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Am. J. Trop. Med. Hyg., 78(2), 2008, pp. 228-234
Copyright © 2008 by The American Society of Tropical Medicine and Hygiene

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Reversibility of Schistosomal Periportal Thickening/Fibrosis after Praziquantel Therapy: A Twenty-Six Month Follow-up Study in Ethiopia

Nega Berhe*, Bjørn Myrvang, AND Svein G. Gundersen
Department of Infectious Diseases, Centre for Imported and Tropical Diseases, Ullevål University Hospital, Oslo, Norway; Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia; Institute for International Health, University of Oslo, Oslo, Norway; Sorlandet Hospital HF and Agder University College, Kristiansand, Norway


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To study outcome determinants of schistosomal periportal thickening/fibrosis (PPT/F), 199 subjects (mean age = 24.0 years, range = 7–68 years), 109 with mild (image pattern C) PPT/F, 69 with moderate (image pattern D) PPT/F, and 21 with severe (image patterns E and F) PPT/F were treated with praziquantel and evaluated every six months for a mean duration of 26 months. Subjects excreting Schistosoma mansoni eggs during any of the six-month evaluations were offered repeat treatment. Thirty-five had some improvement, and 69 had total resolution of PPT/F, of which 63.8% resolved within one year. Compared with subjects with moderate lesions, a significantly higher proportion of subjects with mild lesions had resolution/improvement of PPT/F (40.6% versus 69.7%, P < 0.001). Subjects with severe PPT/F showed no improvement. Resolution of PPT/F was significantly more frequent at a younger age, among seronegative for hepatitis B virus and among those with a lower frequency of post-treatment recurrence of S. mansoni infections.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During inflammatory liver diseases, deposition of extra-cellular matrix is part of normal tissue repair process that is regulated by a multitude of cytokines.1,2 Eggs of Schistosoma mansoni trapped in hepatic sinusoids induce peri-ovular granulomatous lesions and deposition of extra-cellular matrix along damaged portal vein branches. The latter process may lead to development of periportal fibrosis. However, histologic studies of schistosomal liver pathology have demonstrated signs of focal collagen breakdown and resorption along damaged portal vein branches. These findings support the concept that extra-cellular matrix is in a dynamic state of equilibrium between forces of synthesis and those that promote collagen breakdown.3,4

In addition to immune-mediated enhancement of drug efficacy,5–7 the effects of anti-schistosomal chemotherapy on schistosomal liver pathology is largely related to abolition of further insults to the liver through interruption of egg deposition after the death of adult worms, and to its direct effect on mature miracidia within egg granulomas.8,9 Because ultrasonographic findings of schistosomal liver changes are well correlated with histologic liver pathology,10,11 ultrasonography can provide an indirect and yet valid assessment of schistosomal liver changes after chemotherapy. Along this line, studies have shown partial or complete reversibility of schistosomal periportal thickening/fibrosis (PPT/F) in a proportion of subjects who had anti-schistosomal chemotherapy.12–18 The aims of the present study were to assess the outcome determinants of treatment and to quantify the extent of PPT/F reversal using the latest diagnostic staging system of the World Health Organization (WHO).19


MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study area, study subjects, and parasitologic examinations. Detailed description of the study area and methodology has been published elsewhere.20 Briefly, the study was conducted from June 2001 to August 2005 in Kemisse town and in WorkeMado, Cheretee and Chekorso villages, all of which are within the Kemisse administrative zone of northeastern Ethiopia. All study sites are situated within the Borkena River basin, approximately 330 km northeast of Addis Ababa, at an altitude of 1,450–1,500 meters above sea level. Study subjects were recruited from the then ongoing morbidity study (106 subjects) among community members in Kemisse and Cheretee who self-reported for screening (75 subjects) and among subjects who were referred by local health institutions to the temporary clinic of the research team established during the six-monthly follow-ups (18 subjects). Prior to the start of the present study, a pilot study on the control of schistosomiasis was being carried out in Kemisse town21; in the other three study sites there has not been any large-scale use of praziquantel over the last 10 years. Stool samples were processed using 41.7-mg templates according to the modified Kato-Katz technique.22 Quintet Kato-Katz thick smears were examined for each study subject to optimize detection of S. mansoni infection.23

Clinical examination. General clinical examination of each study subject was done with emphasis on detection of pallor, jaundice, fever, splenic/liver enlargement, and presence or absence of superficial abdominal collateral veins. Enlargement of the liver was measured at the mid-sternal and right mid-clavicular line, and the spleen was measured at the left anterior-axillary line, all in centimeters below costal margins, with the subject in supine position. Liver edge and/or splenic tip extending by more than 2 cm below costal margins were considered enlarged.

Ultrasonography. After clinical examination, ultrasonography of the liver was done using an EUB 405 portable ultrasound apparatus (Hitachi Tokyo, Japan) fitted with 3.5-MHz convex abdominal probe. Ultrasound image patterns suggestive of periportal fibrosis were compared with standard images and the corresponding image pattern score was recorded using the WHO-Niamey protocol.19 On the basis of this protocol, image pattern C signifies the presence of ring echoes around vessels in cross-section and pipe-stems parallel with portal vessels; pattern D is presence of an echogenic ruff around portal bifurcation and main-stem with thickening of the walls of main portal vessels; pattern E indicates the presence of hyperechogenic patches expanding into parenchyma, and pattern F indicates the presence of echogenic bands and streaks extending from the main portal vein and its bifurcation to the liver surface. Assessment of the periportal thickening was done by taking inner to inner and outer to outer portal branch wall thickness (PBWT) of 2–3 second branching portal veins. The arithmetic mean differences of these measurements were graded using local and WHO PBWT-for-height standards.19,20 The summation of image pattern score and PBWT score gave the final PPT/F score of each person. In addition, inner to inner diameter of the portal vein was measured at the entry point to the liver and a search for collateral veins was conducted in persons with advanced PPT/F.

Serologic tests. We used disposable syringes and needles to collect venous blood samples from study subjects, and all sera were tested for markers of hepatitis B virus (HBV) (antibodies to hepatitis B virus core antigen, hepatitis B virus surface antigen [HBsAg]) and antibodies to hepatitis C virus (HCV). Markers of HBV were assessed using Hepanostica Enzyme Immunoassay kits (Organon Teknika, Boxtel, the Netherlands, and bioMèrieux, Marcy l’Etoile, France). Reactive samples in either test panels were retested. Tests for antibodies to HCV were conducted using HCV 3.0 Enzyme Immunoassay kits (Ortho-Clinical Diagnostics, Bucks, United Kingdom) and reactive samples were cross-checked using Architect Anti-HCV test kits (Abbott Laboratories, Abbott Park, IL).

Inclusion criterion. The inclusion criterion for patients was ultrasonographically demonstrable schistosomal PPT/F as described in the WHO-Niamey protocol.19

Treatment and follow-up. All subjects were treated with praziquantel (40 mg/kg body weight) at enrollment. Thereafter, praziquantel therapy was offered only for subjects who had demonstrable S. mansoni eggs on any stool examinations every six months. Other helminth infections were treated with one dose of albendazol (400 mg). In addition to general clinical evaluations, liver ultrasound image pattern and PBWT of each subject was monitored during the follow-up sessions every six months and were compared with pre-treatment records.

Ethical considerations. The study was a component of a larger research project entitled "Control of Schistosomiasis with Local Production and Use of the Ethiopian Soap-Berry Endod", which received ethical clearance from National Ethical Clearance Committee of Ethiopia and the Norwegian Board of Medical Research Ethics. All diagnostic and treatment procedures were carried out after obtaining informed consent from each subject or his or her guardians as appropriate.

Statistical analysis. Statistical analysis was done using SPSS statistical software version 10 (SPSS Inc., Chicago, IL). Schistosoma mansoni egg counts per gram of stool (epg) of patients were log-transformed using log (epg + 1). Mean intensities of S. mansoni egg excretions are geometric means. Time required for improvement or resolution of PPT/F was calculated from the start of therapy until the first subsequent evaluation period where the change was demonstrated by liver ultrasonography. Normality and equality of variances were assessed before employing parametric tests. Validity of assumptions of regression modeling was checked after running the regression analysis. One-way analysis of variance with Welch’s test for equality of means was used to compare baseline intensities of S. mansoni egg excretions by categories of patients recruited from the different study sites. Comparisons of mean PBWT measurements before and after treatment were made using the paired samples t-test, and comparisons of proportions were made using the chi-square test. The median test was used for comparisons of median praziquantel treatment courses taken by groups of patients. After univariate analysis, multiple logistic regression analysis was used to quantify the odds ratio of specific factors associated with resolution of PPT/F. Results were considered significant for P values < 0.05. Assessment of the logistic regression model showed that the model predicted correctly 79% of cases. On the basis of residual analysis, the area under the receiver operating characteristic curve (95% confidence interval [CI]) was 0.85 (95% CI = 0.79–0.91). The Hosmer-Lemeshow goodness-of-fit chi-square was 5.2 with P value of 0.74, which indicated that the model fits the data reasonably well.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1Go shows demographic and clinical characteristics of study subjects. A total of 199 subjects with schistosomal PPT/F (115 males and 84 females, mean age = 24.0 years) participated in the study. Among these, 109 had image pattern C, 69 had image pattern D, and 21 had image patterns E and F. Overall, 58 (29.1%) did not have demonstrable S. mansoni eggs at enrollment (Table 1Go). However, 27 (46.5%) of 58 persons initially negative later had S. mansoni eggs on subsequent stool examinations. Pre-treatment and post treatment clinical characteristics of subjects without demonstrable eggs were similar to those of the study subjects who had no recurrence of infection. Furthermore, 28 of the remaining 31 subjects without demonstrable eggs were from the Kemisse and Cheretee study sites, which have comparatively lower prevalence and intensity of S. mansoni infection. Overall, 4% were positive for antibodies to HCV, and 16.1% were positive for HBsAg.


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TABLE 1
Demographic, parasitologic, ultrasonographic, and serologic characteristics of 199 persons with schistosomal PPT/F followed for a mean duration of 26 months in Kemisse zone, northeastern Ethiopia*
 
Splenomegaly was noted in 32.7% of the subjects and 31.2% had mild-to-moderate dilatation of main portal vein (Table 1Go). Overall, 9 (8.3%) of 109 subjects with image pattern C, 35 (50.7%) of 69 with image pattern D, and 21 (100%) of 21 with image patterns E and F had splenomegaly. Pre-treatment baseline intensity of S. mansoni infection and the frequency of subsequent recurrence of S. mansoni infections differed between groups of patients from the four study sites (Table 2Go). Resolution/improvement of PPT/F was highest in the group who had lower intensity of pre-treatment infection and lower subsequent frequency of recurrence of infection (Table 2Go). Overall, 69 (34.7%) patients had resolution and 35 (17.6%) had improvement of PPT/F, which were associated with a significant reduction in PBWT (Tables 2Go–4GoGo). Subjects with resolution of PPT/F were significantly younger than those who showed no improvement (Table 3Go). Resolution/improvement of PPT/F was significantly more frequent among subjects with milder lesions, and subjects with severe lesions did not have a favorable outcome (Table 4Go). Among the 69 subjects who had resolution of PPT/F, 6 (8.7%) of 69 showed resolution within six months, 38 (55.1%) of 69 within 12 months, and the remaining 25 (36.2%) of 69 within ≥ 18 months. For a comparable duration of follow-up and praziquantel treatment sessions, resolution of PPT/F was significantly more common at a younger age, among female subjects, and in those with mild PPT/F and without splenomegaly (Table 4Go). Furthermore, subjects who were seronegative for HBV markers had a significantly better outcome of PPT/F than subjects who were positive for markers of HBV infection (Table 4Go). Logistic regression analysis showed younger age, absence of recurrent S. mansoni infections, having mild PPT/F, and being negative for markers of HBV infection were associated with higher odds for favorable outcome of PPT/F after praziquantel therapy (Table 5Go). However, the sex-related difference in treatment outcome that was observed by univariate analysis was not evident in our multiple logistic regression analysis.


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TABLE 2
Comparisons of pre-treatment and post-treatment Schistosoma mansoni infections and outcomes of PPT/F by study site among 199 persons followed-up for a mean duration of 26 months in northeastern Ethiopia*
 

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TABLE 3
Portal branch wall thickness measurements before and after treatment in relation to outcomes of ultrasonographic image patterns among 199 persons with schistosomal PPT/F in northeastern Ethiopia*
 

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TABLE 4
Comparisons of proportions with resolution/improvement of PPT/F by categories of sex, age, image pattern, and presence of hepatitis markers among 199 persons in northeastern Ethiopia*
 

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TABLE 5
Results of logistic regression analysis with estimates of crude and adjusted odds ratio of factors associated with post-treatment resolution schistosomal periportal thickening/fibrosis, northeastern Ethiopia*
 
Among eight subjects who were positive for antibodies to HCV (three with image pattern C, two with image pattern D, and three with image patterns E and F), none showed resolution of PPT/F. However the number of positive persons was only 8 (4%) of 199, which was too small for any reasonable statistical analysis.

Figures 1Go and 2Go show pre-treatment and post-treatment ultrasound images of subjects with resolution of PPT/F. Figures 3Go and 4Go show ultrasound images of subjects who had no improvement of PPT/F after treatment.


Figure 1
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  		    FIGURE 1. A, Mild periportal thickening/fibrosis (image pattern C), pre-treatment. B, Mild periportal thickening/fibrosis resolved six months after treatment.

 

Figure 2
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  		    FIGURE 2. A, Pre-treatment, moderate periportal thickening/fibrosis (image pattern D). B, Moderate periportal thickening/fibrosis resolved 12 months after two treatment courses.

 

Figure 3
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  		    FIGURE 3. Moderate periportal thickening/fibrosis (image pattern D) showing no changes after two courses of praziquantel therapy during 18 months of follow-up.

 

Figure 4
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  		    FIGURE 4. Severe periportal thickening/fibrosis (image pattern E) showing no changes during 24 months of treatment follow-up.

 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, resolution/improvement of PPT/F was more prevalent at a younger age with mild lesions and in communities with a lower pre-treatment intensity and a lower frequency of post-treatment recurrence/re-infection of S. mansoni infections. Our study subjects were treated an average of twice over a period of 2.5 years. However, resolution/improvement of PPT/F was already noted in some subjects as early as six months after the first treatment session.

Praziquantel therapy was offered to all subjects, although at enrollment, 58 (29%) did not have demonstrable S. mansoni eggs in their initial five Kato-Katz thick smears. Conversely, we observed resolution/improvement of PPT/F after praziquantel therapy, even among subjects who had no demonstrable S. mansoni eggs at enrollment. It is possible that some of these subjects might have had actual infections that may have been missed because of day-to-day variation of egg excretion and the inherent limitations of Kato-Katz thick smears.24–26 The fact that 27 (46.5%) of 58 of the initial egg-negative persons later showed eggs on subsequent examinations supports this possibility. Spontaneous resolution of PPT/F not related to praziquantel therapy is also another possibility. However, we consider it to be a less likely scenario because it is thought to occur in only a few subjects who have no further exposure to infection. In a recent prospective study, resolution was only noted in subjects who had anti-schistosomal therapy; there was worsening or no change in untreated subjects.26 Thus; it is reasonable to assume that the observed resolution of PPT/F in our study subjects can, to a large extent, be ascribed to praziquantel therapy.

Several reports have documented partial or complete resolution of PPT/F after anti-schistosomal chemotherapy, most notably among young subjects.12–18 Moreover, reversibility of periportal fibrosis was observed in some patients as early as 6–7 months post-therapy,15,16,27 and the effect on prevalence of periportal fibrosis was largely appreciable after a delay of over two years.15–18 Furthermore, resolution of PPT/F was reported to be low among subjects from areas with intense transmission and high risk of re-infection.14

Over a mean follow-up period of 26 months, 136 (68.3%) of our study subjects had recurrence of S. mansoni infection, which was more frequent among the groups with high initial prevalence and intensity of infection. In our earlier study in Kemisse town,28 we observed a praziquantel cure rate greater than 80%. However, such high cure rates can be expected in communities with relatively low intensity of transmission as shown by the lower recurrence of infection among our study subjects from Kemisse town. However, on the basis of community infection levels29 and pre-treatment intensity and frequency of subsequent recurrence of infections, the intensity of transmission in the other three study sites appears to be high. In such conditions of intense transmission, praziquantel cure rates have been reported to be low30,31 because of high initial worm loads, rapid re-infection, maturation of pre-patent infections, or a combination of these factors. In areas with intense transmission, patients may harbor immature worms at the time they are treated, and because immature schistosoms are not sensitive to praziquantel,32,33 they may subsequently show recurrence of infection. Thus, at high transmission levels, these patients may continuously be exposed to a variety of antigens from the eggs and adult worms, which leads to sustained inflammation and exposure to profibrotic stimuli, and thus lowers the chance of PPT/F reversal after treatment. This finding suggests that in areas of high transmission, praziquantel treatment may be needed more frequently, at least once a year for several years, before one could observe a significant impact on morbidity levels. Thereafter, treatment may need to be continued for sustainable control of morbidity.

In our series, subjects with HBV co-infection had a significantly less favorable treatment outcome of PPT/F than subjects without HBV co-infection. On the basis of earlier studies, S. mansoni co-infection with either HBV or HCV has been reported to be associated with accelerated deterioration of hepatic function.34–37 Furthermore, hepatitis B and C co-infections may lead to an underestimation of the impact of anti-schistosomal therapy on hepatic fibrosis, especially in adults.38 Hepatitis B is a vaccine-preventable disease. However if one considers the current cost of the vaccine and prevailing high community HBV infection,29,39–41 it needs critical analysis of feasibility and cost-effectiveness before recommending large-scale HBV vaccination programs for Ethiopia.

In summary, schistosomal periportal fibrosis may only be reversible early in the disease course. Because resolution of lesions is highest in children and young adults, currently recommended school age–targeted42 praziquantel-based morbidity control could help avert development of schistosomal periportal fibrosis and its consequences.

Received August 19, 2007. Accepted for publication November 7, 2007.

Acknowledgments: We thank Endashaw Habte and Abraham Redda for excellent laboratory assistance, the staff of Kemisse Health Centre and Cheretee Clinic for unreserved assistance in our fieldwork, and the administrative and technical staff of the Institue of Pathobiology for encouragement and support.

Financial support: This work was supported by Centre for Imported and Tropical Diseases of Ullevål University Hospital and the Norwegian Research Council through project "Control of Schistosomiasis by Local Production and Use of the Ethiopian Soapberry Endod." Nega Berhe is a recipient of PhD scholarship from the Norwegian Statens Lånekasse.

* Address correspondence to Nega Berhe, Department of Infectious Diseases, Centre for Imported and Tropical Diseases, Ulleva °l University Hospital, 0407 Oslo, Norway. E-mail: nega_berhe{at}yahoo.com Back

Authors’ addresses: Nega Berhe, Department of Infectious Diseases, Centre for Imported and Tropical Diseases, Ullevål University Hospital, 0407 Oslo, Norway, Telephone: 47-2211-9097, Fax: 47-2301-6020, E-mail: nega_berhe{at}yahoo.com, the Institute for International Health, University of Oslo, PO Box 1130, N-0318 Oslo, Norway, E-mail: nega.berhe{at}studentmed.uio.no, and the Aklilu Lemma Institute of Pathobiology, Addis Ababa University, PO Box 1176, Addis Ababa, Ethiopia. Bjørn Myrvang, Department of Infectious Diseases, Centre for Imported and Tropical Diseases, Ullevål University Hospital, 0407 Oslo, Norway, Telephone: 47-2211-9097, Fax: 47-2301-6020, E-mail: Bjorn.Myrvang{at}ulleval.no. Svein G. Gundersen, Sorlandet Hospital HF and Agder University College, Box 416, 4604 Kristiansand, Norway, Telephone: 47-3807-4474, Fax: 47-3807-4173, E-mail: s.g.gundersen{at}sshf.no.

Reprint requests: Nega Berhe, Department of Infectious Diseases, Centre for Imported and Tropical Diseases, Ullevål University Hospital, 0407 Oslo, Norway, Telephone: 47-2211-9097, Fax: 47-2301-6020, E-mail: nega_berhe{at}yahoo.com.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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