram models, anisotropy and covariables (socio-economic and geographic factors) can be assigned to accurately construct spatial distribution surface of PTB prevalence employing statistic data sampled from the fifth national TB epidemiological survey in P. R. China,2010, and then the evaluation results were used to explore factors of spatial variations. Finally, the cokriging with global detrending with socio-economic and geographic factors as covariables proved to be the best geostatistical methods for accurately estimating spatial distribution surface of PTB prevalence. The final continuous surfaces of PTB prevalence distribution demonstrated that PTB prevalence were lower in Beijing, Tianjin, Shanghai and southeastern coast China, higher in western and southwestern China, and crossed between low and high in central China. The predicted continuous surface perspicuously illustrated the spatial variations of PTB prevalence that were co-impacted by socio-economic and geographic factors, of which the information can be used to better allocate the limited resources of NTP in P. R. China.Second, the co-endemicity of PTB and intestinal parasitic diseases was investigated at the national-scale. Bayesian geostatistical logistic regression models were fitted separately for PTB and intestinal helminth infection (IHI), which related data of the fifth national TB epidemiological survey and the second national survey for major human parasitic diseases completed in2010and2004, respectively, with socio-economic, climatic, geographical and environmental predictors. Predictors during2001to2010were extracted from the freely accessible open-source databases in various websites. Prevalence risk maps were created for both diseases respectively via Bayesian kriging models. Based on predictive prevalence risk maps, the relative risk (RR) maps of co-endemicity were estimated by Bayesian shared component model that appraised the fraction of variance of spatial RRs shared by both diseases, and those specific for each one, under an assumption that there are the unobserved covariates common to both diseases. Our results indicated that the gross domestic product (GDP) per capita had negative association and the rural regions, the arid and polar zones and the elevation had positive association with PTB prevalence; the GDP per capita and the distance to water bodies had negative association and the equatorial and warm zones and the normalized difference vegetation index had positive association with IHI prevalence. Moderate to high prevalence of PTB and low prevalence of IHI were predicted in western China. Low to moderate prevalence of PTB and low prevalence of IHI were predicted in north of central China and the southeast coastal regions. Moderate to high prevalence of PTB and high prevalence of IHI were predicted in southwestern China. For the prevalence of both diseases, the southwestern regions were the largest clustering areas, where they might have common risk factors, namely socio-economic factors such as GDP per capita. Hence, co-endemic areas are key areas to plan control strategies to combat both diseases’syndemics principally by means of improving local socio-economic conditions.Third, we conducted an epidemiological survey on co-infection of MTB and intestinal parasites in humans. A cross-section survey was conducted in a rural county of Henan Province, P. R. China. Patients with PTB undergoing anti-MTB treatment (PCs) and healthy controls (HCs) matched to geographical area (same village or community), age (±5years) and sex were surveyed using questionnaires. The questionnaires included items of socio-demography, health conditions, hygienic habits and labor in farmlands. Their stool and blood specimens were collected for intestinal parasites detection, routine blood examination and human immunodeficiency virus (HIV) detection. The Pearson χ2tests were used for the univariate analysis (odds ratios [OR] and95%confidence intervals [CI]) of impact factors associated with intestinal parasite infection, and the multivariate logistic regression models were used to adjust for potential confounding factors (adjusted ORs [AOR] and95%CIs). Additionally, we further examined the impact of anti-MTB treatment on infection rates of intestinal parasites by the Mantel-Haenszel χ2tests. A total of369PCs and366HCs were included and all participants were HIV negative. The overall prevalence of intestinal parasites in PCs was14.9%, including intestinal protozoa (7.9%) and helminths (7.6%). The infection spectrum of intestinal parasites was Entamoeba spp.(1.4%), Blastocystis hominis (6.2%), Trichomonas hominis (0.3%), Clonorchis sinensis (0.3%), Ascaris lumbricoides (0.5%), Trichuris trichiura (2.2%) and hookworm (4.6%). The prevalence of intestinal parasites showed no significant difference between PCs and HCs after adjusting for potential confounding factors. There was no factor that affected infection rates of intestinal parasites between two groups, whereas infection of intestinal parasites among PCs was associated with female sex (AOR=2.05,95%CI=1.01-4.17), body mass index (BMI)≤19(AOR=3.02,95%CI=1.47-6.20) and anemia (AOR=2.43,95%CI=1.17-5.03) and infection with HCs was only associated with annual labor time in farmlands>2months (AOR=4.50,95%CI=2.03-10.00). Additionally, there was no significant trend between the infection rates of intestinal parasites and duration of anti-MTB treatment among PCs. It was indicated that the prevalence of intestinal parasites was not found to be higher in PCs and there was no evidence that PTB increased susceptibility to intestinal parasites. However, for patients with PTB, women and patients with comorbidities were more likely to be infected with intestinal parasites.We further divided PCs into four groups as only intestinal protozoan infection (IPI), only intestinal helminth infection (IHI), simultaneously infected with both intestinal protozoa and helminths and no any infection. Then we investigated the prevalence and predictors of only IPI and only IHI among PCs as well as evaluated the effect of duration of anti-MTB treatment on only IPI and only IHI. Overall,7.3%of PCs were only infected with intestinal protozoa, among which prevalence of B. hominis, Entamoeba spp. and T. hominis were6.0%,1.1%and0.3%, respectively;7.0%were only infected with intestinal helminths, among which prevalence of hookworm, T. trichiura, A. lumbricoides and C. sinensis were4.3%,1.9%,0.5%and0.3%, respectively;0.5%were simultaneously infected with intestinal protozoa and helminths. BMI≤18(AOR=3.30,95%CI=1.44-7.54) and raised poultry or livestock (e.g., chicken, duck, pig)(AOR=3.96,95%CI=1.32-11.89) were significantly associated with only intestinal protozoan infection; BMI≤18(AOR=3.32,95%CI=1.39-7.91), anemia (AOR=3.40,95%CI=1.44-8.02) and ever labored barefoot in farmlands (AOR=4.54,95%CI=1.88-10.92) were significantly associated with only intestinal helminth infection among PCs. Moreover, there also was no significant relationship between duration of anti-MTB treatment and infection rates of intestinal parasites including both protozoa and helminths. In any case, preventing malnutrition, avoiding unprotected contact with reservoirs of protozoa, and improving health education for good hygiene habits, particularly wearing shoes outside, are of benefit to prevention of intestinal protozoan and helminth infection among patients with PTB.Last, it is also important to know host’s immune response to co-infection of MTB and intestinal parasites for planning control strategies of both diseases’syndemics. A study showed that humoral and cellular immune responses play protective roles against MTB; however, other study indicated that hookworm infections decrease immune response to hookworm and bystander antigens. To evaluate whether co-infection of MTB and hookworm decreases host’s immune responses, we selected17patients with PTB and hookworm infection,26patients only with PTB15patients only with hookworm infection and24healthy controls without PTB and hookworm infection from participants of the previous epidemiological survey. Expressions of CD3, CD4, CD8, CD10, CD19, CD20, CD21, CD25, CD27, CD38,FoxP3and PD-1in their peripheral blood were assessed on B-and T-cell subsets using multicolor flow cytometry to evaluate B-and T-cell immune response to co-infection. In the settings for co-infection of MTB and hookworm, for B cell (CD19+) subsets, naive B cells (CD10-CD27-CD21+CD20+), plasma cells (CD10-CD27+CD21-CD20-) and tissue-like memory B cells (CD10-CD27-CD21-CD20+) had higher proportions and resting memory B cells (CD10-CD27+CD21+CD20+) had lower proportion than in other groups, whereas frequencies of activated memory B cells (CD10-CD27+CD21-CD20+) did not differ among four groups. And for T cell (CD3+) subsets, frequencies of regulatory T cells (CD4+CD25+Foxp3+), and exhausted CD4+and CD8+T cells (CD4+PD-1+and CD8+PD-1+) were higher and frequencies of activated CD4+and CD8+T cells (CD4+CD38+and CD8+CD38+) were lower in co-infection group than in other groups. In conclusion, both humoral and cellular immune responses might be more suppressed by MTB infection concurrent with hookworm infection, which can lead to the poor treatment outcome of patients with PTB and further increase the probabilities that they infect others. The findings also prove that it is worthwhile to prevent and control co-infection in co-endemic areas of TB and intestinal parasite infections.In conclusion, although we conducted the epidemiological study on co-infection of MTB and intestinal parasites in a rural county of central China, we found that co-endemic risks of TB and intestinal parasite infections are higher in southwestern China than in central China. Therefore, we advise that the epidemiological study on co-infection should be done in southwestern China and intervention measures should be taken to control the advance and onset of co-infection according to the results of the study. We suggest that developing local economy, improving people’s nutrition status, strengthening people’s health education and fostering people’s good sanitary habits have to be integrated each other in interventions in order to control co-infection in high risk areas of co-endemicity. Meanwhile, intestinal parasite infections among patients with PTB, particularly female patients and persistent patients, are better to be evaluated properly, and combination regimen of anti-MTB drugs and anti-parasitic drugs is better to be investigated to make patients with co-infection receive better and standard treatments.