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We performed an electron microscopy study and histological examination of hepatocytes during hepatic echinococcosis. The type of damage to liver cells depended on intrahepatic localization of hydatid cysts, which determined the development of postoperation complications.
Alveolar echinococcosis (AE) is a rare, but potentially severe zoonotic disease caused by Echinococcus (E.) multilocularis. Recent findings indicated an increasing importance of AE for non-human primates living in regions endemic for E. multilocularis. The death of five cynomolgus monkeys (Macaca fascicularis) and a lowland gorilla (Gorilla g. gorilla) due to AE raised concern about the incidence of this parasite in the Basle Zoo. Consequently, a project was initiated to investigate the prevalence amongst an affected group of cynomolgus monkeys, as well as in foxes and mice. Three out of 46 monkeys were seropositive for E. multilocularis antigen. In two of these monkeys and in another three animals, which were seronegative, structures compatible with metacestodal cysts were observed using ultrasonography. Seven out of 35 free roaming foxes caught at the zoo were positive for an intestinal E. multilocularis copro-antigen ELISA, four of them shed taeniid eggs simultaneously. No lesions compatible with AE were present in 50 necropsied mice from the zoo area. These results indicate that the fox population is a potential source to introduce E. multilocularis and may thus represent a risk for the zoo animals.
We report the first case, to the best of our knowledge, of a woman suffering from cystic echinococcosis of the liver, who consequently developed urticaria and acute generalized exanthematous pustolosis (AGEP). Serum immunoglobulin (Ig)E and IgG4 specific to Echinococcus granulosus antigens were detected by immunoblotting. Furthermore, the intracellular cytokine analysis revealed a prevalent T-helper 2 polarization. It can be reasoned that, while the presence of IgE specific to various E. granulosus allergens may be responsible for the chronic urticarial manifestations, the detection of IgG4 specific for E. granulosus antigens, forming immunocomplexes, may be related to the development of the AGEP.
Allergic reactions, such as urticaria, itching and anaphylactic shock, often complicate the course of cystic echinococcosis (CE). To investigate the role of the IgE-immunoreactive recombinant Echinococcus granulosus elongation factor-1 beta/delta (EgEF-1 beta/delta) in the allergic disorders during CE we determined humoral and cell-mediated responses to this antigen in patients with CE grouped according to the clinical presence or absence of allergic reactions. Immunoblotting analysis showed that serum IgE-binding reactivity to EgEF-1 beta/delta differed significantly in patients with and without allergic reactions (38 of 42, 90% vs. 31 of 56, 56%; P < 10(-4)). EgEF-1 beta/delta induced a proliferative response in 14 of 19 (74%) patients' peripheral blood mononuclear cells (PBMC) irrespective of the allergic manifestations and skewed Th1/Th2 cytokine activation towards a preferentially Th2 polarization. Epitope mapping identified an immunodominant epitope of 18 residues with 78% identity and 89% similarity with an IgE-immunoreactive Strongyloides stercoralis antigen. Overall these findings suggest that EgEF-1 beta/delta is an allergenic molecule that may be a general marker of the intensity of CE immune response and that could lead to a deeper understanding of the specific antigen-induced mechanisms underlying allergic reactions in the human host.
By immunological screening of a cDNA library derived from protoscoleces of Echinococcus granulosus with IgE from patients with cystic echinococcosis (CE) and allergic manifestations, we isolated a protein identical to E. granulosus cyclophilin. The protein, named EA21, has close homology with Malassezia furfur cyclophilin allergen (Mal f 6) and with human cyclophilin. Using immunoblotting (IB) with a polyclonal antibody specific to EA21, we identified E. granulosus cyclophilin both in protoscoleces and in sheep hydatid fluid. Of the 58 sera from patients with CE, 29 (50%) were IgE positive to EA21, whereas, despite the high sequence homology, none were IgE positive to Mal f 6 or human cyclophilin. Only 26 of the 58 patients (45%) had IgG specific to EA21, whereas all patients (100%) had IgG specific to Mal f 6 and human cyclophilin. IB analysis showed that serum IgE-binding reactivity to EA21 differed significantly in patients with and without allergic reactions (20 of 25, 80% versus nine of 33, 27%; P < 10(-4)). Conversely, five of the 25 patients who had CE-related allergic manifestations (20%) and 21 of the 33 who did not (63%) had specific IgG4 (P = 10(-3)) and total IgG to EA21. EA21 induced a proliferative response in 15 of 19 (79%) patients' PBMC regardless of the allergic manifestations, but it induced no IL-4 production. Overall, these findings suggest that E. granulosus cyclophilin is a conserved, constitutive, parasite protein that does not cross-react with cyclophilins from other organisms and is involved in the allergic symptoms related to CE.
Seeking better immunological markers indicating the long-term outcome of cystic echinococcosis (CE) after chemotherapy we studied 23 patients receiving albendazole, clinically followed for 8 years, and grouped ultrasonographically according to therapeutic outcome. Antibody responses against a partially purified fraction of hydatid fluid (HFF) and antigen B (AgB) were evaluated by indirect haemagglutination (IHA), ELISA and immunoblotting (IB). Although IHA titres varied over the course of treatment, differences in mean antibody titres to HFF between groups were significant only at 4 years (P = 0.031). IgG isotype expression remained unchanged during follow-up whereas IgE expression decreased in patients with cured or stable disease. AgB disclosed higher IgG4 expression (P < 10(-4); P = 0.025) and lower IgG1 expression than HFF (P < 10(-4); P = 0.022). IHA antibody titres were higher in patients with progressive than in those with cured or stable disease, even in those with the same cyst type. ELISA isotype profiles differed between groups, particularly for type CE 3, 4 and 5 cysts: higher serum IgG1 and IgG3, lower IgG4 and IgE in patients with cured or stable disease. Although combined serological testing provides scarce information on the long-term outcome of CE after chemotherapy it may be useful for reviewing in a retrospective study the outcome of a cyst and for assessing the host-parasite relationship.
We postulated that TAP genes may influence the susceptibility of some individuals to Echinococcus multilocularis infection. Six coding region variants (codons 333 and 637 in TAP1, and 379, 565, 651 and 665 in TAP2) were typed in 94 patients and 100 controls. Thr/Thr homozygosity at TAP2/665 was more prevalent in patients than in controls [64% vs. 45%, respectively; odds ratio (OR) = 2.1 (95% confidence interval (CI) 1.1; 2.7)] and Thr/Ala heterozygozity was less prevalent (32% vs. 50%, respectively) (P = 0.014). Of the 38 patients with progressive lesions, 76% were Thr/Thr, as compared with 55% of patients without progressive lesions and 45% of controls (P = 0.058 and 0.02, respectively), independent of HLA status. To determine whether this association is functionally relevant, functional analyses and/or confirmation in distinct populations of patients with alveolar echinococcosis would be required.
The immunological properties of the purified alkaline phosphatase (pAP) of Echinococcus multilocularis metacestodes have been investigated using alveolar echinococcosis (AE) patient sera in ELISA tests. A comparative study was done with EmC-Ag (crude antigen) and pAP-Ag (purified antigen). When the parasite purified enzyme pAP was used as antigen, the specificity of the ELISA was markedly increased since it reached 100% without any decrease of its sensitivity (100%). The serologic follow-up of AE patients was conducted during several months with these two antigens in three categories of patients: cured, stabilized and aggravated. There was a good correlation between clinical and serologic data when the pAP was used as antigen in ELISA tests. The anti-pAP antibodies titres did change more rapidly than anti-EmC antibodies titres when a recurrence occurred. Modifications of the anti-pAP antibodies levels were also observed during the patient's therapy: mebendazole, albendazole and Isoprinosine. These results suggest that pAP-Ag should be used for the diagnosis and the follow-up of AE patients.
Using an experimental model of hepatic Echinococcus multilocularis infection in C57BL/6J mice, intraperitoneal administration of 0.8 microgram of recombinant IL-12 to mice with an established infection was shown to reduce the parasite burden as soon as two weeks after the end of treatment. At that time, in vitro Echinococcus multilocularis-induced spleen T cell proliferative responses as well as IFN-gamma and IL-5 production were higher in IL-12 treated mice than in untreated mice. Administration of 0.8 microgram of IL-12 at the time of infection was shown to be without effect on the parasite establishment. However, this treatment greatly inhibited the subsequent metacestode development. Indeed, ten weeks after infection, it induced a complete healing in 37.5% of mice. At that time, the development of metastases was inhibited in 68.75% of IL-12-treated mice. This reduction of parasite burden was mainly associated with a strong proliferation of spleen cells to E. multilocularis antigen and with a high IFN-gamma production. Altogether, our results show that IL-12 is of crucial importance in inhibiting the larval growth after the metacestode establishment in the liver and suggest that this cytokine could be of potential value in the treatment of human alveolar echinococcosis.
Zinc is an essential trace element for immune function that plays a role in immune response against parasites. To determine a possible relationship between zinc level and disease status in alveolar echinococcosis (AE), we investigated serum concentrations of zinc, immunoglobulin (Ig)E, IgG, and C-reactive protein (CRP) in 40 AE patients and 20 controls. Patients were classified into three groups: group A: patients after curative surgery, group B: patients with stabilized disease, group C: patients with progressive disease. Patients showed significantly higher levels of IgE and IgG than controls. Amounts of IgE and IgG were related to disease severity, achieving highest levels in group C and lowest in group A. Zinc levels were comparable in patients and controls. However, there was an obvious association between zinc concentration and disease severity. Zinc was far below the normal range in group C (median 9.2 micromol/l) and significantly diminished compared to group B and controls. An inverse pattern was seen for CRP. In conclusion, lowered zinc concentration in progressive cases may be caused by enhanced immune activation but consumption of zinc by the growing parasite may also play a role. Furthermore, decreased zinc levels may contribute to the observed immunosuppression in AE.
The availability of mice carrying a deletion of LT-alpha and tumour necrosis factor (TNF)-alpha genes enabled us to investigate the role of the TNF during alveolar echinococcosis. We compared the growth rate of Echinococcus multilocularis in LT-alphaTNF-alpha +/+ mice to that of mice having either no or only one LT-alphaTNF-alpha functionnal allele. LT-alphaTNF-alpha -/- mice harboured a significantly higher parasite burden than did the other two populations at 5, 10, and 15 weeks of infection, and they did not survive thereafter. Liver metacestodes removed from these mice were alive and the dehydrogenase activities of peritoneal metacestodes were decreased. Liver lesions regressed in most wild-type mice. Indeed, dead parasites were cordoned by granulomas containing numerous macrophages and lymphocytes leading to focal liver fibrosis at an early stage of infection. In contrast, most of LT-alphaTNF-alpha -/- mice harboured metacestodes interspersed with leucocytes, realising purulent abscesses with secondary extensive irregular fibrosis at a late stage of infection. Heterozygous mice had behavioural characteristics intermediate between homozygous mutants and wild-type mice. Levels of E. multilocularis-specific delayed-type hypersensitivity and serum antibodies were slightly decreased in LT-alphaTNF-alpha -/- mice. This study shows that TNF-alpha and/or LT-alpha genes play an essential role in the immune protection mechanisms against E. multilocularis at the site of infection.
To evaluate the diagnostic sensitivity and specificity of immunoelectrophoresis (IEP), indirect haemagglutination (IHA), enzyme-linked immunosorbent assay (ELISA) and immunoblotting (IB), we compared their ability in detecting IgG antibodies to a hydatid fluid fraction (HFF) and to native and recombinant antigen B of Echinococcus granulosus. We tested sera from patients who had cystic echinococcosis (CE) grouped according to their type of cysts (n = 204), from patients with other parasitic diseases (n = 21), lung or liver carcinomas (n = 6) or serous cysts (n = 26) and from healthy controls (n = 90). HFF-IB gave the highest sensitivity (80%) followed by ELISA (72%), IHA (54%) and IEP (31%), respectively. The diagnostic sensitivity significantly (P < 0.01) decreased as cysts matured from type I-II to type VII. Recombinant and native antigen B-IB yielded similar sensitivity (74%). A large number of clinically or surgically confirmed CE patients (20%) resulted negative. In these patients' sera, IB to assess the usefulness of the recombinant E. granulosus elongation factor-1 beta/delta in detecting IgE antibodies yielded 33% of positivity. Our findings underline the need to standardize techniques and antigenic preparations and to improve the performance of immunodiagnosis by characterizing new antigens and detecting distinct immunoglobulin classes.
In the past years, the diagnostic tools applied to identify alveolar (AE) and cystic echinococcosis (CE) in human patients have not only increased in number but also substantially improved in quality. The identification and characterization of species-specific parasite proteins/antigens allowed to generate subsequently recombinant or synthetic polypeptide antigens, as well as corresponding monoclonal antibodies. Some of these new tools have already demonstrated operating characteristics superior to conventional tests used for the immunodiagnosis of CE and AE, and thus may be suggested for routine laboratory application. Powerful molecular techniques, such as the polymerase chain reaction (PCR), have been developed and adapted to advance laboratory diagnosis of AE and CE. Detecting minute amounts of parasite DNA and mRNA, not only to identify but also to characterize the biological status of parasite material, thus becomes a complementary method to synergize immunodiagnostic techniques. This review focuses on recent developments of molecular tools, discussing their potential use as a primary or a supporting diagnostic element. We also outline some future developments to be undertaken in the field of molecular diagnosis, linked to clinical and laboratory problems.
Several cases of hydatid echinococcosis were diagnosed in a laboratory colony of 19 pig-tailed macaques (Macaca nemestrina) at the Paul Ehrlich Institute, Germany. Three hydatid cysts were found in the liver of an euthanized animal. The diagnosis of an Echinococcus granulosus infection was confirmed by histopathology and the results of a specific polymerase chain reaction. The serum of five of 14 other monkeys tested for Echinococcus antibodies using a genus-specific enzyme-linked immunosorbent assay (ELISA) was positive or weakly positive; none of the animals, however, showed specific reactions in a E. multilocularis-specific ELISA. On ultrasonographic examination, alterations in the liver were found in four of the serologically positive monkeys, and two animals showed clinical signs such as progressive anorexia, apathy and icterus. The monkeys had most probably acquired the E. granulosus infection in their breeding colony in Slovenia.
This study was conducted between April 2000 and March 2001, in 12-month period. During the study, local slaughterhouses were visited periodically for 1 year to examine the internal organs (livers, lungs, spleens and hearts) for the presence of cysts and total 1355 cattle, 218 sheep and 104 goats were examined for the cystic echinococcosis (CE). It was found that 13.5% of cattle, 26.6% of sheep and 22.1% of goats were infected with this disease. While cysts in cattle (P < 0.001) and goats (P > 0.05) were found mostly in lungs (88.5 and 82.6%, respectively), but they were mostly found in livers (P > 0.05) in sheep. In addition to this, three spleens and one heart in cattle were infected with CE. In this study, the prevalence of CE and the number of cysts in ruminants were found different when the cattle, sheep and goats examined were stratified based on age. The prevalence and the number of cysts increased with age approaching an asymptotic prevalence of one in the oldest animals (P < 0.05). The number of cysts in cattle, sheep and goats were increasing at a rate of 0.31, 0.63 and 0.42/year, respectively. The economic decrease in the value of the carcasses because of the discarded liver and lung as a result of CE was estimated as 1.1% (7.5 US dollars per cattle) for cattle, 4.37% (3.2 US dollars per sheep) for sheep and 4.26% (2.9 US dollars per goat) for goats. The minimum total loss for all infected animals was determined to be 583 US dollars in infected animals, based on the market prices in the year 2002.
Twenty years after the first cases of echinococcal disease were treated with albendazole, it has become an important component in the overall management of both cystic and alveolar echinococcosis. This paper reviews some of the key steps and issues facing those who work in clinical research and who deal on a day-to-day basis with echinococcal disease. In many situations, chemotherapy alone is sufficient, but it is also used as an adjunct to surgery and to minimally invasive approaches to cyst management. While treatment may not be as effective as hoped, attempts to provide new regimens are progressing to increase cure rates further. There is now a greater understanding of the limitations of all approaches, and treatment guidelines as developed by the World Health Organization are now widely followed. As diagnostic tools are ever more widely available, the question as to who should be treated in endemic communities has to be answered.
Cardiac echinococcosis is a rare condition, and its manifestations are protean depending upon its site of infestation. We report a case of hydatid heart disease presenting like an acute cardiac ischemic episode associated with a rise in serum cardiac enzymes secondary to left ventricular free wall dissection caused by ruptured intramyocardial echinococcal cyst. The resultant complex cardiac anatomy was characterized fully by echocardiographic examination.
In the course of an epidemiological survey concerning the alveolar echinococcosis and its causative agent, Echinococcus multilocularis, the autopsies of 150 wild red foxes captured in the department of the Haute-Savoie between December 1983 and August 1988 disclosed 139 cases of intestinal helminthiasis with cestodes and nematodes; no trematode was found. Multiple infections were frequent. The cestoda recorded consist of the following species: Taenia crassiceps: 44 cases (29%); Echinococcus multilocularis: 34 cases (23%); Taenia polyacantha: 22 cases (14%); Mesocestoides litteratus: 7 cases (4.6%); Amoebotaenia paradoxa: 1 case (0.6%). The Nematoda concerned are: Uncinaria stenocephala: 79 cases (52%); Toxocara canis: 67 cases (44%); Toxascaris leonina: 16 cases (10%); Trichuris vulpis: 12 cases (8%); Pterygodermatites affinis: 8 cases (5%); Trichostrongyloidea sp.: 5 cases (3%). The animals were not examined for Trichinella spiralis. The results are compared with those observed anteriorly in the province of Auvergne (France).