Association between Schistosomiasis Mansoni and Hepatitis C: Systematic Review

Associação entre esquistossomose mansônica e hepatite C: revisão sistemática ABSTRACT OBJECTIVE: To perform a systematic review of the prevalence of the HCV/S. mansoni co-infection and associated factors in Schistosoma mansoni-infected populations. METHODS: The bibliographic search was carried out using the Medline, Lilacs, SciELO, Cochrane Library and Ibecs databases. The criteria for the studies' selection and the extraction data were based on systematic review methods. Forty fi ve studies were found, with nine being excluded in a fi rst screening. Thirteen articles were used for data extraction. RESULTS: The HCV infection rates in schistosomiasis populations range from 1% in Ethiopia to 50% in Egypt. Several studies had poorly defi ned methodologies, even in areas characterized by an association between hepatitis C and schistosomiasis, such as Brazil and Egypt, which meant conclusions were inconsistent. HCV infection rates in schistosomotic populations were heterogeneous and risk factors for acquiring the virus varied widely. CONCLUSIONS: Despite the limitations, this review may help to identify regions with higher rates of hepatitis C and schistosomiasis association. However, more studies are necessary for the development of public health policies on prevention and control of both diseases.

Schistosomiasis is the second most important parasitic infection after malaria and affects more than 200 million people in 74 countries. 56a In this country, six to eight million people are infected with Schistosoma mansoni and about 30 million people live under risk of infection.a The prevalence of Schistosomiasis mansoni (SM) can reach up to 27% of the population in some areas of Northeastern Brazil, 38 turning this country into a major schistosomiasis endemic area in the world.
The diverse clinical patterns observed for this disease depend on many factors, including parasite strain, host genetic background, host nutritional RESUMO OBJETIVO: Realizar revisão sistemática sobre a prevalência da confecção do vírus da hepatite C e Schistosoma mansoni e os fatores de risco associados a indivíduos com esquistossomose.

INTRODUÇÃO
and immunological state, and co-infections. 9,10,16,31,35chistosomiasis may progress to the most advanced stage of disease, the hepatosplenic form (HS).This clinical form is observed in endemic areas and is characterized by portal hypertension that may cause digestive hemorrhage. 28,42,48When SM comes combined with other hepatic disease, especially the Hepatitis C Virus (HCV) infection, the progression of hepatic fi brosis into cirrhosis and hepatocellular carcinoma (HCC) can occur within a few years. 29,40oncomitant SM and HCV infection is observed with high frequency in Egypt 2,7,47 and Brazil. 39patitis C is also considered an important public health issue throughout the world, with approximately 3% of people (about 170 million) being infected with the HCV. 1,2 United Kingdom and USA, 5,41,53,54 and in developing countries, such as Egypt 2,25,26 and Brazil. 6,39,45 Egypt, eight to ten million are infected and 68 million people have been exposed to HCV 52 (a prevalence of 10 to 60%), mainly in rural areas. 15,17,21The prevalence of HCV infection is lower in Brazil than in Egypt and varies from 2.5% to 4.9%, corresponding to approximately 3.9 to 7.6 million people. 11V may be implicated as a factor infl uencing the severity of schistosomiasis in developing countries.Likewise, an infl uence of SM on HCV severity has been suggested by some authors. 29,33,39ere are many contradictory data about the prevalence of HCV/S.mansoni co-infection in SM endemic areas and the risk factors associated with increased susceptibility for HCV infection in a S. mansoni-infected person, especially in the HS form. 2,4,7,49e worldwide relevance of the hepatitis C and schistosomiasis association as a public health issue is mainly due to the severe clinical patterns and high morbidity associated with it, especially in developing countries.This study aimed to perform a systematic review of the prevalence of the HCV/S.mansoni co-infection in SM-infected population living in endemic areas and associated factors.

METHODS
The bibliographic search was performed through a systematic search covering the 1990s and up to May 2011.The terms "Schistosomiasis mansoni" and "Hepatitis C" were utilized to search the Medline, Lilacs, SciELO, Cochrane Library and IBECS databases.These databases fulfi ll the minimum criteria search to conduct a systematic review, in accordance with the literature. 22 1 did not discuss risk factors for acquire HCV infection 1 2 did not measure the prevalence of co-infection 25,34 In 1, the age of the majority subjects enrolled was less than 18 years old 49 4 used the serologic method for evaluate the S. mansoni infection 3,20,24,51 1 was a thesis resume 50 9 articles were excluded: Forty-five publications were obtained through the website search described and a fi rst screening was performed.The criteria adopted for inclusion were: • Studies in scientifi c article formats published on or after 1989, the year in which HCV was discovered; • Titles published in English, Spanish or Portuguese with available abstracts; • Studies performed with human populations.
Nine studies were excluded because they utilized experimental models, were presented as thesis or monograph or were redundant in different databases (Figure ).
A second screening was done by analyzing the 36 selected abstracts.Fourteen studies were excluded because they did not contain information about the prevalence of HCV/S.mansoni association or the risk factors associated with HCV infection in a schistosomiasis population (Figure ).
A total of 22 articles were selected for complete reading.This step was carried out by a pair of reviewers where each one, independently, fi lled a table with the criteria relevant to the articles selected for data extraction. 14,22There was no discordance between the two reviewers in regard to the articles selected, with kappa index = 1 (p < 0.05).The inclusion criteria adopted in this step were: • Population: subjects of both sexes infected by S. mansoni and living in endemic areas; • Age group: > 18 years old; • Measurement of HCV/S.mansoni association: studies that described the methods utilized to measure the prevalence of HCV and S. mansoni infections; • Risk factors: studies that reported the risk factors associated with HCV infection and if there is a correlation with schistosomiasis.
Studies that used only serologic methods to evaluate the prevalence of S. mansoni infection were excluded because the distinction between past and present infection is not possible, raising doubts about the confi rmed SM diagnosis. 20 the 22 articles selected for the last step, 13 fi lled all inclusion criteria and offered data required to analyze the prevalence of hepatitis C and schistosomiasis association in SM endemic areas.The exclusion of the nine articles in the last screening are described in Figure . 1,3,20,24,25,34,49-51

RESULTS
Table 1, 2 and 3 list the 13 articles that were analyzed.
The prevalence of HCV/S.mansoni association ranged from 0.8 37 to 50.0% among the studies, with the highest ranges in Egypt (10 to 50%). 2,9,19,29,30ong the 13 articles included in the fi nal step of the review, ten were cross-sectional studies, 8,9,19,29,30,36,37,39,40,45 one was a retrospective cases series, 6 one was a prospective cases series 2 and the other was a cases series with an external control group. 32Five studies 6,32,39,40,45 were conducted in Brazil, fi ve in Egypt, 2,9,19,29,30 two in Sudan, 36,37 one in Ethiopia 8 and one in Kenya. 9A higher prevalence of HCV infection was found in the SM population of Egypt, compared to the other countries (Table 1).
Eight studies 2,6,19,32,36,37,40,45 sought to determine the serologic prevalence of HCV infection in an SM population and one study proposed to verify any epidemiologic relationship of schistosomiasis and HBV and HCV serologic markers. 30Six studies 6,9,29,37,39,40 aimed to evaluate the severity of hepatic lesions and morbidity of hepatitis C when associated with SM and to correlate this with serologic markers.The mean age of humans enrolled in these studies was 33.7 years and in four articles subjects were > 40 years 6,29,32,36 (Table 2).
The inclusion criteria used by the authors to choose subjects with schistosomiasis were mainly: people living in endemic areas with positive parasitological exams confi rmed by the presence of S. mansoni eggs in stool samples or rectal biopsies (eight studies) and/ or ultrasonography (US) compatible with periportal fibrosis (PPF) (six studies).The epidemiological history was considered in seven studies to compose diagnosis when in conjunction with one or both criteria mentioned above.
The main exclusion criteria adopted for the selected studies was if the person did not live at the study site.
People with no history of contaminated water contact and/or with liver disease caused by alcohol consumption, autoimmune disorders or by Hepatitis viruses A, B, D or with others etiologies were also excluded from these studies.Six studies did not mention the exclusion criteria adopted. 2,9,19,30,32,36e most commonly chosen technique of HCV diagnosis was 3 rd generation anti-HCV ELISA, utilized in fi ve studies. 8,9,36,37,45Four other studies utilized 2 nd generation anti-HCV ELISA. 2,19,29,30The quantifi cation of the viral titers was performed by HCV RNA PCR in seven studies. 6,9,29,36,37,39,40x studies made appropriate epidemiologic and statistical analyses to confi rm the correlation between risk factors associated and HCV infection in SM patients. 19,29,32,36,37,40The other articles suggested possible risk factors without any statistical correlation found (Table 3).
Blood transfusion was cited by seven of them as a risk factor for HCV contamination. 2,6,29,32,39,40,45The second most observed risk factor described in three studies was the antischistosomal mass treatment, due to the use of syringes and nosocomial equipments without proper sterilization. 2,19,29Surgical procedures, 19,29 digestive endoscopy, 45 old age, 9,19 genetic background 9 and hemodialysis 2 were also cited as risk factors for HCV acquisition.Four studies did not fi nd any association between SM infection and an increased risk of acquiring HCV. 8,30,36,37

DISCUSSION
Schistosomiasis is an important public health issue associated with poverty and poor sanitary conditions. 13All studies described were conducted in developing countries since the 1970s, especially in Egypt, Sudan, Ethiopia, Kenya and Brazil, confi rming the impact of this disease in these countries. 13The association between schistosomiasis and hepatitis C has been studied by many authors, showing the importance of research into this condition worldwide (Tables 1, 2 and 3).
The majority of articles were cross-sectional studies (Table 1) and aimed to determine the prevalence of HCV infection in a confi rmed SM population.Crosssectional studies are important in identifying regions in developing countries that need more attention from the government authorities for the implementation of public health policies in regards to treatment and control for both hepatitis C and SM.On this point, this review may help to identify regions where the association of these diseases and the risk factors associated with HCV infection are relevant, and to aid the implementation of prevention and control actions.No risk factor 36,a Genotype 4 was the most prevalent in HS patients.The parenteral therapy was not associated with co-infection The HCV prevalence in HS patients is considered low (4.5%) and the genotype 4 is the most common in Sudan.
No risk factor 37,a 91% had SM 11.2% had anti-HCV+, only 2.2% were HCV RNA PCR+ Between 21 and 40 years old, the anti-HCV reactivity was 7.8% HCV infection has low prevalence in Sudan and the anti-SM parenteral therapy cannot be associated with co-infection.
No risk factor 8 65.9% were positive for SM 1.3% subjects with SM were positive for HCV The highest prevalence was found among children It is necessary to integrate helminth control targeting school-aged children to reduce the risk of PPF in future.
Age older 9 Genetic background OPG mean was higher among the Kenyans than Egyptians The PPF pattern was higher among Egyptians Hepatitis C is 3 times more prevalent among Egyptians Geographical differences are observed in relation to PPF patterns among the two populations.HCV is associated with active infection only among Egyptians, who present more severity and morbidity for co-infection.
Blood transfusion 40,a 57% were positive for HBV or HCV or both HCV infection may contribute to severity of liver damage when the subject has the HSS form.
Anti-SM therapy (76%) 29,a Blood transfusion (22.2%)Nosocomial exposure The mortality in group C was 48% after 6 years in comparison with group A (12%) and B (3%).HCC is most frequent in co-infected (33%) patients than mono-infected.Mortality was not affected by age, HCV RNA titer or genotype virus Patients co-infected are characterized by more advanced liver disease, higher HCV RNA titers, predominance of HCV genotype 4, higher infl ammatory activity, incidence of cirrhosis and HCC with much higher mortality rate.
Blood transfusion 6 84.6% of anti-HCV+ had HCV RNA PCR+ with high aminotransferases, more cell decompensation and high rate of chronic hepatitis The rate of hepatitis B and C markers in HSS patients is higher than control group and it is responsible for a high frequency of liver damage.
History of surgeries 19,a Anti-SM parenteral treatment Anti-HCV was positive in 10.3% of subjects and 5% was positive for anti-HBV and anti-HCV Hepatitis B and C are the major public health problems in Egypt.Studies about epidemiology, natural history, risk factors and modes of transmission are necessary.
No signifi cance between groups was found for blood transfusion 39 The HCV prevalence in co-infected group was higher (22%) than in control group (2% A few studies pointed to a correlation between diseases with morbidity patterns, progression of liver damage 29,39 and risk factors 2,6,9,19,29,30,36,37,39,40,45 in acquiring HCV. It could be useful to understand the clinical course of this particular condition and for treatment choices (Tables 2 and 3).When schistosomiasis and hepatitis C association is established, the clinical course develops into severe hepatocellular damage.Viral persistence and hepatic cirrhosis can develop faster than in mono-infected people. 6,29e high percentage of HCV infection in schistosomiasis populations of different countries caught the attention of the scientifi c community for the variable prevalence of disease association rates. 8,19,36,37,40,45The rates ranged from 10 to 50% in Egypt, 2,9,19,29,30 mainly due the mass treatment of the schistosomiasis infected population in the 1970s.This public policy was not adopted in other countries and similar prevalence rates cannot be observed. 8,36,37There is a lack of a relationship between the high prevalence of HCV infection in schistosomiasis endemic areas and risk factors, although many of them were.
Disease association rates in Brazil, although not as high as in Egypt, can be considered relevant due to the high morbidity when HCV is present.When the study was conducted with hospital patients in Brazil, disease association rates were up to 20%. 32,39,40Confl icting results among studies on HCV/S.mansoni association in Brazil, 6,40,45,46,b reinforce the need for further studies of this condition, especially with appropriate methodologies for prevalence and risk factor evaluations.Methodological issues are the main problem of the majority of studies worldwide, suggesting the inadequacy of study designs.
The serologic method was the most commonly used method of evaluating HCV infections, including recently developed techniques adapted from the older versions.The 3 rd generation ELISA is performed by many research groups, since it is a fast and relatively cheap technique. 8,9,36,37,45Some authors reject this method because, in S. mansoni, infection could produce auto-antibodies against HCV epitopes, mimicking HCV infection. 3However, this immunoglobulin (Ig) production is not well defi ned in the literature and the auto-Ig's ratios are low, which can be differentiated from HCV infection by increasing the cut-off point.As for schistosomiasis diagnosis, the method of choice continues being Kato-Katz test, based on the presence of S. mansoni eggs in stool samples or in rectal biopsies, and US patterns to evaluate the periportal fi brosis. 43,55This review confi rms that no signifi cant diagnosis methods have been developed for either disease over the last decades.
The current systematic review also considered risk factors associated with an increased chance of acquiring HCV infection when the subject has SM. 19,29,32,36,37,40hese data may be useful to direct monitoring and treatment campaigns for both diseases and may contribute to lower prevalence and morbidity rates in the future.
Blood transfusion was the risk factor most cited 6,32,39,40,45 in Brazil and the anti-schistosomiasis parenteral mass therapy, 2,19,29 in Egypt.Poorly sterilized syringes and equipment used during these campaigns 21,26 may be the key to increased chances of acquiring HCV.
In the HS schistosomiasis form, common in endemic areas, the subject presents esophageal varices in most cases as a consequence of periportal hypertension and disease severity in SM. 43 Disruption of these veins can cause digestive bleeding and blood transfusion may be required for patient survival.b The serological screening in Brazilian blood banks did not include anti-HCV markers before 1993, in spite of the recent discovery of HCV.Blood transfusion before this year can be considered as a risk factor for HCV acquisition. 12The lack of proper sterilization of equipment and reused syringes during anti-schistosomiasis parenteral mass therapy 21,23 increases the chance of HCV infection in SM patients in Egypt.The causes of HCV infection are different among the countries and in most cases the public policies are adopted as a refl ex.
In most articles, the risk factors were based on patient reports and epidemiological history, without significant statistical analyses.More studies are needed to clarify HCV transmission routes and risk factors for HCV/S.mansoni association.The last study on this issue was published in 2008, pointing to the lack of research in this area.
In conclusion, this revision shows the lack of well-designed studies with appropriate methodology for evaluating the prevalence of this condition in areas of endemic schistosomiasis.Despite the limitations of this study, the results may help to identify regions with higher HCV/S.mansoni association rates.New public health policies attempting to reduce the current high prevalence and morbidity rates observed in hepatitis C and schistosomiasis could be proposed, especially in SM endemic regions.

Figure .
Figure.Flowchart of the systematic review results of selected publications.
It is also the most important cause of liver disease and HCC in developed countries, including the a Maciel RCR.Enzimas caniculares na forma hepatoesplênica da esquistossomose mansoni [dissertação de mestrado].Recife: Universidade Federal de Pernambuco; 2006.

Table 1 .
Authors, type of studies and their objectives.
a Authors used the logistic regression multivariate method to analyze the risk factors associated with HCV acquisition in an SM population.HSS: Heaptocellular carcinoma; HCV: Hepatitis C Virus; SM: Shistosomiasis mansoni; HBV: Hepatitis B Virus

Table 2 .
Systematic review of results of Hepatitis C Virus and Schistosoma mansoni diagnosis and prevalence of Hepatitis C Virus/ mansoni association.

Table 3 .
Risk factors, results and conclusion of studies selected.
Authors who used the logistic regression multivariate method to analyze the risk factors associated with Hepatitis C Virus acquisition in a Schistosomiasis mansoni population.