Critical medical ecology and intersectionality perspectives in schistosomiasis prevention and control in selected communities in Mindanao, the Philippines

Schistosomiasis japonica remains a public health concern in many areas of the Philippines. Periodic Mass Drug Administration (MDA) to at-risk populations is the main strategy for morbidity control of schistosomiasis. Attaining MDA coverage targets is important for the reduction of morbidity and prevention of complications due to the disease, and towards achieving Universal Health Care. The study employed a qualitative case study design. Key informant interviews and focus group discussions were conducted to provide in-depth and situated descriptions of the contexts surrounding the implementation of MDA in two selected villages in known schistosomiasis-endemic provinces in Mindanao in the Philippines. Data analysis was done using the Critical Ecology for Medical Anthropology (CEMA) model coupled with the intersectionality approach. It was found that within various areas in the CEMA model, enabling as well as constraining factors have been encountered in MDA in the study settings. The interplay of income class, geographical location, gender norms and faith-based beliefs may have led to key populations being missed during the conduct of MDA in the study sites. The constraints faced by the target beneficiaries of MDA, as well as programme implementers, must be addressed to enhance service delivery and to control morbidity due to schistosomiasis. Improving compliance with MDA also requires a holistic, integrated approach to addressing barriers to participation, which are shaped by wider socio-political and power structures.

From the One Health Perspective: Schistosomiasis Japonica and Flooding

Schistosomiasis is a water-borne parasitic disease distributed worldwide, while schistosomiasis japonica localizes in the People’s Republic of China, the Philippines, and a few regions of Indonesia. Although significant achievements have been obtained in these endemic countries, great challenges still exist to reach the elimination of schistosomiasis japonica, as the occurrence of flooding can lead to several adverse consequences on the prevalence of schistosomiasis. This review summarizes the influence of flooding on the transmission of schistosomiasis japonica and interventions responding to the adverse impacts from the One Health perspective in human beings, animals, and the environment. For human and animals, behavioral changes and the damage of water conservancy and sanitary facilities will increase the intensity of water contact. For the environment, the density of Oncomelania snails significantly increases from the third year after flooding, and the snail habitats can be enlarged due to active and passive diffusion. With more water contact of human and other reservoir hosts, and larger snail habitats with higher density of living snails, the transmission risk of schistosomiasis increases under the influence of flooding. With the agenda set for global schistosomiasis elimination, interventions from the One Health perspective are put forward to respond to the impacts of increased flooding. For human beings, conducting health education to increase the consciousness of self-protection, preventive chemotherapy for high-risk populations, supply of safe water, early case finding, timely reporting, and treating cases will protect people from infection and prevent the outbreak of schistosomiasis. For animals, culling susceptible domestic animals, herding livestock in snail-free areas, treating livestock with infection or at high risk of infection, harmless treatment of animal feces to avoid water contamination, and monitoring the infection status of wild animals in flooding areas are important to cut off the transmission chain from the resources. For the environment, early warning of flooding, setting up warning signs and killing cercaria in risk areas during and post flooding, reconstructing damaged water conservancy facilities, developing hygiene and sanitary facilities, conducting snail surveys, using molluscicide, and predicting areas with high risk of schistosomiasis transmission after flooding all contribute to reducing the transmission risk of schistosomiasis. These strategies need the cooperation of the ministry of health, meteorological administration, water resources, agriculture, and forestry to achieve the goal of minimizing the impact of flooding on the transmission of schistosomiasis. In conclusion, flooding is one of the important factors affecting the transmission of schistosomiasis japonica. Multi-sectoral cooperation is needed to effectively prevent and control the adverse impacts of flooding on human beings, animals, and the environment.

The Dynamics of Hepatic Fibrosis Related to Schistosomiasis and Its Risk Factors in a Cohort of China

China has had a long history against schistosomiasis japonica. The most serious prognosis of chronic schistosome infection is hepatic fibrosis, which develops into advanced schistosomiasis if the process is not effectively controlled. After a more than seven decades endeavor, China has gained remarkable achievements in schistosomiasis control and achieved transmission control nationwide (infection rate of schistosomes in residents and domestic animals both less than 1%) by 2015. However, new advanced schistosomiasis cases emerge annually in China, even in areas where the transmission of schistosomiasis had been interrupted. In the present study, the residents (>5 years old) in a schistosomiasis endemic village were examined for schistosomiasis every year during 1995–2019 by the modified Kato–Katz thick smear method and/or miracidium hatching technique. Residents who were identified to have an active infection method were treated with praziquantel at a dose of 40 mg/kg body weight. Ultrasonography was carried out to assess the liver morbidity related to schistosomiasis in 1995 and 2019, respectively. The prevalence of schistosomiasis among residents presented a downward trend annually, from 17.89% (175/978) in 1995 to 0 (0/475) in 2019. Among 292 residents who received ultrasound scan both in 1995 and 2019, 141 (48.29%) presented stable liver damage, while liver fibrosis was developed severely in 86 (29.45%) and reversed in 65 (22.26%) residents. Univariate and multivariate analysis showed that anti-fibrosis treatment was the protective factor against schistosomiasis hepatic fibrosis. Males, residents aged 38 and above, fishermen, and people who did not receive anti-fibrosis treatment were groups with higher risk of liver fibrosis development. Our results revealed that although the infection rate of schistosome dropped significantly in endemic areas, liver fibrosis was still developing among some residents, even though they had received deworming treatment. Liver protection/anti-fibrosis treatment should be administered in endemic regions and regions with historically uncontrolled transmission to slow down the deterioration of hepatic fibrosis among patients in schistosomiasis endemic areas.

Inhibition of COX-2 Ameliorates Murine Liver Schistosomiasis Japonica Through Splenic Cellular Immunoregulation

We have reported the positive association of cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) axis with liver fibrosis induced by Schistosoma japonicum (Sj) infection, and TLR4 signaling controlled this axis. However, how COX-2 regulated immune response during Sj infection is still unclear. Here we further studied the effect of COX-2 specific inhibitor-NS398 on liver granulomatous inflammation, fibrosis and explored the mechanisms via evaluating different immune cell during Sj infection.The results showed that NS398 significantly reduced the size of liver granuloma, spleen and mesenteric lymph node (MLN) and alleviated chronic granulomatous inflammation. Mechanically, it might be via decreasing the numbers of Sj-induced T helper type 1 (Th1), Th2, T follicular helper (Tfh), T follicular regulatory cells (Tfr) and germinal center B (GCB) cells to alleviate the liver inflammation and fibrosis. In addition, there were no difference of the numbers of macrophages, neutrophils, MDSCs,Th17 and total B cells in the spleen of the mice with or without NS-398 treatment. Our above data suggests that COX-2/PGE2 inhibition may represent a potential therapeutic approach to schistosomiasis japonica.

Development of a Recombinase Polymerase Amplification Assay for Schistosomiasis Japonica Diagnosis in the Experimental Mice and Domestic Goats

Although the prevalence of schistosomiasis japonica has declined gradually in China, more accurate and sensitive diagnostic methods are urgently needed for the prevention and control of this disease. Molecular diagnostic methods are advantageous in terms of sensitivity and specificity, but they are time-consuming and require expensive instruments and skilled personnel, which limits their application in low-resource settings. In this study, an isothermal DNA amplification assay and recombinase polymerase amplification (RPA) combined with lateral flow dipstick (LFD) were set up. It was used to detect S. japonicum infections in experimental mice and domestic goats by amplifying a specific DNA fragment of S. japonicum. The lower limit of detection for the LFD-RPA assay was evaluated using dilutions of plasmid containing the target sequence. Cross-reactivity was evaluated using genomic DNA from eight other parasites. The effectiveness of the LFD-RPA assay was verified by assessing 36 positive plasma samples and 36 negative plasma samples from mice. The LFD-RPA assay and real-time PCR were also used to assess 48 schistosomiasis japonica-positive plasma samples and 53 negative plasma samples from goats. The LFD-RPA assay could detect 2.6 femtogram (fg) of S. japonicum target DNA (~39 fg genomic DNA of S. japonicum), only 10-fold less sensitive than real-time PCR assay. There was no cross-reactivity with DNA from the other eight parasites, such as Haemonchus contortus and Spirometra. The whole amplification process could be completed within 15 min at 39°C, and the results can be observed easily using the LFD. The sensitivity and specificity of the LFD-RPA assay were 97.22% (35/36, 95% CI, 85.47%–99.93%) and 100% (36/36, 95% CI, 90.26%–100%) in mice, and 93.75% (45/48, 95% CI, 82.80%–98.69%) and 100% (53/53, 95% CI, 93.28%–100%) in goats. By comparison, the sensitivity and specificity of real-time PCR were 100% (36/36, 95% CI, 90.26%–100%) and 100% (36/36, 95% CI, 90.26%–100%) for mice, and 97.92% (47/48, 95% CI, 88.93%–99.95%) and 100% (53/53, 95% CI, 93.28%–100%) for goats. The LFD-RPA assay exhibits high sensitivity and specificity for the diagnosis of schistosomiasis japonica, and it is an alternative method for diagnosis schistosomiasis japonica in low resource setting.

Performance of the point-of-care circulating cathodic antigen test in the diagnosis of schistosomiasis japonica in a human cohort from Northern Samar, the Philippines

Background Zoonotic schistosomiasis, caused by Schistosoma japonicum, remains a major public health problem in the Philippines. This study aimed to evaluate the commercially available rapid diagnostic point-of-care circulating cathodic antigen (POC-CCA) test in detecting individuals infected with S. japonicum in a human cohort from an endemic area for schistosomiasis japonica in the Philippines. Methods Clinical samples were collectedin 18 barangays endemic for S. japonicum infection in Laoang and Palapag municipalities, Northern Samar, the Philippines, in 2015. The presence of CCA in filter-concentrated urine samples (n = 412) was evaluated using the commercial kits and the results were converted to images, which were further analyzed by ImageJ software to calculate R values. The diagnostic performance of the immunochromatographic POC-CCA test was compared using the Kato-Katz (KK) procedure, in-house enzyme-linked immunosorbent assays (ELISAs) and droplet digital (dd) PCR assays as reference. Results The POC-CCA test was able to detect S. japonicum-infected individuals in the cohort with an eggs per gram of faeces (EPG) more than or equal to 10 with sensitivity/specificity values of 63.3%/93.3%. However, the assay showed an inability to diagnose schistosomiasis japonica infections in all cohort KK-positive individuals, of which the majority had an extremely low egg burden (EPG: 1–9). The prevalence of S. japonicum infection in the total cohort determined by the POC-CCA test was 12.4%, only half of that determined by the KK method (26.2%). When compared with the ELISAs and ddPCR assays as a reference, the POC-CCA assay was further shown to be a test with low sensitivity. Nevertheless, the assay exhibited significant positive correlations with egg burden determined by the KK technique and the target gene copy number index values determined by the ddPCR assays within the entire cohort. Conclusions By using in silico image analysis, the POC-CCA cassette test could be converted to a quantitative assay to avoid reader-variability. Because of its low sensitivity, the commercially available POC-CCA assay had limited potential for determining the status of a S. japonicum infection in the target cohort. The assay should be applied with caution in populations where schistosome parasites (especially S. japonicum) are present at low infection intensity. Graphic abstract

High prevalence of Schistosoma japonicum by perfusion in naturally exposed water buffalo in a region of the Philippines endemic for human schistosomiasis

In the past decade, ecological surveys emphasized rats and dogs as the most significant animal reservoirs for Schistosoma japonicum (S.j) in the Philippines. However, recent studies demonstrated 51–91% prevalence of schistosomiasis among water buffalo using qPCR in the Sj endemic regions in the Philippines. In order to resolve the inconsistency of reported surveys regarding Sj endemicity among carabao, a domestic water buffalo that is the most important draught animal, we introduced 42 schistosome negative water buffalo to Macanip, Jaro municipality, Leyte, the Philippines, a subsistence rice-farming village that has been the focus of schistosomiasis japonica studies of our group for the past 20 years. We conducted perfusion to the remaining 34 buffalo that survived 10 months of nature exposure and Typhoon Haiyan. Thirty-three water buffalo were found to be positive with at least 1 pair of worms from the mesenteric vein. The infection rate is 97%, with the worm burden of 94 (95% confidence interval, 49–138 worms) worms. To our knowledge, this is the first report about S. japonicum worm burden in naturally infected water buffalo in the Philippines. The fact that with less than one-year of exposure, in this human schistosomiasis endemic area, only 1 out of 34 water buffalo was uninfected is striking. Urgent attention is needed for a cost-effective technique for monitoring Sj infection in animals and humans. Meanwhile, intervention implementation, including water buffalo treatment and vaccination, should be taken into consideration.

Schistosome eggs stimulate reactive oxygen species production to enhance M2 macrophage differentiation and promote hepatic pathology in schistosomiasis

Schistosomiasis is a neglected tropical disease of public health concern. The most devastating pathology in schistosomiasis japonica and mansoni is mainly attributed to the egg-induced granulomatous response and secondary fibrosis in host liver, which may lead to portal hypertension or even death of the host. Schistosome eggs induce M2 macrophages-rich granulomas and these M2 macrophages play critical roles in the maintenance of granuloma and subsequent fibrosis. Reactive oxygen species (ROS), which are highly produced by stimulated macrophages during infection and necessary for the differentiation of M2 macrophages, are massively distributed around deposited eggs in the liver. However, whether ROS are induced by schistosome eggs to subsequently promote M2 macrophage differentiation, and the possible underlying mechanisms as well, remain to be clarified during S. japonicum infection. Herein, we observed that extensive expression of ROS in the liver of S. japonicum-infected mice. Injection of ROS inhibitor in infected mice resulted in reduced hepatic granulomatous responses and fibrosis. Further investigations revealed that inhibition of ROS production in S. japonicum-infected mice reduces the differentiation of M2, accompanied by increased M1 macrophage differentiation. Finally, we proved that S. japonicum egg antigens (SEA) induce a high level of ROS production via both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and mitochondria in macrophages. Our study may help to better understand the mechanism of schistosomiasis japonica-induced hepatic pathology and contribute to the development of potential therapeutic strategies by interfering with ROS production.

Cost-effectiveness analysis of the integrated control strategy for schistosomiasis japonica in a lake region of China: a case study

Background Schistosomiasis japonica remains an important public health concern due to its potential to cause severe outcomes and long-term sequelae. An integrated control strategy implemented in the Peoples’ Republic of China has been shown to be effective to control or interrupt the transmission of schistosomiasis. The objective of this study is to estimate the disease burden of schistosomiasis and assess the cost-effectiveness of the integrated control strategy focused on different major interventions at three stages for schistosomiasis control in a lake setting, to provide reference for policy making or planning. Methods Annual cost data of schistosomiasis control during 2009–2019 were obtained from the control program implementers in Jiangling County, Hubei Province, China. Economic costs are provided in constant 2009 Chinese Yuan (CNY). Epidemiological data of schistosomiasis were collected from the Jiangling county station for schistosomiasis control. Disease burden of schistosomiasis was assessed by calculating years of life lost (YLLs) owing to premature death, years lived with disability (YLDs) and disability-adjusted life years (DALYs). DALYs were calculated as the sum of YLLs and YLDs. We then conducted a rudimentary cost-effectiveness analysis by determining the ratio by dividing the difference between the average cost of integrated control strategy at transmission control (2013–2016) or transmission interruption (2017–2019) and the average cost at stage of infection control (2009–2012) with the difference between the DALYs of schistosomiasis at different control stages. Descriptive statistics on the costs and DALYs were used in the analysis. Results The total economic costs for schistosomiasis control in Jiangling County from 2009 to 2019 were approximately CNY 606.88 million. The average annual economic costs for schistosomiasis prevention and control at stages of infection control (2009–2012), transmission control (2013–2016), and transmission interruption (2017–2019) were approximately CNY 41.98 million, CNY 90.19 million and CNY 26.06 million respectively. The overall disease burden caused by schistosomiasis presented a downward trend. Meanwhile, the disease burden of advanced cases showed an upward trend with the DALY increased from 943.72 to 1031.59 person-years. Most disease burden occurred in the age group over 45 years old (especially the elderly over 60 years old). Taking the infection control stage as the control, the incremental cost-effectiveness ratio of integrated control strategy was CNY 8505.5 per case averted, CNY 60 131.6 per DALY decreased at transmission control stage and CNY −2217.6 per case averted, CNY −18 116.0 per DALY decreased at transmission interruption stage. Conclusions The disease burden of schistosomiasis decreased significantly with the implementation of the integrated prevention and control strategy. Surveillance and management on elder population should be strengthened to decrease diseases burden. There remains a need for well-conducted studies that examine the long-term cost-effectiveness of the integrated control strategy for schistosomiasis. Graphic Abstarct