Dominique-Angèle Vuitton

An epidemiological and ecological study of human alveolar echinococcosis transmission in south Gansu, China.

Human alveolar echinococcosis (AE) is usually a rare, highly pathogenic zoonotic disease, transmitted across the northern hemisphere between fox and rodent hosts. In China the first cases were described in 1965; however very few epidemiological studies have been undertaken since. Following identification in 1991 of a serious focus of human AE in south Gansu province, detailed village-based community and ecological studies were carried out between 1994 and 1997. Hepatic ultrasound mass screening with serological testing (five tests) identified 84/2482 new AE cases (3%). An overall prevalence of 4.1% (135/3331) was recorded for the area when previous cases were also included. Based on a seropositive result only, without an ultrasound scan indication, no additional AE cases were identified. Of the evolutive AE cases, 96% were seropositive in at least one test, while up 15-20% of individuals who exhibited hepatic calcified lesions and 12-15% exhibiting hepatic nodular lesions were seropositive for specific Em2 or Em18 antibodies. Village (n=31) human AE prevalence rates varied from 0 to 15.8%. Questionnaire analysis indicated that total number of dogs owned over a period was a risk factor (P<0.006), but not a history of red fox hunting (P>0.6). Rodent ecology studies revealed an association between density indices of voles (Microtus limnophilus) and village AE prevalence rates, on the one hand, and village landscape characterised by a ratio of scrub/grassland to total area above 50% (P<0.005). Long-term transmission of Echinococcus multilocularis and risk of zoonotic infection of south Gansu farmers may be related ultimately to a process of deforestation driven by agriculture. This in turn probably results in creation of optimal peri-domestic habitats for rodents that serve as intermediate host species (such as M. limnophilus) and subsequent development of a peri-domestic cycle involving dogs.

A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France.

Objectives Alveolar echinococcosis of the liver is a very rare and severe parasitic disease due to the growth of the larva of Echinococcus multilocularis. The aim of this paper was to describe a 20‐year study of the epidemiological, clinical and therapeutic aspects of alveolar echinococcosis in eastern France. Design One hundred and seventeen consecutive cases, diagnosed and followed in our liver unit, were studied from 1972 to 1993. Methods Data from 85 patients followed since 1983 (period B) were compared to data from a first series of 32 patients (period A) collected from 1972 to 1982; 1983 was chosen as the cut‐off year because of the numerous changes that occurred in the diagnosis, follow‐up and treatment of the disease at this time, in particular the introduction of parasitostatic benzimidazoles. Results The results of patient follow‐up were evaluated in December 1997. The cumulative prevalence was 2.5 per 100 000 persons in period A whereas it reached 6.6 per 100 000 in period B. The annual incidence in period B was 7.3 on average, compared with 2.7 in period A. Twenty‐nine per cent of patients from period B were asymptomatic at the time of diagnosis compared with 10% in period A. This change was correlated with less advanced liver lesions, and was related to the extensive use of abdominal ultrasound, and from 1987, serological screening. Curative resections were performed in 24% of the cases in period B versus only 3% in period A. From 1986, liver transplantations were performed in eight patients from period A and 13 patients from period B. In period B, palliative surgery was frequently replaced by radiological non‐operative procedures to treat abscesses and jaundice. From 1982, 73 patients received benzimidazoles for a period of time ranging from 4 to 138 months. Stabilization of the lesions was observed in two‐thirds of the patients. Episodes of jaundice or digestive haemorrhage due to portal hypertension were 31.5 and 11 times less frequent respectively in patients from period B compared with period A. Actuarial survival at 5 years improved from 67% in period A to 88% in period B in patients of similar age. Conclusions Radical changes in the diagnosis and the management of alveolar echinococcosis have occurred during the last decade. Together they have contributed to an improvement in the status of the patients affected by this very severe parasitic disease. Eur J Gastroenterol Hepatol 12:327‐336

Interactions between landscape changes and host communities can regulate Echinococcus multilocularis transmission

An area close to the Qinghai-Tibet plateau region and subject to intensive deforestation contains a large focus of human alveolar echinococcosis while sporadic human cases occur in the Doubs region of eastern France. The current review analyses and compares epidemiological and ecological results obtained in both regions. Analysis of rodent species assemblages within quantified rural landscapes in central China and eastern France shows a significant association between host species for the pathogenic helminth Echinococcus multilocularis, with prevalences of human alveolar echinococcosis and with land area under shrubland or grassland. This suggests that at the regional scale landscape can affect human disease distribution through interaction with small mammal communities and their population dynamics. Lidickers ROMPA hypothesis helps to explain this association and provides a novel explanation of how landscape changes may result in increased risk of a rodent-borne zoonotic disease.

Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report.

Background. Alveolar echinococcosis (AE) of the liver is a rare and severe parasitic disease. It behaves like a slow-growing liver cancer, and liver transplantation (LT) has been proposed in advanced cases since 1985. The aim of this retrospective study was to collect all AE transplant cases in Europe, analyze the results, and specify the usefulness of LT for this unusual indication. Methods. A questionnaire was sent to 83 LT centers from July 1996 to December 1999. Results. Sixty-five centers responded: 45 AE patients (mean age, 45.8 years) underwent an LT procedure at 16 LT centers. The mean interval between diagnosis and LT was 5 years. One patient died during the hepatectomy phase. Five-year survival was 71%. Five-year survival without recurrence was 58%. The nine early deaths were mostly related to bacterial or fungal infections, or both, in patients in bad condition when LT was performed. Six patients had a graft AE reinfection. Five late deaths were related directly to ongoing AE. In the other cases, benzimidazole (BZM) therapy seemed to stabilize AE residues. Conclusions. This unique experience indicates that LT is feasible for life-threatening AE. Specific management is needed to optimize the results: earlier decision for LT in incurable symptomatic biliary AE, pre- and post-LT BZM therapy, meticulous pre-LT evaluation to identify extrahepatic extension, and an immunosuppressive regimen kept to a minimum.

Assessment of the epidemiological status of Echinococcus multilocularis in foxes in France using ELISA coprotests on fox faeces collected in the field

The aim of this study was to estimate the relevance of Echinococcus multilocularis coproantigen detection in fox faeces collected in the field to identify different levels of endemicity for Echinococcus multilocularis on a large scale (n x 10 km(2)). Six study sites were selected in a high endemicity area and two study sites in a low endemicity area in eastern France on the basis of landscape composition. Sampling was undertaken in the winters of 1996-97, 1997-98 and 1998-99. At each site, (i) necropsy and intestine examination was undertaken on a sample of shot foxes (total number of foxes, 222), and (ii) fox faeces were collected in the field along road verges, and scored for degradation status (total number of faeces, 625). Fox faeces were also sampled in a control area (n=30) in western France in the summer of 1998. Intestines were examined according to the sedimentation method. Echinococcus multilocularis coproantigens were detected by using two ELISA tests: EM-ELISA and EmA9-ELISA. The necropsy prevalence in high and low endemicity areas was 63.3% and 19.4%, respectively, and the distribution of adult worms in the fox population was highly overdispersed (75.5% of the total biomass was harboured by 11.6% of foxes). Using the two ELISA tests, there was no difference in the detection of E. multilocularis coproantigens in field faeces, regardless of the degradation status. The medians of EM- and EmA9-ELISA OD values of field faeces in high endemicity area were significantly higher than in low endemicity area (P<0.001 for both ELISA). The distribution of EM-ELISA OD values in low endemicity area was significantly higher (P=0.002) than in the control area. Moreover, for the two ELISA, the observed ELISA OD value distributions in high endemicity area, low endemicity area and control area seemed representative of the distribution of adult worms in fox populations. These results indicate that E. multilocularis coproantigen detection in field faeces could serve for large-scale surveillance, as an alternative to necropsy.

Cellular immunity in experimental Echinococcus multilocularis infection. II. Sequential and comparative phenotypic study of the periparasitic mononuclear cells in resistant and sensitive mice.

Cellular immune responses have been shown to be associated with differential evolutions of E. multilocularis infection in intermediate hosts. A relationship between course of delayed‐type hypersensitivity (DTH) against parasitic antigens and receptivity of murine strains has been demonstrated recently. The aim of this study was to correlate resistance and sensitivity to E. multilocularis infection with the phenotypic patterns of cells within the periparasitic granuloma. Evolution of the ratios, macrophages/T lymphocyte and Lyl/Ly2 T lymphocytes, was associated with the receptivity of the strains. Persistence of numerous L3T44+T lymphocytes and low numbers of macrophages and Ly2+T lymphocytes were observed in the ‘resistant’ C57BL.10 mice. Comparison of the results with course of the DTH against E. multilocularis antigens showed that the particular phenotypic pattern observed in resistant mice was associated with a particular profile of DTH after infection. These results and similar observations in human alveolar echinococcosis suggest that cell composition of the periparasitic granuloma might be of crucial importance in controlling the spontaneous development of E. multilocularis larvae in the intermediate host.

Genotyping of human cystic echinococcosis in Xinjiang, PR China

The Xinjiang Uygur Autonomous Region, multi-ethnic province in northwestern China, is one of the most important foci of human cystic echinococcosis (CE) in the world. Two Echinococcus granulosus genotypes (G1 and G6) are known to infect the intermediate hosts in this area but, to date, the source of the human infection remains unclear. The current study aimed to genetically analyse 67 hydatid cysts removed from 47 CE patients for which epidemiological, clinical and serological data were also recorded. Mitochondrial cox 1 gene sequencing suggested that the E. granulosus G1 genotype is the major source of infection (45/47 CE patients). Nevertheless, for the first time in China, 2 patients were found with hydatid cysts of the G6 genotype. In addition, 45 E. granulosus gravid tapeworms, isolated from 13 dogs, were genotyped. The majority of adult worms (42/45) exhibited the G1 genotype, whereas 3 adult tapeworms with the G6 genotype were found in one dog, that also harboured E. granulosus tapeworms of the G1 genotype. This sympatric occurrence of G1 and G6 genotypes of E. granulosus, not only in the same area but also in the same definitive host, raises the interesting question of putative genetic recombination between these E. granulosus genotypes.

Indications and results of liver transplantation for Echinococcus alveolar infection: an overview.

BackgroundAlveolar echinococcosis (AE) of the liver, caused by the larval stage of the fox tapeworm Echinococcus multilocularis, has the characteristics of a slow-growing liver cancer. It is one of the rare parasitic diseases for which a parasitolytic drug is not yet available, and AE is lethal in the absence of appropriate therapeutic management. Complete surgical resection of the parasite at an early stage of infection provides favourable prospects for cure, but, due to a long clinical latency, many cases are diagnosed at an advanced stage, so that partial liver resection can be performed in only 35% of patients. Benzimidazole (BZM) treatment is given in inoperable cases but these compounds are only parasitostatic, and lifelong therapy is required. During the past 20 years some centres have considered liver transplantation (LT) for the treatment of incurable AE.MethodsOur review summarizes the results of this experience based on a series of 47 European patients who received transplants between 1985 and 2002, tries to specify the real place of LT for AE, and underlines the measures that could be undertaken in the future to improve the results.ResultsFive-year survival was 71%. Five-year survival without recurrence was 58%. Major technical difficulties related either to previous laparotomies or to the loco-regional involvement were observed. The nine early deaths concerned AE patients with a long past-history of symptomatic AE (iterative cholangitis, secondary biliary cirrhosis). Five late deaths were directly related to ongoing AE, located in the brain in three cases, a very rare AE location that was not investigated before LT in these patients.ConclusionsIn general, the pre-LT screening for distant AE metastases appeared insufficient in this series. Heavy immunosuppressive schemes, absence or delayed re-introduction of BZM after LT have clearly played a role in this unfavourable course. This unique experience indicates that, despite major technical difficulties, LT for incurable AE is feasible and could be discussed in very symptomatic cases. Before LT, interventional radiology should be preferred to repeated laparotomies. Pre-LT and post-LT BZM treatment is mandatory. A careful evaluation of possible distant metastases should be done before the decision for LT is made. After LT, the possibility of an ongoing AE must be permanently kept in mind. This could be reduced by lightening the immunosuppressants, carefully following the specific circulating antibodies, and applying a systematic radiological evaluation, not only to the graft but also to the lungs and the brain.

Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. I. Comparison of patients with progressive and abortive lesions

To clarify the role of Th1‐ and Th2‐type cytokines in the various outcomes of human alveolar echinococcosis (AE), the cytokine immune response of self‐cured patients was studied and compared with those of progressive AE patients and healthy subjects. Self‐cured patients were divided into two groups according to the following clinical features: subjects who had positive Echinococcus multilocularis serologies and hepatic calcifications typical of AE were classified as ‘abortive AE’ patients, and those who had positive E. multilocularis serologies but no hepatic lesions or calcifications detectable by ultrasonography were classified as ‘positive serology’ subjects. Secretions of IL‐5, IL‐10 and interferon‐gamma, and expression of IL‐5 mRNA were evaluated in peripheral blood mononuclear cells (PBMC) stimulated in vitro with the mitogen phytohaemagglutinin‐C or specific E. multilocularis antigenic preparations. The cytokine profile of abortive AE patients was the opposite of that observed in progressive AE patients. An intermediate profile was observed in positive serology subjects. PBMC from abortive AE patients, whether non‐stimulated or stimulated with PHA and antigenic preparations, secreted significantly lower levels of IL‐10 than those isolated from progressive AE patients. Our observations seem to confirm the regulatory role of IL‐10 in the immunopathology of human AE.

Effects of cyclosporin a on the course of murine alveolar echinococcosis and on specific cellular and humoral immune responses against Echinococcus multilocularis

The effects of cyclosporin A (CsA) on Echinococcus multilocularis (E. multilocularis) metacestode growth, and on the specific immune responses of the hosts, were examined in AKR mice. Mice were intra-peritoneally infected with a metacestode homogenate. CsA (40 mg kg(-1) day(-1)) was injected subcutaneously from the 45th day after infection (Group 1), and from the day before infection (Group 2) until the day of autopsy (days 125 and 80, respectively). Results showed that unlike ths situation with some other helminthiases, CsA had no antiparasitic effect, although it lengthened the maturation time of protoscoleces in Group 1. The parasitic burden, unmodified in Group 1, was significantly enhanced in Group 2. This enhancement was associated with a decrease in antibody levels, whereas the delayed-type hypersensitivity was decreased in the two groups. These results confirm the role of cellular immunity in controlling the first stages of the larval development of E. multilocularis and indicate the necessity for a careful follow-up of any recurrence of alveolar echinococcosis in patients treated with CsA after liver transplantation.