Influence of the host related factors in the development of the hepatosplenic form of schistosomiasis mansoni

The frequency of hepatosplenomegaly in endemic areas is not proportional to the fecal ova count. This may be explained by epidemiological genetic. The occurrence of two or more cases of schistosomal hepatosplenomegaly in nuclear family is much higher than expected. The concentration is higher among siblings than it is among mothers and children of further and children. It is not significant between father and mother. If the mother, instead of the father has hepatosplenic schistosomiasis the relative risk for the child to acquire hepatosplenomegaly is at least five times (the maternal affect). The inbreeding is highler in the hepatosplenic than in the hepatointestinal patients. In some areas in Brazil the hepatosplenic form of the schistosomiasis mansoni occurs with much higher frequency in whites than in blacks. After treatment, reversion of hepatosplenic schistosomiasis occurs more frequently in non-whithers. It seems that the resistance of blacks to the hepatosplenic form of schistosomiasis may be related to the glyoxalase system , perhaps associated to another genetic marker. The hepatosplenic schistosomiasis is less frequent in longilineal individuals. In some areas the hepatosplenic form of schistosomiasis is more frequent in A blood group of ABO sistem. The family heredograms do not suggest a single mendelian inheritance, but probably a multifactorial and possibility poligenic one.

Harmonization of research and control in schistosomiasis

I have been employed by several different organizations during over 30 years working on schistosomiasis, the majority spent in endemic areas of Caribean, South America, Africa and the Western Pacific. Much of the work is best classified as applied research but sometimes it strayed to the extremes of either public health control programmes or pure research. Over this period, there have been several significant research developments that have altered our whole approach to control. Ideally, research and control should complement each other but, in reality, they sometimes have conflicting objectives. Public health workers understandably wish to provide immediate, shot-term protection to the communities in their care, but research workers may, within ethical limits, reasonably want to observe untreated communities for extended periods in order to understand the underluing process of transmission, disease pathogenesis and immunity to help develop more effective control measures. An example of this situation has occured recently in Senegal where water development projects seem to have favoured the introduction and spreed of Schistosoma mansoni in the Senegal River Basin. I have been asked to be the scientific consultant to the newly formed ESPOIR programme, linking European research organizations and the Senegal Ministry of Health, to reconcile the conflictiong aims of public health workers, wishing to use whatever funds can be obtained for an immediate chemotherapy to try to eliminate the focus, at present confined to the vicinity of a relatively small, commercially run sugar irrigation scheme; and research workers who see a rare chance to study the development of immune mechanisms in a adults in a community not previously exposed to the infection. This information could prove invaluable in understanding the development of immunity and the pathogenesis of disease, leading eventually to the development of vaccines to revolutionise the future approach to schistosomiasis...

The role of egg antigens, cytokines in granuloma formation in murine schistosomiasis mansoni

The induction of granuloma formation by soluble egg antigens (SEA) of Schistosoma mansoni is accompanied by T cell-mediated lymphokine production that regulates the intensity of the response. In the present study we have examined the ability of SDS-PAGE fractioned SEA proteins to elicit granulomas and lymphokine production in infected and egg-immunized mice. At the acute stage of infection SEA fractions (<21, 25-30, 32-38, 60-66, 70-90, 93-125, and > 200 kD) that elicited pulmonary granulomas also elicited IL-2, IL-4 lymphokine production. At the chronic stage a diminished number of fractions (60-66, 70-90, 93-125, and > 200 kD) were able to elicit granulomas with an overall decrease in IL-2, IL-4 production. Granulomas were elicited by larval-egg crossreactive and egg-specific fractions at both the acute and chronic stage of the infection. Examination of lymphokine production from egg-immunized mice demonstrated that as early as 4 days IL-2 was produced by spleen cells stimulated with <21, 32-38, 40-46, 93-125, and >200 kD fractions. By 16 days, IL-2production was envoked by 8 of 9 fractions. IL-4 production at 4 days in response to all fractions was minimal while at 16 days IL-4 was elicited with the < 21, 25-30, 50-56, 93-125, and > 200 kD fractions. The present study reveals differences in the range of SEA fractions able to elicit granulomas and IL-2, IL-4 production between acute and chronic stages of infection. Additionally, this study demonstrates sequential (IL-2 followed by IL-4) lymphokine production during the primary egg antigen response.

Recent advances in immunity to human schistosomiasis

For many years the epidemiological significance of immunity in human schistosomiasis has been the subject of inconclusive debate. Recently, the results of studies from Brazil and Kenya, on Shistosoma mansoni and from Zimbabwe and The Gambia on S. haematobium have confirmed the importance of protective immunity. In communities in endemic areas the development of immunity to infection only occurs after many years of exposure. In part this due to the slow development of antibodies wich are protective but also to the earlier development of antibody isotypes which lack protective capacity and wich are capable of interfering with the functioning of protective antibodies. Protective antibodies appear to be of the IgE class but some IgG subclasses may be also be important. Initially, blocking antibodies were thought to be predominantly IgM and IgG2 but IgG4 also seems to posses blocking activity. The early production of blocking antibodies and late production of protective antibodies may be indicative of cytokine induced immunoglobulin class swiching caused by the sequential involvment of different lymphokines.

Molecular and cellular basis of hepatic fibrogenesis in experimental schistosomiasis mansoni infection

Morbidity in schistosomiasis mansoni occurs primaryly as a result of the complications of hepatic fibrosis. Yet, the pathogenesis of schistosomal hepatic fibrosis is poorly understood. The fact that hepatic egg granuloma is the hallmark of this infection suggests a potential role for granulomatous inflamation in hepatic fibrogenesis. Our studies in a murine schistosomiasis model indicate that hepatic granuloma cells secrete a variety of fibrogenic cytokines that may initiate the scarring process. Among these cytokines, we identified a novel protein that we designated fibroplast stimulating factor-1 (FsF-1). FsF-1 is a lymphokine that can stimulate fibroplast growth and matrix synthesis. A notable feature of hepatic fibrosis in this model is that production of FsF-1 and other granuloma-derived fibrogenic cytokines is down-regulated in chronic infection, an event that may be under immunological control. The spontaneous reduction of FsF-1 secretion presumably accounts for reduced scar formation late in infection of mice. In the context of relevant clinical studies, our findings engender the hypothesis that Symmer's fibrosis may develop in a small suppopulation of individuals as a result of immunogenetically-determined dysregulation of fibrogenic cytokine production.

Serum laminin in hepatosplenic human schistosomiasis

Serum laminin level was measured in chronic schistosomiasis. A significant increase in the mean serum laminin levels was observed in patients with hepatosplenic (HS) schistosomiasis (2,57 ± 0,83U/ml), as compared to those in patients with the hepatointestinal (HI) form of the disease (1,38 ± 0,45-U/ml) and in the control group (1,15 ± 0,31 U/ml). In the HS patients there was a significant direct relatiom between serum laminin and percutaneous splenic pulp pressure (r = 0,68). These findigs are compatible with an increased production of lamin in hepatosplenic schistosomiasis with may be related to the observed enlarged liver and spleen basement membranes in such disease.

Morphological features of collagen degradation in advanced hepatic schistosomiasis of man

Optical and electron microscopical evidences of focal matrix degradation were frequently seen in liver sections taken from patients with periportal ("pipe-stem") fibrosis caused by schistosomiasis mansoni. Besides present of focal areas of rarefaction, fragmentation and dispersion of collagen fibers, the enlargend portal spaces also showed hyperplasia of elastic tisue and disarray of smooth muscle fibers following the destrution of portal vein branches. Ultrastructural cahnges represented by focal lytic and/or electron dense alterations of colagen fibrils were similar to those first seen in experimental material and designated as "chronic collagen degradation". Elastin and related microfibrils were also affected by focal condensation, fragmentation, distorsion and dissolution. Schistosome eggs were scanty in the tissue sections examined. Matrix degradation represented involuting changes related to the progressive diminution of parasite aggression, which occurs spontaneously with age or after cure by chemotherapy. Changes of focal matrix degradation now being described represent the basic morphological counterpart of periportal fibrosis involution documented clinically, especially by ultrasonography, in patients with hepatosplenic schistosomiasis submitted to curative chemotherapy.

The value of ultrasonography in assessment of portal hypertension in hepatosplenic schistosomiasis

Ultrasonography can reveal most of the manifestations of portal hypertension complicating hepatosplenic, schistosomiasis. However, direct demonstration of gastroesophageal varices by ultrasonography is still very difficult. An attempt was done to correlate sonographic features of portal hypertension with the degree of fibrosis to screen patients having varices and predicting their chance of bleeding. The results obtained were found to be consistent with the esophagogastric endoscopy and with history of hematemesis. Four parameters were used, size of spleen, degree of periportal fibrosis, presence of collaterals and portal vein diameter. A pilot field survey was also done adopting the same principle.

Schistosomiasis research funding: the TDR contribution

In spite of the recent decline in financial support on the part of some major donors, the overall international support for schistosomiasis research in current US dollars has been holding steady. However, when adjusted for inflation, a clear decline during the last decade appears and only in a few countries has this decline been balanced by increased national or bilateral funding. The prevailing level of support for schistosomiasis research is barely sufficient to maintain estabilished laboratories and researchers, and highlights the need to attract young investigators. The important goal of brunging a new generation of scientists into the field of schistosomiaisis can only be achieved by a considerable long-term increase in funding, both at the national and the international levels. A break-through in current research emphasizing improved techniques for control is needed to encourage donors and governments to improve the situation.

New approaches to social and economic research on schistosomiasis in TDR

This paper describes new approaches to social and economic research being developed by the Social and Economic Research component of the Special Programme for Research and Trainning in Tropical Diseases of the World Health Organization. One of these is a study to acess the possibility of identifying high risk communities for urinary schistosomiasis through a "mailed"questionaire approach distributed through an existing administrative system, thereby eliminating the need for face-to-face interviews by the research or disease control team. This approach, developed by the Swiss Tropical Institute in Ifakara, Tanzania, i s currently being tested in seven other African countries. The paper also describes a change of emphasis of economic research on schistosomiasis, focusing on the intra-household effects of the disease on rural households, rather than, as previously done, studying the impact of the disease on the productivity of individual wage labourers. Other priorities involve the identification of epidemiological information neede for improoved decision-making regarding acceptable treatment strategies in endemic areas with limited financial capacity, as well as research on how the adverse effects of economic development projects can be alleviated.

Effector functions of eosinophils in schistosomiasis

The dual function of eosinophils is clearly illustred in schistosomiasis. Well equipped in membrane receptors for immunoglobulins and complement, and due to the presence of granule basic proteins, eosinophils can become cytotoxic for parasite larvae and thus participate to protective immunity. However mediators can also exert their cytolytic effect on normal cells or tissues, inducing therefore pathology. Through ADCC mechanisms against schistosome larvae in vitro involving different antibody isotypes (IgG, IgE and IgA) and also in experiments performed in vivo, eosinophils have been clearly involved in protective immunity. Although no direct evidence of the protective role of eosinophils were brought in humans, the striking association of eosinophil-dependent cytotoxic antibody isotypes with resistance to reinfection (for instance IgE and IgA antibodies), whereas in vitro blocking antibody isotypes (IgG4, IgM) were detected in susceptible subjects, strongly, suggested the participation of eosinophils in antibody-dependent protective immune response. However eosinophils could also participate to granuloma formation around S. mansoni eggs and consequently to the pathological reactions induced by schistosomiasis.

Experimental murine schistosomiasis mansoni: estabilishment of the chronic phase of the disease

After the acute hyperergic phase of schistosomal infection, the chronic phase of the disease corresponds to the estabilishment of a relative equilibrium between the host and the parasite. This involves: (1) A shift from the predominance of the TH2 response observed in the acute phase, to the predominance of the TH1 response in the chronic phase of the disease, with modification of lymphokine and immunoglobulin secretions patterns. (2) Redistribution of hosts responses to parasite, with predominance of systemic controls in the acute phase, and a shift towards local tissue responses in the chronic phase. This redistribution relieves the hyperergic responses involving the whole body of the host, and delimits cellular and molecular reactions to parasites to only those tissues that are directly involved by the adult parasites and their eggs. Mobilization of eosinophil granulocytes in schistosomal periovular granulomas is one of examples of this redistribution.

Cross-sectional and evolutive studies of schistosomiasis mansoni in untreated and mass treated endemic areas in the southeast and northeast of Brazil

Cross-sectional and evolutive studies on schistosomiasis mansoni were carried out before and after mass treatment in the endemic areas of Capitao Andrade and Padre Paraíso, state of Minas Gerais, Riachuelo, state of Sergipe, Alhandra, state of Paraíba, and Aliança, Alegre and Coroatá, lowland of the state of Maranhao, Brazil, in the last eighteen years. The studies included clinical and fecal examination by the Kato-Katz quantitative technique, skin testfor Schistosoma mansoni infection, evaluation of man-water contact and other epidemiological investigations such as infection rate and dynamic of the snail population. Results showed: (1) Higher prevalence of S. mansoni infection, greater egg load elimination and higher and earlier morbidity of the chronic froms of the disease in the southeast areas of Capitao Andrade and Padre Paraíso; (2) The incidence of hepatosplenic form is higher in some family clusters, in whites and mullattos in all the endemic areas but develop earlier in the southeast; (3) The prevalence and morbidity of schistosomiasis are decreasing both in the mass treated northeast and in the untreated southeast areas; (4) The mass treatment reduces rapidily the prevalence of the infection and the morbidity of the disease but can not control it because of the frequent reinfections due to the intensity of man-water contact.

Portal hypertension in schistosomiasis: pathophysiology and treatment

In heavily infected young patients, there is a "non-congestive" phase of the disease with splenomegaly which can improve after chemoterapy. A strong correlation between hepatosplenic form and worm burden in young patients has been repeatedly shown. The pattern of vascular intrhepatic lesions seems to depend on two mechanisms: (a) egg embolization, with a partial blocking of the portal vasculature; (b) the appearance of small portal collaterals along the intrahepatic portal sistem. The role played by hepatitis B virus (HBV) and C virus infections in the pathogenesis of liver lesions is variably considered. Selective arteriography shows a reduced diameter of hepatic artery with thin and arched branches outlining vascular gaps. A rich arterial network , as described in autopsy cases, is usually not seen in vivo, except after splenectomy or shunt surgery. An augmented hepatic arterial flow was demonstrated in infected animals. These facts suggest that the poor intrahepatic arterial vascularization demonstrated by selective arteriography in humans is due to a "functional deviation"of arterial blood to the splenic territory. The best results obtained in treatment of portal hypertension were: esophagogastric desvascularization and splenectomy (EGDS), although risk of rebleeding persists; classical (proximal) splenorenal shunt (SRS) should be abandoned; distal splenorenal shunt may complicate with hepatic encephalopaty, although later and in a lower percentage than in SRS. Propranolol is currently under investigation. In our Department, schistosomotic patients with esophageal varices bleeding are treated by EGDS and, if rebleeding occurs, by sclerosis of the varices.

Alternative approaches in schistosomiasis control

Measures for for the control of schistosomiasis were implemented in Egypt begining 1922. This shows that developing endemic countries are facing this problem for near 70 years. However, results in the control of this infection have not been satisfactorily obtained in spite of the technologies and strategies recently developed. The idea that the social and economic components are relevant in the control of schistosomiasis is not new although its extension and profundity have not usually been well understood. More recently; most of the workers have recognized that the distribution of the prevalence rates of schistosomiasis should not be neglected in the control of the infection. At present field work projects on the control of schistosomiasis are being developed in rural areas of two Brazilian states (Espirito Santo and Pernanbuco). The adopted strategy aims to interfere in the complex relationships between amn and his bio-social-cultural environment, without forgeting tha the unequal distribution of the space is a consequence of the political and economic organization of the Society.