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Reversibility of Schistosoma mansoni-associated morbidity after yearly mass praziquantel therapy: ultrasonographic assessment
TRANSACTIONS
OFTHE
Reversibility praziquantel
ROYAL
SOCIETY
OFTROPICAL
MEDICINE
AND
HYGIENE
(1998) 92,451-453
of Schistosoma mansoni-associated morbidity therapy: ultrasonographic assessment
451
after yearly mass
I? Boisierl, C.-E. Ramarokoto l, V. E. Ravaoalimalala3, L. Rabarijaonal, J. Serieye2, J. Roux’ and I Unit& d’Epid&niologie et de Parasitologic, Institut Pasteur de Madagascar, B.I? 1274, Antananarivo 101, l? Esterrel Madagascar; 2Service de Radiologie, Centre Hospitalier Soavinandriana, B.I? 6 his, Antananarivo 101, Madagascar; 3Direction de la Lute contre les Maladies Transmissibles, Minis&e de la San& B.I? 460, Antananarivo 101, Madagascar Abstract A parasitological, clinical and ultrasonographic longitudinal study was undertaken in 1993 in a focus hynerendemic for Schistosoma mansoni infection in the central highlands of Madagascar. All the inhabitants were svstematicallv treated with praziquantel. A complete examination and treatment were repeated each year. Among the 289 villagers who underwent the complete 3 years’ follow up, 65.9% excreted eggs at the initial survev and the mean eaa count of infected individuals was 202 ecrasin. In 1996, the urevalence of infection was 19.3% with a m&r egg count of 27 eggs/g and, among i&bit&ts aged ;44 years, only one was found to be infected. The proportion of individuals complaining of bloody stool decreased from 24.9% in 1993 to 8.4% in 1996. Compared to the initial clinical examination, the age-adjusted prevalence of splenomegaly was significantly lower in 1996, but remained high: 62% in the lo-14 years age group and 59% in individuals aged >24 years. Ultrasonographic examination after 3 years of praziquantel therapy showed a marked decrease of the overall prevalence of schistosomal hepatic fibrosis, from 28% in 1993 to 10.3% in 1996. This improvement had already been achieved during the second year of followup for most subjects. Usually, the reversal of morbidity affected individuals classified as stage 1 at the beginning of the study. Stage 3 was not observed in the last 2 surveys. One patient’s ascites disappeared during the follow-up, associated with a significant reversal of periportal fibrosis. Our results indicate that repeated praziquantel therapy can lead to improvement of liver morbidity and the prevention of the development of schistosomal hepatic fibrosis, even in an old-established hyperendemic focus. Keywords:
Madagascar
schistosomiasis, Schistosoma mansoni, chemotherapy, praziquantel, morbidity, fibrosis, ultrasonography,
Introduction Although schistosomiasis, especially schistosomiasis mansoni, is an important public health problem in Madagascar, nothing has been done to control the infection at a national level. A national programme against schistosomiasis based on chemotherapy is in the planning stage. Initially, the programme should aim to control morbidity in hyperendemic areas by means of repeated mass treatment, and several surveys have been undertaken in order to help the public health authorities to define the stratew that will be imulemented. We present in this paper the data obtained from 3 years’ follow-up of a community in the central highlands of Madagascar, after several rounds of mass praziquantel therapy. Population
and Methods
The first survey was carried out in the village of Belaaera (584 inhabitants). endemic for Schistosoma manso%, between June and November 1993. All the inhabitants were invited to take part in the study. For each individual, a standardized case history was recorded concerning signs of schistosomiasis mansoni and a clinical examination was performed. Spleen enlargement was quantified from 0 to 5 according to Hackett’s classification (HACKETT, 1944). Two Kato thick smears were prepared for each subject from a single fresh stool sample and the slides were examined by the same team of experienced microscopists. The mean egg loads were calculated as geometric means (GM) of eggexcreting individuals only per gram of faeces (eggs/g). Ultrasonographic examination of the liver was performed in a village house by an experienced ultrasound observer who was unaware of the patients’ status for S. mansoni infection. A Microimager 2000@ ultrasonograph (Ausonics Ltd, Sidney, Australia) was used with 35 MHz sectorial transducers, a 9 inch [23 cm] additional monitor, and a printer. Morbidity was estimated Address for correspondence: Dr Pascal Boisier, Unite d’Epid&miologie, Institut Pasteur, BP. 1274, Antananarivo 101. Madaeascar; _ fax +261 20 22 284 07, e-mail boisier @maki.pasteur.mg
according to the classification proposed by THE CAIRO WORKING GROUP (1992), with slight modifications (BOISIER et al., 1995). First, we standardized measurements of right and left liver lobes and of portal vein diameter by correction for individual body height. Secondly, we found stage 1 not sufficiently specific, so we recognized a borderline stage IA, corresponding to a periportal measurement of 3 mm without any other abnormalitv. Thirdlv, as it is imnossible to distinguish the respect&e roles &malaria and schistosomiasis in the aetiology of splenomegaly, spleen size was not taken into account in the staging of morbidity. Later, in the light of our experience, we considered that only people with stage 1B or higher had indubitable morbidity. We therefore recoded all the results from the initial surveys and, in the present paper, the former stages 0 and 1A are amalgamated as stage 0 and the former stage 1B is named stage 1. After initial examination, all individuals, except pregnant women, were treated with praziquantel in a single oral dose of 40 mgikg, whether or not they were excreting eggs, and randomly assigned to 2 groups, A and B. All members of both groups were examined parasitologically, clinically and ultrasonographically and given praziquantel at 12, 24 and 36 months, again whether or not they were passing eggs. In addition, in group A only, parasitological and clinical examination and praziquantel administration were also done after 6 and 18 months without regard to parasitological results. After month 24, due to the absence of any difference between the results from groups A and B, all the participating individuals received treatment only once a year and the 2 groups were considered together for the remaining follow-up. For statistical analysis, Pearson’s x 2 test, the Kruskal-Wallis test and Wilcoxon’s test for matched series were used whenever appropriate. A value of PcO.05 was considered significant.
Results Of the 482 inhabitants aged >2 years who were examined by ultrasonography in 1993, 289 (60%) took part in the complete 3 years’ follow-up. The latter group did
I? BOISIER ETAL.
452
Table 1. Overall prevalence stool among 289 individuals
of Schistosoma who completed
infection, mean egg count and prevalence three years’ follow-up
of bloody
mansoni
Individuals excreting eggs (%) Geometric mean egg count (eggs/g)a Overall geometric mean egg count (eggs/g)b Reduction ( %)c Individuals complaining of bloody stool (%)
1993
1994
1995
1996
65.7 202 32.7 24.9
25.8 5a 2.9 91.1 Note d
9.9 69 1.5 95.4 4.6
19.3 27 1.9 94.2 8.4
=Only individuals excreting eggs. bAil289 individuals; geometric mean=exp(log,[geometric mean of egg excreters]xCpercentage of egg excretors/lOO]). CCalculated for 1994 as lOOx[(geometric mean for 1993-geometric mean for 1994)/geometric mean for 19931, and similarly for other years. dIncomplete data. Table 2. Results of ultrasonographic examination of the liver (graded according to THE CAIRO WORKING GROUP, 1992) before (1993) and after (1996) three annual treatments with praziquantel given to 289 mansoni who completed three years’ follow-up individuals in an area endemic for Schistosoma
1993 Stage Stage Stage Stage Total
0 1 2 3
Stage 0
Stage 1
205 44 10 0 259
2 6 7 1 16
100-
8 8 1 0 1
90
--
80
--
70
--
60
--
50
--
40
--
30
--
20
--
1996 Stage 2
Stage 3
Total
1 1
0 0
208 51
: 14
0 0
255 289
350
-
300 -i;o -3 250 -~ P t p 200 -2 ; 150 -$
I 100-8 50
10 --
--
o+
O/-G-b 5 to 9
10to 14
15to 24 Age
25
to 44
245
(ye-9
5 to 9
10to I4
15to 24
25
to 44
>45
Age (Y-4
Fig. 1. Prevalence of Schistosonzamansoni infection according to age among 289 individuals completing 3 years’ follow-up: 1993 (+), 1994 (0), 1995 (A) and 1996 (W).
Fig. 2. Geometric mean .Schistosomamunsoni egg counts (epgzeggsig) of infected individuals according to age, among 289 individuals completing 3 years’ follow-up: 1993 (*), 1994 (0), 1995 (A) and 1996 (W).
not differ significantly from those who did not complete follow-up in intensity of infection or morbidity assessed by ultrasonography, but they were significantly older (23.2 vs. 20.1 years, P
phy revealed no obvious pathological alteration in the enlarged spleens. As the assessment of morbidity did not differ significantly between groups A and B (Fig. 3), the 2 groups were amalgamated after November 1995. The results of ultrasonographic examination before and after 3 years of praziquantel therapy are presented in Table 2. Stage 3 was not observed in the last 2 surveys and there was a significant improvement in liver morbidity between 1993 and 1996 (PC1 Oe4). During the initial ultrasonographic examination, ascites was present in 2 individuals classified as stage 3. The first subject underwent splenectomy 18 months later. His ascites disappeared and a decrease of periportal thickness was also observed, but that could have been due to the operation. In the second subject, disappearance of the ascites and reduction of the periportal fibrosis could not be explained by anything other than praziquantel therapy. Improvement of liver morbidity was evident during the
453
REVERSALOF SCHISTOSOA4.4 MANSONIMORl3IDITY
q Stage 1
q Stage 3
0 A
B Nov. 1993
A
B Nov. 1995
Fig. 3. Prevalence of hepatic morbidity in individuals infected with Schistosoma mansoni receiving once yearly (A) or twice yearly (B) praziquantel therapy, among 308 individuals completing 2 years’ follow-up. The stages are those of THE CAIRO WORKING GROUP (1992).
second year of follow-up in most of the participants. However, one woman had no evidence of morbidity until 1995 but presented one year later with ultrasonographic patterns of stage 2. This woman had received praziquantel each year and was excreting eggs at each examination except that in 1994: 192 eggs/g in 1993, 204in1995,and12in1996. Discussion
Yearly administration of praziquantel in a community where S. mansoni infection was hyperendemic produced a marked decrease of the prevalence and intensity of infection, even in the absence of transmission control measures other than basic health education. There was considerable reduction of morbidity related to S. rnansoni infection following repeated praziquantel therapy, clearly indicating that praziquantel can result in reversal of morbidity in patients presenting a significant level of pathology. Previous publications have already demonstrated substantial reversal of specific liver lesions after antischistosomal therapy with praziquantel in Sudan (MOHAMED-ALI et al., 1991; DOEHRWG-SCHWERDTFEGER~~CZZ.,~~~~;HOMEIDA~~ al., 1996), and our findings are consistent with their conclusions. Recent work on an experimental murine model of S. mansoni infection has led to a fuller understanding of the hepatic fibrosis and especially its decrease, which has been related to abrogation of the expression of the transforming growth factor gene TGFpl (KFZSINA et al., 1994). The possible reversibility of some complications like ascites remains poorly documented, but we observed one fully convincing case; this must be possible only in patients in early stage 3, without long-established advanced portal hypertension. We cannot explain why liver morbidity increased in a few individuals in spite of repeated praziquantel administration. There is no reason to believe that the treatment itself could have been responsible. Further studies are needed to identify individuals at particular risk of hepatosplenic complications even when receiving praziquantel therapy. In the initial survey, the overall prevalence of hepatitis B surface antigen (HBsAg) in Belagera was found to be 18.6% (821442) and the overall seropositivity rate for
malaria was 84.3% using an indirect immunofluorescence assay. There was no significant relationship bepresence of HBsAg positivity tween and ultrasonographic liver changes, and malaria could not have influenced our results because we did not consider spleen size when assessing morbidity. On the other hand, malaria was probably jointly responsible for splenic enlargement. Therefore, the low level of reversal of splenomegaly after 3 annual treatments with praziquante1 is perhaps not surprising. However, neither the high frequency nor the age distribution of splenomegaly that were noted in our study are observed in other communities with similar seasonal patterns of malaria transmission in Madagascar in the absence of S. mansoni infection. The absence of additional benefit from twice yearly praziquantel chemotherapy, compared to annual administration, has been noted in Zambia on the basis of clinical and parasitological observations (SUKWA, 1993), and our ultrasonographic examination supports this observation. However, this may not be the case in areas with more intense transmission than occurs in the central highlands of Madagascar. Although our aim of defining a strategy to control the morbidity related to S. mansoni infection was not achieved, it seems probable that 2 rounds of annual praziquantel therapy given to the whole population of an area, followed by annual administration targeted at children and young adults, would constitute a realistic policy in communities with an initially high prevalence of S. mansoni infection in the central highlands of Madagascar. References
Boisier, l?, Serieye, J., Ravaoalimalala, V. E., Roux, J. & Esterre, l? (1995). Ultrasonographical assessmentof morbidity in Madagascar: a community-based study in a rural population. Transactions of the Royal Sociey of Tropical Medicine and Hygiene, 89,208-2 12. Doehring-Schwerdtfeger,
E., Abdel-Rahim,
I. M., Kardorff,
R., Kaiser, C., Franke, D., Schlake, J., Richter, J., Elsheikh, M., Mohamed-Ali, Q. & Ehrich, J. H. H. (1992). Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity twenty-three months after treatment with praziquantel. Avnerican Journal of Tropical Medicine and Hygiene, 46, 409-415. Hackett, L. W. (1944). Spleen measurement in malaria. Journal of the National Malaria Society, 3, 121-123. Homeida, M. M. A., Eltoum, I. A., Ali, M. A., Suliaman, S. A., Elobied, E. A., Mansour, M., Saad, A. M. & Bennet, J. L. (1996). The effectiveness of annual versus biennial mass chemotherapy in reducing morbidity due to schistosomiasis: a prospective study in Gezira-Managil, Sudan. American Journal of Tropical Medicine and Hygiene, 54, 140-l 45. Kresina, T. F., He, Q., Esposti, S. D. & Zern, M. A. (1994). Gene expression of transforming growth factor p 1 and extracellular matrix proteins in murine Schistosoma mansoni infection. Gastroenterology, 107,773-780. Mohamed-Ali, Q., Doehring-Schwerdtfeger, E., Abdel-Rahim, I. M., Schlake, J., Kardorff, R., Franke, D., Kaiser, C., Elsheikh, M., Abdalla, M., Schafer, I? & Ehrich, J. H. H. (1991). Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity seven months after treatment with praziquantel. American Journal of Tropical Medicine and Hygiene, 44,444&E 1. Sukwa, T. Y. (1993). A community-based randomized trial of praziquantel to control schistosomiasis morbidity in schoolchildren in Zambia. Anna& of Tropical Medicine and l’arasitology, 87, 185-194. The Cairo Working Group (1992). The use of diagnostic ultrasound in schistosomiasis-attempts at standardization of methodology. Acta Tropica, 51, 45-63. Received 7 July 1997; revised 27 April publication 29 April 1998
1998; accepted for
OFTHE
Reversibility praziquantel
ROYAL
SOCIETY
OFTROPICAL
MEDICINE
AND
HYGIENE
(1998) 92,451-453
of Schistosoma mansoni-associated morbidity therapy: ultrasonographic assessment
451
after yearly mass
I? Boisierl, C.-E. Ramarokoto l, V. E. Ravaoalimalala3, L. Rabarijaonal, J. Serieye2, J. Roux’ and I Unit& d’Epid&niologie et de Parasitologic, Institut Pasteur de Madagascar, B.I? 1274, Antananarivo 101, l? Esterrel Madagascar; 2Service de Radiologie, Centre Hospitalier Soavinandriana, B.I? 6 his, Antananarivo 101, Madagascar; 3Direction de la Lute contre les Maladies Transmissibles, Minis&e de la San& B.I? 460, Antananarivo 101, Madagascar Abstract A parasitological, clinical and ultrasonographic longitudinal study was undertaken in 1993 in a focus hynerendemic for Schistosoma mansoni infection in the central highlands of Madagascar. All the inhabitants were svstematicallv treated with praziquantel. A complete examination and treatment were repeated each year. Among the 289 villagers who underwent the complete 3 years’ follow up, 65.9% excreted eggs at the initial survev and the mean eaa count of infected individuals was 202 ecrasin. In 1996, the urevalence of infection was 19.3% with a m&r egg count of 27 eggs/g and, among i&bit&ts aged ;44 years, only one was found to be infected. The proportion of individuals complaining of bloody stool decreased from 24.9% in 1993 to 8.4% in 1996. Compared to the initial clinical examination, the age-adjusted prevalence of splenomegaly was significantly lower in 1996, but remained high: 62% in the lo-14 years age group and 59% in individuals aged >24 years. Ultrasonographic examination after 3 years of praziquantel therapy showed a marked decrease of the overall prevalence of schistosomal hepatic fibrosis, from 28% in 1993 to 10.3% in 1996. This improvement had already been achieved during the second year of followup for most subjects. Usually, the reversal of morbidity affected individuals classified as stage 1 at the beginning of the study. Stage 3 was not observed in the last 2 surveys. One patient’s ascites disappeared during the follow-up, associated with a significant reversal of periportal fibrosis. Our results indicate that repeated praziquantel therapy can lead to improvement of liver morbidity and the prevention of the development of schistosomal hepatic fibrosis, even in an old-established hyperendemic focus. Keywords:
Madagascar
schistosomiasis, Schistosoma mansoni, chemotherapy, praziquantel, morbidity, fibrosis, ultrasonography,
Introduction Although schistosomiasis, especially schistosomiasis mansoni, is an important public health problem in Madagascar, nothing has been done to control the infection at a national level. A national programme against schistosomiasis based on chemotherapy is in the planning stage. Initially, the programme should aim to control morbidity in hyperendemic areas by means of repeated mass treatment, and several surveys have been undertaken in order to help the public health authorities to define the stratew that will be imulemented. We present in this paper the data obtained from 3 years’ follow-up of a community in the central highlands of Madagascar, after several rounds of mass praziquantel therapy. Population
and Methods
The first survey was carried out in the village of Belaaera (584 inhabitants). endemic for Schistosoma manso%, between June and November 1993. All the inhabitants were invited to take part in the study. For each individual, a standardized case history was recorded concerning signs of schistosomiasis mansoni and a clinical examination was performed. Spleen enlargement was quantified from 0 to 5 according to Hackett’s classification (HACKETT, 1944). Two Kato thick smears were prepared for each subject from a single fresh stool sample and the slides were examined by the same team of experienced microscopists. The mean egg loads were calculated as geometric means (GM) of eggexcreting individuals only per gram of faeces (eggs/g). Ultrasonographic examination of the liver was performed in a village house by an experienced ultrasound observer who was unaware of the patients’ status for S. mansoni infection. A Microimager 2000@ ultrasonograph (Ausonics Ltd, Sidney, Australia) was used with 35 MHz sectorial transducers, a 9 inch [23 cm] additional monitor, and a printer. Morbidity was estimated Address for correspondence: Dr Pascal Boisier, Unite d’Epid&miologie, Institut Pasteur, BP. 1274, Antananarivo 101. Madaeascar; _ fax +261 20 22 284 07, e-mail boisier @maki.pasteur.mg
according to the classification proposed by THE CAIRO WORKING GROUP (1992), with slight modifications (BOISIER et al., 1995). First, we standardized measurements of right and left liver lobes and of portal vein diameter by correction for individual body height. Secondly, we found stage 1 not sufficiently specific, so we recognized a borderline stage IA, corresponding to a periportal measurement of 3 mm without any other abnormalitv. Thirdlv, as it is imnossible to distinguish the respect&e roles &malaria and schistosomiasis in the aetiology of splenomegaly, spleen size was not taken into account in the staging of morbidity. Later, in the light of our experience, we considered that only people with stage 1B or higher had indubitable morbidity. We therefore recoded all the results from the initial surveys and, in the present paper, the former stages 0 and 1A are amalgamated as stage 0 and the former stage 1B is named stage 1. After initial examination, all individuals, except pregnant women, were treated with praziquantel in a single oral dose of 40 mgikg, whether or not they were excreting eggs, and randomly assigned to 2 groups, A and B. All members of both groups were examined parasitologically, clinically and ultrasonographically and given praziquantel at 12, 24 and 36 months, again whether or not they were passing eggs. In addition, in group A only, parasitological and clinical examination and praziquantel administration were also done after 6 and 18 months without regard to parasitological results. After month 24, due to the absence of any difference between the results from groups A and B, all the participating individuals received treatment only once a year and the 2 groups were considered together for the remaining follow-up. For statistical analysis, Pearson’s x 2 test, the Kruskal-Wallis test and Wilcoxon’s test for matched series were used whenever appropriate. A value of PcO.05 was considered significant.
Results Of the 482 inhabitants aged >2 years who were examined by ultrasonography in 1993, 289 (60%) took part in the complete 3 years’ follow-up. The latter group did
I? BOISIER ETAL.
452
Table 1. Overall prevalence stool among 289 individuals
of Schistosoma who completed
infection, mean egg count and prevalence three years’ follow-up
of bloody
mansoni
Individuals excreting eggs (%) Geometric mean egg count (eggs/g)a Overall geometric mean egg count (eggs/g)b Reduction ( %)c Individuals complaining of bloody stool (%)
1993
1994
1995
1996
65.7 202 32.7 24.9
25.8 5a 2.9 91.1 Note d
9.9 69 1.5 95.4 4.6
19.3 27 1.9 94.2 8.4
=Only individuals excreting eggs. bAil289 individuals; geometric mean=exp(log,[geometric mean of egg excreters]xCpercentage of egg excretors/lOO]). CCalculated for 1994 as lOOx[(geometric mean for 1993-geometric mean for 1994)/geometric mean for 19931, and similarly for other years. dIncomplete data. Table 2. Results of ultrasonographic examination of the liver (graded according to THE CAIRO WORKING GROUP, 1992) before (1993) and after (1996) three annual treatments with praziquantel given to 289 mansoni who completed three years’ follow-up individuals in an area endemic for Schistosoma
1993 Stage Stage Stage Stage Total
0 1 2 3
Stage 0
Stage 1
205 44 10 0 259
2 6 7 1 16
100-
8 8 1 0 1
90
--
80
--
70
--
60
--
50
--
40
--
30
--
20
--
1996 Stage 2
Stage 3
Total
1 1
0 0
208 51
: 14
0 0
255 289
350
-
300 -i;o -3 250 -~ P t p 200 -2 ; 150 -$
I 100-8 50
10 --
--
o+
O/-G-b 5 to 9
10to 14
15to 24 Age
25
to 44
245
(ye-9
5 to 9
10to I4
15to 24
25
to 44
>45
Age (Y-4
Fig. 1. Prevalence of Schistosonzamansoni infection according to age among 289 individuals completing 3 years’ follow-up: 1993 (+), 1994 (0), 1995 (A) and 1996 (W).
Fig. 2. Geometric mean .Schistosomamunsoni egg counts (epgzeggsig) of infected individuals according to age, among 289 individuals completing 3 years’ follow-up: 1993 (*), 1994 (0), 1995 (A) and 1996 (W).
not differ significantly from those who did not complete follow-up in intensity of infection or morbidity assessed by ultrasonography, but they were significantly older (23.2 vs. 20.1 years, P
phy revealed no obvious pathological alteration in the enlarged spleens. As the assessment of morbidity did not differ significantly between groups A and B (Fig. 3), the 2 groups were amalgamated after November 1995. The results of ultrasonographic examination before and after 3 years of praziquantel therapy are presented in Table 2. Stage 3 was not observed in the last 2 surveys and there was a significant improvement in liver morbidity between 1993 and 1996 (PC1 Oe4). During the initial ultrasonographic examination, ascites was present in 2 individuals classified as stage 3. The first subject underwent splenectomy 18 months later. His ascites disappeared and a decrease of periportal thickness was also observed, but that could have been due to the operation. In the second subject, disappearance of the ascites and reduction of the periportal fibrosis could not be explained by anything other than praziquantel therapy. Improvement of liver morbidity was evident during the
453
REVERSALOF SCHISTOSOA4.4 MANSONIMORl3IDITY
q Stage 1
q Stage 3
0 A
B Nov. 1993
A
B Nov. 1995
Fig. 3. Prevalence of hepatic morbidity in individuals infected with Schistosoma mansoni receiving once yearly (A) or twice yearly (B) praziquantel therapy, among 308 individuals completing 2 years’ follow-up. The stages are those of THE CAIRO WORKING GROUP (1992).
second year of follow-up in most of the participants. However, one woman had no evidence of morbidity until 1995 but presented one year later with ultrasonographic patterns of stage 2. This woman had received praziquantel each year and was excreting eggs at each examination except that in 1994: 192 eggs/g in 1993, 204in1995,and12in1996. Discussion
Yearly administration of praziquantel in a community where S. mansoni infection was hyperendemic produced a marked decrease of the prevalence and intensity of infection, even in the absence of transmission control measures other than basic health education. There was considerable reduction of morbidity related to S. rnansoni infection following repeated praziquantel therapy, clearly indicating that praziquantel can result in reversal of morbidity in patients presenting a significant level of pathology. Previous publications have already demonstrated substantial reversal of specific liver lesions after antischistosomal therapy with praziquantel in Sudan (MOHAMED-ALI et al., 1991; DOEHRWG-SCHWERDTFEGER~~CZZ.,~~~~;HOMEIDA~~ al., 1996), and our findings are consistent with their conclusions. Recent work on an experimental murine model of S. mansoni infection has led to a fuller understanding of the hepatic fibrosis and especially its decrease, which has been related to abrogation of the expression of the transforming growth factor gene TGFpl (KFZSINA et al., 1994). The possible reversibility of some complications like ascites remains poorly documented, but we observed one fully convincing case; this must be possible only in patients in early stage 3, without long-established advanced portal hypertension. We cannot explain why liver morbidity increased in a few individuals in spite of repeated praziquantel administration. There is no reason to believe that the treatment itself could have been responsible. Further studies are needed to identify individuals at particular risk of hepatosplenic complications even when receiving praziquantel therapy. In the initial survey, the overall prevalence of hepatitis B surface antigen (HBsAg) in Belagera was found to be 18.6% (821442) and the overall seropositivity rate for
malaria was 84.3% using an indirect immunofluorescence assay. There was no significant relationship bepresence of HBsAg positivity tween and ultrasonographic liver changes, and malaria could not have influenced our results because we did not consider spleen size when assessing morbidity. On the other hand, malaria was probably jointly responsible for splenic enlargement. Therefore, the low level of reversal of splenomegaly after 3 annual treatments with praziquante1 is perhaps not surprising. However, neither the high frequency nor the age distribution of splenomegaly that were noted in our study are observed in other communities with similar seasonal patterns of malaria transmission in Madagascar in the absence of S. mansoni infection. The absence of additional benefit from twice yearly praziquantel chemotherapy, compared to annual administration, has been noted in Zambia on the basis of clinical and parasitological observations (SUKWA, 1993), and our ultrasonographic examination supports this observation. However, this may not be the case in areas with more intense transmission than occurs in the central highlands of Madagascar. Although our aim of defining a strategy to control the morbidity related to S. mansoni infection was not achieved, it seems probable that 2 rounds of annual praziquantel therapy given to the whole population of an area, followed by annual administration targeted at children and young adults, would constitute a realistic policy in communities with an initially high prevalence of S. mansoni infection in the central highlands of Madagascar. References
Boisier, l?, Serieye, J., Ravaoalimalala, V. E., Roux, J. & Esterre, l? (1995). Ultrasonographical assessmentof morbidity in Madagascar: a community-based study in a rural population. Transactions of the Royal Sociey of Tropical Medicine and Hygiene, 89,208-2 12. Doehring-Schwerdtfeger,
E., Abdel-Rahim,
I. M., Kardorff,
R., Kaiser, C., Franke, D., Schlake, J., Richter, J., Elsheikh, M., Mohamed-Ali, Q. & Ehrich, J. H. H. (1992). Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity twenty-three months after treatment with praziquantel. Avnerican Journal of Tropical Medicine and Hygiene, 46, 409-415. Hackett, L. W. (1944). Spleen measurement in malaria. Journal of the National Malaria Society, 3, 121-123. Homeida, M. M. A., Eltoum, I. A., Ali, M. A., Suliaman, S. A., Elobied, E. A., Mansour, M., Saad, A. M. & Bennet, J. L. (1996). The effectiveness of annual versus biennial mass chemotherapy in reducing morbidity due to schistosomiasis: a prospective study in Gezira-Managil, Sudan. American Journal of Tropical Medicine and Hygiene, 54, 140-l 45. Kresina, T. F., He, Q., Esposti, S. D. & Zern, M. A. (1994). Gene expression of transforming growth factor p 1 and extracellular matrix proteins in murine Schistosoma mansoni infection. Gastroenterology, 107,773-780. Mohamed-Ali, Q., Doehring-Schwerdtfeger, E., Abdel-Rahim, I. M., Schlake, J., Kardorff, R., Franke, D., Kaiser, C., Elsheikh, M., Abdalla, M., Schafer, I? & Ehrich, J. H. H. (1991). Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity seven months after treatment with praziquantel. American Journal of Tropical Medicine and Hygiene, 44,444&E 1. Sukwa, T. Y. (1993). A community-based randomized trial of praziquantel to control schistosomiasis morbidity in schoolchildren in Zambia. Anna& of Tropical Medicine and l’arasitology, 87, 185-194. The Cairo Working Group (1992). The use of diagnostic ultrasound in schistosomiasis-attempts at standardization of methodology. Acta Tropica, 51, 45-63. Received 7 July 1997; revised 27 April publication 29 April 1998
1998; accepted for