Schistosoma mansoni -related periportal brosis; are APRI and PSDR levels of any potential utility in a well-timed selection of patients for targeted endoscopy in a resource-limited setting?: a case-control clinic-based study

Background Schistosoma mansoni related hepatic brosis is usually associated with hemodynamic alteration with increased mortality due to bleeding varices. The diagnosis of varices before bleeding imposes a big challenge in resource-limited countries using endoscopy. Published evidence on the utility of non-invasive clinical tools in predicting the presence of varices among patients with S. mansoni related periportal brosis is still inadequate including APRI and PSDR levels. This study describes the determinants of portal varices and assesses the potential utility of the APRI and PSDR level in the discrimination of portal varices among patients with S. mansoni related periportal brosis. Methods All patients with periportal brosis were cross-sectionally assessed for the presence of esophageal varices at Bugando medical centre, in Mwanza Tanzania. Socio-demographic, laboratory and ultrasound data were collected for analysis using STATA 13. The prevalence of varices and associated factors were determined, and the sensitivity and specicity of independent factors were assessed to determine their utility in discriminating presence of varices in patients with PPF. Results In total, 250 patients were included in this study, 109 (43.6%; 95%CI: 37.3-.49.9) of them had varices. On multivariate analysis the odds of having varices were independently increased among patients with higher median APRI levels, (1.51; vs. 0.9; AOR: 5.6; 95%CI: 3.1-10.1; p=<0.001) and PSDR levels that were lower than 5700 (AOR: 3.9; 95%CI: 2.0-7.6; p<0.001. Both APRI and PSDR levels had signicantly high sensitivity and specicity in predicting the presence of esophageal varices. Conclusions This study indicates that varices are a common encounter among patients with S. mansoni related periportal brosis and it is independently associated with higher median APRI and lower PSDR levels suggesting that these tools are potential discriminators of varices in this subgroup of patients. The reproducibility of these results should further be assessed longitudinally as potential non-invasive tools


Abstract
Background Schistosoma mansoni related hepatic brosis is usually associated with hemodynamic alteration with increased mortality due to bleeding varices. The diagnosis of varices before bleeding imposes a big challenge in resource-limited countries using endoscopy. Published evidence on the utility of non-invasive clinical tools in predicting the presence of varices among patients with S. mansoni related periportal brosis is still inadequate including APRI and PSDR levels. This study describes the determinants of portal varices and assesses the potential utility of the APRI and PSDR level in the discrimination of portal varices among patients with S. mansoni related periportal brosis.
Methods All patients with periportal brosis were cross-sectionally assessed for the presence of esophageal varices at Bugando medical centre, in Mwanza Tanzania. Socio-demographic, laboratory and ultrasound data were collected for analysis using STATA 13. The prevalence of varices and associated factors were determined, and the sensitivity and speci city of independent factors were assessed to determine their utility in discriminating presence of varices in patients with PPF.
Conclusions This study indicates that varices are a common encounter among patients with S. mansoni related periportal brosis and it is independently associated with higher median APRI and lower PSDR levels suggesting that these tools are potential discriminators of varices in this subgroup of patients. The reproducibility of these results should further be assessed longitudinally as potential non-invasive tools in selecting patients at high risk of having esophageal varices who could bene t from the targeted endoscopic intervention in a resource-limited setting like ours.

Background
Chronic Schistosoma mansoni infection is a common cause of morbidity and mortality in resourcelimited setting where its transmission is ongoing. While 91.0% of the world's Schistosoma burden is found in Sub Saharan Africa (SSA), more than54 million people are infected with S. mansoni in this region [1]. Morbidity reports indicate that over 20 million people are chronically infected and S. mansoni related periportal brosis is reportedly the commonest and the most serious complication of chronic Schistosoma mansoni infection with high morbidity and mortality [2,3].
About 0.2 million deaths are reported annually in SSA due to complications of chronic S. mansoni infection. Heavy periportal oviposition occurs in S. mansoni infection with intense granuloma formation that ultimately graduates into periportal brosis (PPF), portal hypertension and formation of esophageal varices [4,5]. Field-based studies indicate that close to 50.0% of people who are chronically infected with S. mansoni have periportal brosis and in the hospital setting more than 70.0% of patients with periportal brosis have been found to have attendant portal varices [6][7][8].
However, these patients are often diagnosed late already with fatal bleeding varices, with mortality which may be as high as 29.0% even with the best available care [9,10]. This is partly due to limited access to upper digestive endoscopy as a gold standard diagnostic modality in the most resource-limited setting.
Endoscopy is of maximal advantage when it is well-timed before incident bleeding [11] which would enable early identi cation of patients who could bene t from preventive treatment against bleeding varices and hence scale down the magnitude of subsequent mortality.
The formation of varices is linearly related to brosis and splenic size; but also inversely related to thrombocyte levels among others [12][13][14][15]. Out of these tests that are used in daily clinical practice some non-invasive tools have been developed including Alanine aminotransferase (AST) to platelet count (PTC) ratio index (APRI) and Platelet to splenic diameter ration (PSDR) levels. The APRI levels have been used to assess the severity of brosis in patients with PPF with excellent sonographic and histological correlation [16,17], however, there is still a paucity of studies describing the utility APRI levels in the prediction of varices in patients with periportal brosis. The data on the use of PSDR levels in discriminating presence of portal varices among patients with periportal brosis is also still scarce as compared to patients with liver cirrhosis [12,13,18].
This study was designed to assess the utility of the APRI and PSDR levels in the prediction of varices among patients with periportal brosis in a Schistosoma endemic area of Tanzania. This information is clinically important in maximizing the sorting-out patients at high risk of having varices and who could bene t from further interventions to mitigate the impact of late diagnosis.

Material And Methods
A cross-sectional study using retrospective data was done among patients with PPF between 2015 and 2019 at Bugando Medical Centre (BMC). The diagnosis of PPF was made sonographically as done previously [19] and details regarding portal vein diameter (PVD), splenic diameters (SPD) and the presence of ascites were documented. The participants also underwent a test for active S. mansoni infection either by Urine Circulating Cathodic Antigen (CCA) or stool Kato Katz (KK). Hepatitis B surface antigen (HBsAg), liver injury (AST and ALT), and Complete blood count (CBC) was also done among others. Finally, all patients underwent upper digestive endoscopy to assess the presence of esophageal varices and all patients received praziquantel (PZQ) twice a year; propranolol was added if they had small varices and band ligation for those with large varices.
A minimum sample size of 207 patients was estimated from the Lisle-Kish formula for cross-sectional studies, assuming 16.0% of patients with PPF had varices [20] with an allowable error of 0.05 at 95%con dence interval (CI). Eligible patients with PPF were serially recorded in a special gastroenterology registry. The patients' les were reviewed, and socio-demographic information, clinical presentation like abdominal distension, hematemesis, and melaena, ultrasound (UTS) details including SPD, PVD, and ascites; test results for Schistosoma mansoni, CBC, AST, ALT, serum Albumin (ALB) and upper digestive endoscopy results were extracted for analysis.
Data were computerized using Epi data version 3.1 and STATA version 13 (Stata Corp LP, college station, TX) was used for analysis. Continuous variables were summarized as medians with interquartile range (IQR) and categorical variables as proportions with percentages. AST to platelet count (PTC) ratio index (APRI) and Platelet (PTC) to splenic diameter (SPD) were calculated as done previously [21,22]. The presence of varices was noted and expressed as a percentage with 95% Con dence Interval (CI) and its correlates were assessed. Based on earlier data and our own experience, socio-demographic factors, level of brosis (APRI values), markers of decompensation (ascites, serum albumin) and platelet to splenic diameter ration (PSDR) [4,12,13,[23][24][25] were assessed for the association. The odds ratio (OR) with 95%CI was calculated by logistic regression to assess the degree of association between the various factors and the presence of esophageal varices.
Factors with p < 0.2 on the univariate model were included in the multivariate model and the level of signi cance was set at p < 0.05. The goodness of t for the nal model was assessed subsequently [26].
The sensitivity and speci city of independent factors in the nal model were also assessed to determine their discriminative ability. The Receiver Operating Characteristic (ROC) curves were used according to Hanley and McNeil's method to determine the cut points with the best sensitivity and speci city for continuous variables which were reported as proportions with 95%CI [27].

Ethical Clearance
The permission to conduct and publish the ndings from this study was sought from the Catholic University of Health And Allied Sciences (CUHAS)/BMC joint ethical committee with an ethical clearance certi cate number 907/2019. The patients' information was handled by the researcher alone and their identi ers including names and registration numbers were not included in the nal analysis to further conserve con dentiality.

Results
General study characteristics among 250 participants with periportal brosis   (Table 2) where patients with esophageal varices were more likely to have higher APRI levels (Fig. 1&3) as compared to their variceal negative counterparts. The PSDR levels, on the other hand, were inversely related to the presence of portal varices (Fig. 2&3). On the multivariate model the odds of having varices were independently increased among patients with higher median APRI levels, (1.51; vs. 0.9; AOR: 5.6; 95%CI: 3.1-10.1; p = < 0.001) and PSDR levels that were lower than 5700 (AOR: 3.9; 95%CI: 2.0-7.6; p < 0.001). Actives S. mansoni and having ascites had a non-signi cant positive association with the presence of varices with P > 0.05 (Table 3).   The assessment for the good of tness of the nal model did not demonstrate any gross lack of t (Area under ROC curve: 0.8585; p = 0.314) (Fig. 4). The assessment for discriminative ability indicated that higher APRI levels, (cut point:  (Table 4).

Discussion
The objective of this study was to determine the prevalence and correlates esophageal varices and assess its potential discriminators among patients with S. mansoni related periportal brosis. In this study, a total of 109 (43.6%) participants with periportal brosis were found to have esophageal varices, which were more likely to occur among patients with higher median APRI levels and those with PSDR levels lower than 5700. The APRI and PSDR levels were both signi cantly sensitive and speci c in predicting the presence of esophageal varices in this subgroup of patients.
The prevalence of varices in this study is similar to an earlier report of 45.0% from Uganda [28] and 47.0% reported from Sudan [29]. On the contrary, the prevalence of varices in this study is lower than what was reported earlier in Sudan, (43.6% vs. 67.0%) [30] and Saudi, (43.6% vs. 72.0%) among patients with PPF [8]. However, the current prevalence is higher than the prevalence of 16.0% reported recently from Sudan [20]. The differences in the prevalence of varices in these studies could partly be due to the difference in the severity of liver brosis among studied participants since portal varices have been reported to have a linear relation with brosis level [14].
In this study, age, alcohol use, active S. mansoni, presence of ascites, APRI and PSDR levels were assessed for their independent association with esophageal varices in the nal model, and the prediction ability of factors with the independent association was further determined by calculating their sensitivity and speci city. Active S. mansoni was previously reported to have an independent association with the presence of varices in a study done by Awilly et al. among patients with upper digestive tract bleeding [31]. In our study, the presence of active S. mansoni infection had only a non-signi cant positive correlation with the presence of varices, (AOR: 2.7; IQR: 0.9-7.7; P = 0.074).
A positive correlation between the presence of portal varices and advanced brosis by ultrasound has been described previously [4,32,33], in turn, some studies have reported a positive correlation between liver brosis determined by ultrasound with the APRI levels [16,34]. The current nding that the portal varices in patients with PPF were independently common in patients with higher median APRI levels suggest that APRI levels can be used to select patients at high risk of having varices in areas with limited services. This correlation suggests that varices develop in advanced PPF which in turn is associated with liver dysfunction and reduced thrombocyte count [35][36][37]. In the current study, we similarly observed a signi cant proportion of patients with elevated serum aspartate aminotransferase levels (ALT) and thrombocytopenia as summarized in Table 1.
A combination of AST and PTC into the APRI score in this study has suggested that besides the prediction of brosis severity [16,34], this noninvasive tool can potentially be used in discriminating the presence of varices among patients with PPF. In this study, APRI levels had a sensitivity and speci city of 82.5 and 80.1% respectively at a cut point of 1 The current study is liable to some limitations; including the fact that this is a single-center study, its results may not be generalizable. But also there was no report of brosis grading by ultrasound as done in other studies. Being a cross-sectional study the temporal relationship between the outcome and exposure variables is di cult to ascertain. However, even with these limitations, the ndings from this study are still important, especially in resource-limited settings where the burden of Schistosoma related morbidity is high with serious resource restriction. The current results suggest that these tools may potentially be useful in the selection of patients at high risk of having varices for targeted endoscopic intervention in resource-limited settings. Longitudinal studies to further assess the performance of these tools with larger sample sizes are warranted. Authors' contributions DWG, HDM& SBK: participated in designing of the study; EFM, PMM& DCM; acquired the data; DWG& BRK: did data analysis and interpretation; DWG: did manuscript drafting. All the authors signi cantly reviewed the manuscript for its intellectual content and agreed on the nal version.