A.G.P. Ross

Schistosomiasis in the People's Republic of China: Prospects and Challenges for the 21st Century

SUMMARY Schistosomiasis japonica is a serious communicable disease and a major disease risk for more than 30 million people living in the tropical and subtropical zones of China. Infection remains a major public health concern despite 45 years of intensive control efforts. It is estimated that 865,000 people and 100,250 bovines are today infected in the provinces where the disease is endemic, and its transmission continues. Unlike the other schistosome species known to infect humans, the oriental schistosome, Schistosoma japonicum, is a true zoonotic organism, with a range of mammalian reservoirs, making control efforts extremely difficult. Clinical features of schistosomiasis range from fever, headache, and lethargy to severe fibro-obstructive pathology leading to portal hypertension, ascites, and hepatosplenomegaly, which can cause premature death. Infected children are stunted and have cognitive defects impairing memory and learning ability. Current control programs are heavily based on community chemotherapy with a single dose of the drug praziquantel, but vaccines (for use in bovines and humans) in combination with other control strategies are needed to make elimination of the disease possible. In this article, we provide an overview of the biology, epidemiology, clinical features, and prospects for control of oriental schistosomiasis in the Peoples Republic of China.

Mathematical modelling of schistosomiasis japonica: comparison of control strategies in the People's Republic of China

We present the first mathematical model on the transmission dynamics of Schistosoma japonicum. The work extends Barbours classic model of schistosome transmission. It allows for the mammalian host heterogeneity characteristic of the S. japonicum life cycle, and solves the problem of under-specification of Barbours model by the use of Chinese data we are collecting on human-bovine transmission in the Poyang Lake area of Jiangxi Province in China. The model predicts that in the lake/marshland areas of the Yangtze River basin: (1) once-yearly mass chemotherapy of humans is little better than twice-yearly mass chemotherapy in reducing human prevalence. Depending on the heterogeneity of prevalence within the population, targeted treatment of high prevalence groups, with lower overall coverage, can be more effective than mass treatment with higher overall coverage. Treatment confers a short term benefit only, with prevalence rising to endemic levels once chemotherapy programs are stopped; (2) depending on the relative contributions of bovines and humans, bovine treatment can benefit humans almost as much as human treatment. Like human treatment, bovine treatment confers a short-term benefit. A combination of human and bovine treatment will dramatically reduce human prevalence and maintains the reduction for a longer period of time than treatment of a single host, although human prevalence rises once treatment ceases; (3) assuming 75% coverage of bovines, a bovine vaccine which acts on worm fecundity must have about 75% efficacy to reduce the reproduction rate below one and ensure mid-term reduction and long-term elimination of the parasite. Such a vaccination program should be accompanied by an initial period of human treatment to instigate a short-term reduction in prevalence, following which the reduction is enhanced by vaccine effects; (4) if the bovine vaccine is only 45% efficacious (the level of current prototype vaccines) it will lower the endemic prevalence, but will not result in elimination. If it is accompanied by an initial period of human treatment and by a 45% improvement in human sanitation or a 30% reduction in contaminated water contact by humans, elimination is then possible.

Epidemiology of Schistosoma japonicum in China: morbidity and strategies for control in the Dongting Lake region

Dongting Lake, covering a very large surface water area of 2691km(2), is located in Hunan Province in the southern part of the Peoples Republic of China. It is the second-largest freshwater lake in China and plays an important role in regulating the amount of water in the Yangtze River, Chinas longest river. The annual water level of the lake changes by as much as 15m, rising in summer and falling in winter. Asian schistosomiasis has been endemic in the Dongting Lake region for centuries and it has had a devastating effect on the public health of the local people. After a difficult struggle for more than four decades, a concerted programme, supported by the World Bank Loan and instigated in 1992, has resulted in remarkable progress in the control of the disease in many endemic areas of the region. However, the great challenge remains to consolidate and maintain the achievements made to date. The Schistosoma japonicum intermediate host (Oncomelania hupensis hupensis) snail habitats are huge, estimated at 1768km(2) in 1996; these are increasing at a rate of 34.7km(2) annually due to high silt deposition from the Yangtze River itself and from the connecting rivers in Hunan province, and construction of embankments in the Dongting Lake region. It is anticipated that the construction of the Three Gorges Super Dam, the largest engineering project ever undertaken, will substantially extend the range of the snail habitats and increase the number of new schistosomiasis cases. In many areas, human re-infections with S. japonicum after drug (praziquantel) treatment remain unacceptably high (up to 20% of those treated are re-infected annually) due to occupational (mainly fishing) water contact. This paper reviews the history and the current status of schistosomiasis control in the lake region, it explores the epidemiological factors which influence the prevalence of the infection and the disease it causes, and it provides insight into future approaches to control which might finally eradicate the infection.

Schistosomiasis control in the People's Republic of China

Schistosomes, snail-transmitted trematodes (blood flukes), cause a major parasitic disease that ranks second only to malaria in terms of human suffering in the tropics. Schistosoma japonicum has occupied its ecological niche in China for thousands of years; through natural selection it has evolved survival mechanisms that make it difficult (if not impossible) to eradicate. As discussed here by Allen Ross, Li Yuesheng, Adrian Sleigh and Don McManus, vaccination, in combination with current control strategies, may significantly reduce the morbidity of this disease and ultimately improve the quality of life for those living adjacent to endemic zones. This article provides a special focus in Hunan province and examines the potential impact of the Three Gorges Super Dam Project on schistosomiasis control.

Two-year impact of praziquantel treatment for Schistosoma japonicum infection in China: re-infection, subclinical disease and fibrosis marker measurements.

We studied a community cohort of 193 individuals exposed to endemic Schistosoma japonicum infection in the Dongting Lake region of China to assess subclinical morbidity and the 2-year benefit of curative therapy (praziquantel) administered in 1996. Prevalence and intensity of S. japonicum infection before treatment were 28% and 192 eggs per gram faeces (epg), respectively. Two years after cure, 22% of the cohort were re-infected, but with a lighter intensity (67 epg). Sixty-four subjects (37%) showed significant improvement in ultrasound parenchyma images after treatment and 51 subjects (54%) showed significant improvement of periportal fibrosis. Left-lobe enlargement also reversed (P < 0.05) and splenomegaly reversed in 6 of 8 cases and developed in only 1. Two years post-treatment a dilated portal vein became less frequent, but the decline was not significant (16% vs 11%, P < 0.05). The serum levels of laminin and collagen IV associated with re-infection and intensity and hyaluronic acid levels correlated with ultrasound findings (P < 0.01). Overall, treatment induced a marked decrease in subclinical hepatosplenic morbidity attributable to S. japonicum although low-intensity re-infection after treatment remained relatively frequent. Stratified analysis and logistic models evaluated potential confounding factors for assessment of treatment effects on hepatic fibrosis. S. japonicum infection and moderate-heavy alcohol intake interacted: improvement in parenchymal morbidity was impeded among drinkers (P < 0.05). Chemotherapy focused on at-risk residents controls prevalent subclinical hepatic fibrosis but re-infection indicates the need for complementary control strategies.

Diagnosis of schistosomiasis japonica in Chinese schoolchildren by administration of a questionnaire

This paper describes a rapid, simple, cost-effective questionnaire for screening school-aged children at risk for Asian schistosomiasis in China. Five hundred and thirty-two children, aged 8-14 years, were selected from 3 schools in an area moderately endemic for Schistosoma japonicum in Hunan province. The questionnaire, comprising 15 multiple-choice questions, was administered by teachers in order to collect both ethnographic and epidemiological data relevant to current S. japonicum infections. This was followed by Kato-Katz thick smear stool examinations, miracidium hatching tests, and soluble egg antigen-enzyme linked immunosorbent assays in order to validate the efficacy of the questionnaire approach. The results from a combination of all 3 procedures indicated that the overall schistosomiasis prevalence in the 3 schools was 29.9% (138/472). Six risk factors (episodes of diarrhoea, frequency of water contact, school grade attained, weakness, past history of S. japonicum infection(s), and whether a subject had been previously treated for schistosomiasis) in the questionnaire were determined by logistic regression to be highly statistically significant predictors of individual current infection. The sensitivity (93.7%), specificity (91.9%) and low cost (c. US

Measuring exposure to S. japonicum in China. I. Activity diaries to assess water contact and comparison to other measures

0.6/true positive case) associated with the 6 variables model make the questionnaire approach a very useful diagnostic tool for screening marshland and lake communities at high risk for schistosomiasis in China before selective treatment with praziquantel or diagnostic follow-up. An even simpler 3 variables yes/no model was derived from the questionnaire and found to be nearly as good at predicting individual infection (sensitivity 86.2% and specificity exceeding 97.6%) and extremely simple to use. If validated in other ecological settings in China the questionnaire, modified or as presented here, could be adopted by the national schistosomiasis control programme.

HLA class II antigens positively and negatively associated with hepatosplenic schistosomiasis in a Chinese population.

We introduce a new method, activity diaries, in order to evaluate human water contact among fishing communities in an area moderately endemic for Schistosoma japonicum in the Dongting Lake region of Southern China. Two hundred and forty-nine subjects (76% male) were followed prospectively over a 9-month-period in order to verify exposure and reinfection. Exposure was determined crudely with questionnaires, direct 12-h water observations, and more precisely with activity diaries and an adjusted exposure model which took into account the time of day, the duration of contact and the percent body surface area in contact with water. Cohort subjects filled in activity diaries for an average of 85 days as compared with 2 days for the direct water observations. The typical unadjusted mean daily water contact (duration) based on the activity diaries was 53 min with 62% of this time spent in fishing. In contrast, the direct water observations revealed an average daily duration of 149 min with 53% of the time spent in fishing. Human water contact patterns (min/day) by site, activity and body part exposed were examined with the activity diaries. Individuals in the 36-49-year-old age range had the highest degree of water contact. Most of this daily contact occurred by males on the hands (mean+/-S.D.; 83.53+/-67.80 min/day) while fishing (mean+/-S.D.; 87.84+/-8.88 min/day) on the lake (mean+/-S.D.; 85.98+/-69.90 min/day). There was a strong positive log correlation (r=0.95) between the crude and adjusted (based on our derived exposure model) diary outcomes for the entire study sample, however, at higher exposure levels this relationship was differentially weaker (r=0.70). Results from this study suggest that current methods used in evaluating schistosomiasis exposure in China may overestimate and bias measures of the risk of infection. Activity diaries adjusted for the time of day, duration and the percent body surface area exposed are cost-effective and practical instruments to accurately quantify human exposure in the vast lake regions of Southern China where most of the endemic schistosomiasis japonica occurs.

Human susceptibility to Schistosoma japonicum in China correlates with antibody isotypes to native antigens

To identify possible associations between host genetic factors and the onset of liver fibrosis following Schistosoma japonicum infection, the major histocompatibility class II alleles of 84 individuals living on an island (Jishan) endemic for schistosomiasis japonica in the Poyang Lake Region of Southern China were determined. Forty patients exhibiting advanced schistosomiasis, characterised by extensive liver fibrosis, and 44 age and sex-matched control subjects were assessed for the class II haplotypes HLA-DRB1 and HLA-DQB1. Two HLA-DRB1 alleles, HLA-DRB1*0901 (P=0.012) and *1302 (P=0.039), and two HLA-DQB1 alleles, HLA-DQB1*0303 (P=0.012) and *0609 (P=0.037), were found to be significantly associated with susceptibility to fibrosis. These associated DRB1 and DQB1 alleles are in very strong linkage disequilibrium, with DRB1*0901-DQB1*0303 and DRB1*1302-DQB1*0609 found as common haplotypes in this population. In contrast, the alleles HLA-DRB1*1501 (P=0.025) and HLA-DQB1*0601 (P=0.022) were found to be associated with resistance to hepatosplenic disease. Moreover, the alleles DQB1*0303 and DRB1*0901 did not increase susceptibility in the presence of DQB1*0601, indicating that DQB1*0601 is dominant over DQB1*0303 and DRB1*0901. The study has thus identified both positive and negative associations between HLA class II alleles and the risk of individuals developing moderate to severe liver fibrosis following schistosome infection.

Antibody isotype responses, infection and re-infection for Schistosoma japonicum in a marshland area of China.

Antibody isotypic responses (IgE, IgA, IgG1, IgG2, IgG3 and IgG4) to Schistosoma japonicum antigens--adult worm (AWA), soluble egg (SEA) and the recombinant proteins TEG (22.6-kDa tegumental antigen, Sj22) and PMY (paramyosin, Sj97)--were measured (in 1998) in a cohort of 179 Chinese subjects 2 years post-treatment. Subjects in the highest intensity re-infection group (> 100 eggs per gram faeces) had significantly higher levels of IgG1 and IgG4 against AWA. Analysis of IgG4/IgE ratios for AWA and SEA linked IgG4 excess to re-infection and IgE excess to non-re-infection. Two years after chemotherapeutic cure, 29 subjects, who were re-infected or never infected but highly water-exposed, were classified as epidemiologically susceptible (n = 15) or epidemiologically insusceptible to infection (n = 14). IgG4 levels against native antigens (AWA and SEA) were higher in susceptible and IgE levels were higher in insusceptible but antibody responses to the recombinant proteins (PMY and TEG) showed no clear pattern or difference between susceptibility groups. These and earlier findings provide evidence that immunity develops against schistosomiasis japonica in China and that susceptibility/resistance correlates with antibody isotypes against native schistosome antigens.