Schistosomiasis, Upper Gastrointestinal Bleeding, and Health Related Quality of Life Measurements in Rural Africa

Introduction Health related quality of life (HRQOL) measurements, which include disability weights, are important endpoints of health care delivery. These measurements are scarce for patients with upper gastrointestinal bleeding (UGIB) in rural sub-Saharan Africa (SSA) where schistosomiasis is endemic. Methods and materials In 2014, we studied HRQOL measurements among patients with UGIB in SSA where schistosomiasis is endemic. Participants included adult inpatients and outpatients with a history of UGIB at a primary health facility. We measured HRQOL using the EuroQoL 5-dimension (EQ-VAS/EQ5D) instrument and derived disability weights from EQ-VAS and EQ5D measurements. We proled each participant’s medical history, physical examination, laboratory tests, imaging, and endoscopy ndings. These were summarized through descriptive and inferential statistics. derived disability weights [F(4,100)=9.35, p<0.0000,R-squared =0.27] and EQ5D derived disability weights [F(4,100)=23.24, p<0.0000, R-squared =0.44]. Within these models, all four factors were signicantly predicted higher disability weights, P-value <0.05. Conclusions In our study, older age, female gender, those with ascites or acute UGIB had the highest disability weights, and the greatest probability of having higher disability weights among patients with a history of UGIB where schistosomiasis is endemic. These ndings are unique and improve the denitions of different health states among patients with UGIB and schistosomiasis.


Introduction
Upper gastrointestinal bleeding (UGIB) is a frequent cause of hospitalization and death in sub-Saharan Africa where S.mansoni is endemic. It often results in bleeding varices than bleeding peptic ulcer disease. The main causes of varices in sub-Saharan Africa include periportal brosis due to S.mansoni infection and liver cirrhosis (hepatitis B/C and alcoholic liver disease) [1][2][3][4]. Upper gastrointestinal bleeding among patients with varices is a medical emergency that usually presents with hematemesis, melena, hypotension, severe anemia, and sometimes recurrent variceal hemorrhage [5]. In chronic schistosomiasis, recurrent variceal hemorrhage usually occurs within 6 weeks of hospitalization after the initial episode of Page 3/22 acute variceal hemorrhage and is associated with a high risk of death. It is shown one out of ten persons with UGIB due to chronic schistosomiasis will die within 6 weeks of acute variceal hemorrhage and 3 out of 10 persons will re-bleed over the same period [6]. Early diagnosis and appropriate preventive therapy are therefore recommended for those who experience variceal UGIB due to schistosomiasis. This has been shown to mitigate disease progression, prevent new acute episodes of UGIB, and decrease hospital admissions [7][8][9]. However, the impact of these interventions remains elusive due to the paucity of baseline or follow-up data on measures of health-related quality of life (HRQOL) from this patient population. Health related quality of life measurements are important endpoints of health care delivery.
Health related quality of life measurements are surrogate markers of disability or health loss or disease impact, and can be used to evaluate treatment response [10,11].
Few studies from brazil and china have described health losses among patients with chronic schistosomiasis. These studies showed increased disability among those with severe periportal brosis or advanced disease [7,12,13].
On the other hand, data about health-related quality of life measurements about chronic schistosomiasis and/or related complications like UGIB and ascites is scarce [14]. We studied health related quality of life measurements among patients with UGIB at a rural primary health facility in sub-Saharan Africa where S. mansoni is endemic.

Materials And Methods
This was a cross sectional study that involved individuals attending the outpatient department (OPD) of Pakwach health centre IV and inpatients admitted with acute severe UGIB at the same health facility. Pakwach health centre is a rural primary health care facility located at the banks of the Albert Nile in a region that is a hot spot for S.mansoni infection. Pakwach health centre provides outpatient and inpatient health care services to a population who are mainly sherpersons and/or farmers. Epidemiological data suggest close to 50% of the populations served by this facility are actively infected with S.mansoni despite over a decade of Praziquantel chemotherapy. Medical records from the facility indicated about 120 patients every year are admitted for acute UGIB attributable to chronic schistosomiasis. Eligibility for study participation included written informed consent and ascent, all patients ≥ 12 years of age with a medical history of UGIB (past or current). We excluded pregnant women, HIV positive individuals, and any participant unable to have endoscopy for UGIB. Upper gastrointestinal bleeding was de ned by any lifetime history of hematemesis, melena, or hematochezia.
Participants at the OPD were systematically enrolled while inpatients were consecutively recruited over 6 weeks. A detailed medical history that included socio-demographic data, exposure to schistosoma species or alcohol, treatment of schistosomiasis and time from the last treatment, history of UGIB, and other relevant past medical history. Participants were examined for stigmata of chronic liver disease, and vital signs [15,16].
Measures of health-related quality of life were obtained using the three-level European Quality of Life 5-Dimensions (EQ-5D-Y) questionnaire and the visual analogue scale (EQ-VAS) from the EuroQol Group (EQ-5D™).
The EQ-5D-Y is a multi-attribute utility instrument. The EQ-5D represents measures of personal well-being. It has 5 dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is scored as three levels: no problems (level 1), some problems (level 2), and extreme problems (level 3). The EQ-5D data was converted into an index of health (EQ5D index) using crosswalk values from Zimbabwe. The index represents a measure of health from 0 for death to 1 for perfect health. The EQ-VAS is a scale that varies from 0, the worst imaginable health state, to 100, the best imaginable health state. The EQ-VAS asks patients to indicate their overall health on a vertical visual analogue scale( 0 to 100).
The EQ-VAS and EQ5D index were then transformed to disability weights (DW) by the formulas [ EQVAS-DW = 1-(VAS/100)] and [EQ5D index -DW = 1-EQ5D index] respectively. A disability weight is a weight factor that re ects the severity of the disease on a scale from 0 (perfect health) to 1 (equivalent to death).
Disability weights characterize the amount of health loss associated with speci c health outcomes, and are used to calculate years lived with disability [12,[17][18][19].
Blood was analyzed generating 3-part hematology indices (using a compact Sysmex KX-21 hematology analyzer), hepatitis B and C viral blood serology results (obtained from commercially available rapid diagnostic test kits), and malaria antigen test results (from rapid diagnostic test kits). Stool microscopy was performed for ova and urine for schistosomiasis using the urine circulating cathodic antigen (CCA) test by Rapid diagnostics. Trans-abdominal ultrasonography performed by a trained sonographer according to the modi ed World Health Organization Niamey protocol using the SONOSTAR model SS8, a portable ultrasound with a 3.5 MHz convex probe. Upper digestive endoscopy was performed using a Pentax EPKi digital video processor and a Pentax 9.8 mm video gastroscope after a local anesthetic (Xylocaine spray) by a gastroenterologist.
Data was transcribed from questionnaires and later entered into a Microsoft Access database. This was edited to ensure quality and exported to Stata version 16 (STATA Corp, Lakeway, College Station, Texas, USA). Descriptive and inferential statistics were generated describing the study population and measures of HRQOL (EQVAS, EQ5D, EQ5D index, EQVAS-DW, and EQ5D index-DW), and factors associated with EQVAS-DW, and EQ5D index-DW. Other variables were designated covariates. Categorical data were summarized as proportions with standard errors (95% con dence intervals). Continuous data were summarized as means, medians, standard deviations (SD), and 95% con dence intervals. However, interquartile ranges were also generated for some medians. We generated a number of linear regression models describing the association between potential independent variables and the two separate dependent outcomes (EQVAS-DW and EQ5D index-DW). Selection of appropriate covariates and the best model was guided by background knowledge, signi cance criterion, information criteria, and penalized likelihood methods in Stata. We presented standardized beta coe cients for the best models with their standard errors and p-values. These were reported as percentage points ( percentage points = beta coe cient x 100). A signi cance level (p-value < 0.05) was considered, and con dence intervals or standard errors supported inference. These results were summarized as text, in tables, and as gures.

Ethics statement
This was a routine cross-sectional study that involved human participants. It was approved by School of Medicine, Makerere University, Institutional review board, Kampala, Uganda (#REC REF2011-244), and the Uganda National Council for Science and Technology, Kampala, Uganda (UNCST approval #, HS 1620).
The study was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from all participants.

Results
The study was conducted over 6 weeks between the months of July and August 2014.
All participants had a past or current medical history of UGIB. One fth (23 participants out of 107 enrolled) presented as medical emergencies and were admitted with acute severe upper gastrointestinal bleeding over the study period. We screened 324 at the outpatient's department over the same period and were able to enroll 84 patients with a past medical history of UGIB. The youngest was 25 years and the oldest 71 years. The median age was 45 years, interquartile range of 13 years. The female-male ratio was 3 to 2. Most participants were long-term residents of Pakwach. All participants had frequent contact with the waters of the Nile and nearly all were either sherpersons or farmers by occupation. Among our participants, 54% had a prior diagnosis of intestinal schistosomiasis, 88% had ever received Praziquantel in the past, 8% had active infection at the time of enrolment, 90% had splenomegaly on physical exam, and 96% had periportal brosis and/or cirrhosis at ultrasonography. All reported experiencing UGIB with 96% reporting at least one lifetime episode of hematemesis, and 96% reporting a past admission for UGIB. No participant has ever had an endoscopy for UGIB nor was on propranolol for prevention of recurrent variceal bleeding. Endoscopy was performed on all 107 participants during the study. Following endoscopy, we found 86 had varices, 8 had both varices and peptic ulcers, and 21 had peptic ulcers alone.

EQ5D-Y, EQ-VAS, and derived disability weights
Measures of the 5 dimensions of health revealed 80(76%) participants had some or extreme problems in self-care, 92(88%) participants reported some or extreme anxiety or depression, and 93(89%) participants reported experiencing some or extreme pain or discomfort. Only 39(37%) participants reported some or extreme problems in their mobility. However, 48(46%) participants were able to undertake their usual activities without any problems, Fig. 1.
The median health index for 105 available participant records was 0.66 with IQR = 0.102 and the mean index was 0.62, SD = 21. The median visual analogue score (VAS) was for 105 available participants, Multiple regression of factors associated with EQVAS-DW and EQ5D index-DW) Multiple linear regression revealed age, female gender, ascites, and acute UGIB predicted EQ-VAS derived disability weights [F(4,100) = 9.35, p < 0.0000,R-squared = 0.27] and EQ5D derived disability weights [F(4,100) = 23.24, p < 0.0000, R-squared = 0.44]. Within these two best models, all ve factors were signi cantly associated with higher disability weights, Table 3. Put simply, the probability of having a higher EQ5D-DW was increased by 0.5 percentage points for every year lived, 12 percentage points if one was female, 13 percentage points if diagnosed with ascites, and 13 percentage points if one experienced acute UGIB. While the probability of having a higher EQVAS-DW was increased by 0.4 percentage points for every year lived, 7 percentage points if one was female, 15 percentage points if diagnosed with ascites on ultrasound, and 28 percentage points if one experienced acute UGIB, Table 3. *-spleen could not be palpated because of tense ascites for 5 participants.
** ultrasound evaluation could not be completed because of tense ascites for 2 participants.
# Stool was not performed for 1 participant.

Discussion
Our study assessed health-related quality of life measures among adult patients with UGIB at a rural primary health care facility in sub-Saharan Africa where S.mansoni is endemic. To the best of our knowledge, no other study has described similar ndings from rural sub-Saharan Africa. Our study participants were at the highest risk of schistosomiasis because of frequent contact with the waters of the River Nile. Ninety seven percent had moderate to severe periportal brosis, 90% had splenomegaly, and 80% varices. This clinical pro le is in keeping with a diagnosis of hepatosplenic schistosomiasis [20].
The differential diagnosis of such a pro le is liver cirrhosis. This was less likely because of the low prevalence of alcohol misuse and viral hepatitis B or C infections. We also found a low prevalence of stigmata of chronic liver disease including ascites, hepatic encephalopathy, and jaundice. These stigmata are more frequent in liver cirrhosis than hepatosplenic schistosomiasis [21]. Peptic ulcer disease was infrequent and was less likely to be the cause of UGIB among our participants.
Prior to enrollment, none of our participants had endoscopy and no participant with varices was on propranolol for prevention of recurrent variceal bleeding. Current care guides recommend endoscopy for all with UGIB and/or propranolol for those with UGIB and varices [22][23][24].
Evaluation on EQ-5D primary data showed our participants reported more problems in all the ve measured health domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) than one comparable HRQOL study on hepatic schistosomiasis from brazil. In addition, the mean and median VAS score from our study were also lower than the same HRQOL study from brazil [7]. These differences were greatest for the domains of welfare and anxiety/depression. We think this could be explained by population differences in disease severity (all our participants experienced UGIB, which is considered a severe disease) or differences in quality of health care services between the two study populations. On the other hand, our EQ-5D estimates (index and VAS) are similar to what has been reported by a systematic review on health state estimates among patients with advanced chronic liver disease [25]. This upholds our earlier assertion that our participants had severe liver disease.
From the transformed EQ-VAS and EQ5D index measurements, the average disability weights in our study population were found to be between 0.3 to 0.43. Average disability weights for hematemesis alone were between 0.20-0.44. These are similar to what has been published by the "Global Burden of Disease Study 2017" that reported disability weights of between 0.21 to 0.46 for hematemesis and schistosomiasis [26,27]. Other disability weights reported by the same study, "ascites and schistosomiasis" and "anemia and schistosomiases" were 4 to 5 times lower than what we found. On the other hand, the "Global Burden of Disease Study 2017" did not provide disability weights for acute UGIB.
Simply put, our nding supports the ongoing argument that the "Global Burden of Disease Study 2017" probably underestimated the health impact of schistosomiasis [14].
The highest disability weights in our study were found among those who had all the three symptoms of UGIB (hematemesis, melena, and hematochezia) at enrollment, acute UGIB, acute UGIB with varices, ascites, and edema. We determined from multivariable analysis that older age, female sex, ascites, and acute UGIB were associated with the greatest probability of higher disability weights among those with UGIB and schistosomiasis. Similar ndings have been reported by researchers from brazil and china for the factors age, female sex, and ascites [7,12]. To the best of our knowledge, no study has directly linked the occurrence of acute UGIB and schistosomiasis to higher disability. What is known is that acute UGIB is the main reason for hospitalization and death among patients with schistosomiasis due to S.mansoni [3,4,28,29]. It therefore stands to reason that preventing acute UGIB could probably decrease health loss in this population [8]. In the same way, addressing ascites in this population could also decrease health loss. This assertion is supported by published research which shows many acute illnesses requiring hospitalization are usually associated with increased disability. Preventing hospitalization decreases disability or health loss [30].
Our study has limitations. These are related to our cross-sectional study design, the use of the measurement tool (EuroQol EQ-5D/EQ-VAS), and our relatively small study sample size. Although the EuroQol EQ-5D/ EQ-VAS is a generic tool, its use in schistosomiasis or UGIB worldwide is limited. As such, more studies are required to con rm our ndings.
Nevertheless, our study provides new HRQOL measurements from rural Africa. These measurements are important in de ning the different health states among patients with UGIB and schistosomiasis. The study also provides credible disability weights that are crucial for estimation of the global burden of disease and for health policy.

Conclusions
Adult patients with upper gastrointestinal bleeding from this part of rural Sub-Saharan Africa where S.
mansoni is endemic frequently have varices, portal hypertension, splenomegaly, and ultrasound evidence of liver disease (periportal brosis and/or cirrhosis). Our study participants at this primary health facility experienced poor health. This was suggested by the large proportion of participants admitted (past or present) for UGIB, low health utility estimates, and relatively high disability weights. Older age, female gender, those with ascites or acute UGIB had the highest disability weights, and the greatest probability of having higher disability weights or the lowest health-related quality of life. These ndings are new, unique, and improve the de nitions of different health states among patients with UGIB and schistosomiasis.
Lastly, our ndings highlight the pressing need for primary, secondary, and tertiary prevention of ascites and acute UGIB in this patient population.

Declarations
Consent for publication

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