1. Introduction
Schistosomiasis is a zoonotic parasitic disease that is caused by the trematode flukes of
Schistosoma spp., mainly endemic in 78 countries and territories of Asia, Africa, and South America [
1], which is still one of the most serious global public health problems [
2].
Schistosomiasis japonica is widely distributed in 12 provinces (cities and autonomous regions) in China [
3], posing a serious threat to human health and socio-economic development [
4,
5]. Although schistosomiasis has been in a state of low endemicity in China [
6], new challenges have emerged. Some patients with chronic schistosomiasis who have not received timely and thorough treatment are gradually developing into advanced schistosomiasis [
7,
8]. A total of 30,170 cases of advanced schistosomiasis still exist in China [
9], while some of them are discovered and reported in areas where the transmission of schistosomiasis has been interrupted [
10].
Clinical presentation varies in chronic schistosomiasis cases, but many cases present mild symptoms or an absence of symptoms thus leading to misdiagnosis or a lack of treatment. Advanced schistosomiasis is mainly characterized by liver and spleen lesions, such as periportal hepatic fibrosis, portal hypertension, spleen enlargement, and congestion [
11]. Tissue fibrosis that is caused by egg deposition is the most serious outcome of schistosome infection. The long course of the disease, high treatment costs, and poor prognosis impose huge psychological and economic burdens on patients and their families [
12,
13,
14]. Schistosomiasis is an immune disease, and its pathological basis is the immune response of the host to schistosomes and eggs [
15]. The schistosome eggs that are produced by adult worms in the portal venous system enter the liver with the bloodstream. Due to the large diameter of the eggs, they stay in front of the hepatic sinus to block the blood vessels and release egg antigens to sensitize delayed allergic T-lymphocytes, resulting in delayed sensitization. Allergy-sensitized T-lymphocytes produce a series of lymphokines attracting inflammatory cells (including macrophages, lymphocytes, eosinophils, etc.) to gather around the eggs, causing a series of inflammation to form egg granulomas. In the egg granulomas, macrophages release pro-fibrotic cytokines to activate hepatic stellate cells (HSCs) to transform into myofibroblasts, which produce a large amount of extracellular matrix (ECM) and secrete pro-fibrotic factors [
16,
17,
18], resulting in an imbalance between fiber generation and degradation. Without effective intervention, fibrogenesis progresses further and eventually develops into advanced schistosomiasis. Complete recovery from advanced schistosomiasis is difficult to achieve, therefore, with the increasing disease burden of advanced schistosomiasis cases in the entire schistosomiasis disease spectrum, it is necessary to provide effective preventive strategies for early detection, early diagnosis, and early treatment, which will benefit the control and elimination of schistosomiasis and decrease the burden of the schistosomiasis population. However, few studies that are related to this have been conducted so far.
Currently, the main diagnostic methods for schistosomiasis liver fibrosis are: (1) histological examination, which is a reliable method for diagnosing liver fibrosis, but has great trauma to the tissue, and the sampling site cannot reflect the overall condition of the patient’s liver; (2) imaging methods, ultrasonography is the most widely used method for diagnosing schistosomiasis liver disease or assessing curative effectiveness based on grading of liver fibrosis; (3) detecting biomarkers of serum or plasma, including extracellular matrix components, degradation products, and metabolism of enzymes and cytokines, etc., which is readily assayed and non-invasive [
19,
20], but its specificity needs to be assessed as liver parenchymal damage that is caused by schistosomiasis, chronic hepatitis B, and cirrhosis may lead to abnormal synthesis of coagulation factors, anticoagulant substances, and fibrinolytic substances [
20]. As the liver is the main site for the synthesis of coagulation factors, anticoagulant substances (such as AT-III, PC, PS) and fibrinolytic substances (such as PLG) in the blood, liver parenchymal damage may lead to abnormal synthesis of those factors or substances [
20]. In our previous study, we found that more than 50% of patients with advanced schistosomiasis had abnormal levels of D-dimer in plasma, and there were weak positive correlations between the concentration of D-dimer and the grade of hepatic fibrosis [
21]. The result indicated that some special biomarkers that were detected in peripheral blood might be used for predicting the occurrence of advanced schistosomiasis.
This study was designed to analyze and compare peripheral blood-related metabolic indicators in patients with chronic schistosomiasis and advanced schistosomiasis to select specific predictive diagnostic indicators and establish a Fisher discriminant analysis for advanced Schistosomiasis japonica, to achieve early detection and early intervention, and effectively reduce the new cases of advanced schistosomiasis japonica.
3. Discussion
Schistosomiasis is a serious parasitic disease that is characterized by immunopathological damage. The deposition of eggs in the liver induces an immune response leading to liver inflammation and fibrosis [
22,
23]. If the process of liver fibrosis for patients cannot be effectively controlled, it will develop into advanced schistosomiasis, manifesting portal hypertension, splenomegaly, and complications including hypersplenism, esophageal variceal bleeding, and hepatic encephalopathy, etc. [
4,
13]. Patients may experience physical, psychological, and economic burden due to prolonged and recurrent illness and high treatment costs [
24,
25]. Significant fibrosis is a hallmark of liver disease progression, and early diagnosis guides significance for subsequent clinical treatment decisions. In addition, early and effective intervention for a population that once had chronic schistosomiasis can avoid the occurrence of advanced schistosomiasis, which is not only beneficial to public health service for the residents in endemic areas, but also is of great significance for improving prognosis and survival quality.
A liver biopsy is a special test for diagnosing liver fibrosis, providing auxiliary information for accurate diagnosis and prognosis of liver disease, but its invasiveness makes it limited in clinical applications. In recent years, with the use of non-invasive liver fibrosis markers in the clinical practice, the prediction, and monitoring of chronic liver disease are increasingly independent of liver biopsy. Studies on non-invasive markers of liver fibrosis are seen in other chronic liver diseases. Whereas few studies have been conducted on the diagnosis of hepatic fibrosis in schistosomiasis, it was observed in our follow-up that patients with chronic schistosomiasis could have fibrosis progression after discontinuation of anthelmintic drugs.
In this study, we retrospectively analyzed 36 humoral (serum/plasma) markers and related clinical data of 271 schistosomiasis patients (132 CS cases, 139 AS cases) and found that HGB, MON, GLB, GGT, APTT, VIII, and Fbg were related to fibrosis. The new non-invasive diagnostic function model that we established can predict the possibility of chronic schistosomiasis cases developing into advanced schistosomiasis cases. The model is sufficiently reliable in diagnosing fibrosis and predicting the progression of liver fibrosis.
Previously, it was found that hepatitis B virus infection and schistosomiasis interacted in liver damage [
26]. Recent studies have also shown that there was no significant correlation between HBV infection status and the development of CS to AS (ascites type) [
27], the correlation analysis of this study further showed that HBV infection in CS cases was not an influencing factor in the development of AS.
There are three markers reflecting coagulation function in the FDA model that was constructed from seven markers in this study. The parasitism and migration of
S. japonicum in the venous system, and the deposition of eggs in liver tissue causes specific pathological reactions in its definitive hosts [
28]. Theoretically, vascular injury first induces a local inflammatory response, followed by an imbalance of the coagulation and fibrinolytic systems, and their interactions ultimately lead to a systemic pathological response in the host. Systemic coagulation, as a follow-up response to inflammation of schistosomes, plays an important role in the compensation of parasitic immunity [
29,
30,
31]. However, to maintain the homeostasis of the blood system, the oversecreted fibrin in coagulation needs to be further degraded by fibrinolytic factors such as plasminogen and plasmin [
32]. Previous studies have reported abnormal coagulation function in patients with schistosomiasis, especially in patients with advanced schistosomiasis [
29,
30,
31,
32]. If the coagulation and anticoagulation systems, as well as the fibrinolytic and antifibrinolytic systems are balanced, a hypercoagulable state or bleeding tendency may occur, with elevations of VIII mainly seen in hypercoagulable states and thrombotic diseases [
33,
34,
35], this may be due to the deposition of a large number of eggs in the mesenteric blood vessels after infection with schistosomes, and the egg antigen stimulates the blood vessel wall and activates the coagulation system. Currently, there are no clinically useful serum biomarkers or assays to assess fibrosis in patients with advanced schistosomiasis. APTT-activated partial thromboplastin time, Fbg fibrinogen, and factor VIII activity may be good candidates.
In summary, we found that the discriminant function that was established by the use of body fluid (serum/plasma) markers can effectively warn the occurrence of AS. FDA is a reliable prediction model with strong practicability. It plays an important guiding role in effectively controlling the occurrence of AS and lays a solid foundation for achieving the goal of schistosomiasis elimination. We will further carry out early treatment intervention for CS patients who may develop into AS cases, and establish the best treatment strategy for patients with chronic schistosomiasis to effectively prevent the development of AS.
Being an exploratory study with a small sample size, the participants in our study were selected from different schistosomiasis endemic counties (cities, districts) of Jiangxi province which might present a certain representativeness. In addition, a series of independent comparisons were conducted in our study which might increase the statistical error. Thus, further study that is based on an increased sample size or random sampling strategy should be conducted to verify the results that were explored in our study.