[Human cystic hydatidosis in Italy: a public health emergency? Past to present]. / Idatidosi cistica umana in Italia: un problema di salute pubblica? Passato e presente.

Starting from 1991 the Central Office of Statistics ISTAT, according to changed regulations on notification of infective diseases, stopped reporting official national data on human hydatidosis. On the other hand until then notified data, concerning only about a hundred cases per year in mean during the last decades and just 36 in 1991, appeared unreliable, suggesting a diffusion far from the actual. Owing to specific studies on different research groups it is possible to try to describe a not exhaustive but indicative pattern of trend of human hydatidosis in Italy. More recent publications regarding different regions report an annual mean incidence rate of surgical cases of 9.77/100,000 inhabitants in Sardinia, of 1.57 in Emilia Romagna, of 2.30 in Sicily and of 2.33 in Apulia, the latter encompassing only hepatic cysts treated in the region, irrespective of residence of subjects. A comparison with previous studies regarding the period between 1948-1952 and 1980-84 respectively, indicates an increase in the more recent surveys. However, as even underlined by Authors, former surveys were not all-embracing (for example not including patients from private Clinics etc). On the other hand during time, improvements in surgical as well in anaesthesiological skills have made surgery possible in patients previously inoperable, and particularly in old subjects. Conversely, at present, availability of alternative therapies such as chemotherapy, PAIR or modified PAIR-based techniques may allow cases to avoide surgical surveys. However, actual parasite burden in humans may be estimated by assessing the trend of likely young cysts, as due to recent infections. Rate of pulmonary cysts, that are sure to be young, was of 48.6%/100,000 inhab. in 1952 in Italy, then falling to 18.2 in 1980-84 in the 9 considered regions, to 12.7 in Sicily (1989-91), 6.5 in Emilia-Romagna (1989-93) and 15.7 in Sardinia (1990-95). Another "class" of surely young cysts regards all cysts in young age group that necessarily have been recently infected. Ratio of infection rates in the old/young people was around 1 in 1941-52 but was exceeding 3 in 1980-84. In addition available data from more recent surveys indicate that ratio is at present still relatively low in Sardinia (3.9), where sheep-breeding is widespread, and dog-livestock-man interaction is most likely to exist, and conversely is very high in Emilia-Romagna (5.75) where pastoral economy is not prevalent (just 92,000 sheep). Actual trend both parasitological and in terms of public health would ameliorate if studies were provided with long temporary series. In Sardinia all hydatid cases surgically treated from 1969 to 1995 have been registered and analysed with a standardized methodology. During the considered period incidence appears nearly unvaried (16.9 in 1969 vs 15.8 in 1985), with a fall only for the last 5 years (9.1 in 1995), and with an increase regarding 1984-88 period. Analysis according to cyst localization strongly suggests that fall in the last period is only weakly related to hepatic cysts, that conversely are near completely responsible of rise in 1984-88. On the contrary for pulmonary cysts, i.e. young cysts, a slow but continuous and significant decrease (from 6.5 in 1969 to 1.4 in 1995) is evident. In the same way the above- mentioned old/young ratio rises from 1.7 (1969-79) to 3.9 (1990-95). On the whole analysed data suggest that although parasitic burden, strong in central-south Italy for decades, is now slow lowering due to structural changes and improvements in general conditions of life rather to specific preventive actions, human hydatidosis still represents a public health problem that will continue in the future as, because of latency, incidence rates will stay long relevant.

Natural history of cystic echinococcosis in humans.

This study provides a contribution to understanding of the natural history of the hydatid cyst during its evolution in the human liver examining the high morphostructural variability of larval forms of Echinococcus granulosus. A detailed study of a large sample of intact cysts removed from patients surgically treated by means of total pericystectomy, has enabled to outline the different developmental stages of the parasite over time, up to its death and complete degeneration.

Immunobiology of cystic echinococcosis.

The present report focuses on the ability of cystic echinoccocosis metacestode to survive for a long time, despite host immunity, by developing avoidance strategies. The tactics believed to come into play, ranging from intrinsic parasitic factors to host-related mechanisms, are briefly discussed and the importance of studies on experimental models is highlighted particularly in relation to furthering the theoretical understanding of the dynamic equilibrium between host and parasite, and to the feasibility of practical approaches in controlling the disease by artificial manipulation of the immunoregulatory mechanisms.

Human cystic echinococcosis in Sardinia during the 20th century.

At the beginning of the 20th century in Sardinia human Cystic Echinococcosis was considered a highly endemic disease by all the health operators. In the early twenties the number of reported cases was 429, but incidence appeared rising due to increase in availability of data and to improvements in diagnosis. The fall of personal and public hygienic conditions together with the drift from urban to rural areas during the second world war, had in fact facilitated the possibilities of infection, causing a strong growth of surgical cases during the post war years, so that incidence rate remains high and almost unvaried until the end of the eighties. Comparative analysis of young and probably old cysts indicates that this high rate of surgical cases was attributable to treated hepatic cysts in elderly. On the contrary the continuous reduction in the number of young cysts clearly shows a slow but constant decrease of the infection rate.

Causality or coincidence: may the slow disappearance of helminths be responsible for the imbalances in immune control mechanisms?

Intestinal infection continues to be a problem worldwide and helminths, which currently infect billions of individuals, are primary culprits. The major burden of disease falls on the populations of developing countries, given that over the last four to five decades helminth infections are disappearing in industrialized societies. In developing countries, a major source of immunomodulatory signals in post-natal life are parasites, particularly helminths, which, unlike most bacteria and viruses, selectively stimulate Th2 function. Helminths and their eggs are probably the most potent stimulators of mucosal Th2 responses. Responses elicited by worms can modulate immune reactions to other parasites, bacterial, viral infections and several unrelated diseases. Bacterial and protozoal infections may also protect against atopy and asthma, through the induction of the Th1 regulatory responses. Today, people in developed countries often live in ultra-hygienic environments, avoiding exposure to viruses, bacteria, ectoparasites and endoparasites, particularly helminths. Perhaps failure to acquire worms and experience mucosal Th2 conditioning predisposes to unrelated diseases. In contrast to this hypothesis it has also been suggested that Th2 responses can make the host more susceptible to other important diseases and to contribute to the spread of them.

Morphological variability and degenerative evolution of human hepatic hydatid cysts.

The findings are presented of a macro and microscopic investigation of 89 hydatid hepatic cysts removed intact from 59 patients by total pericystectomy. Detailed analysis revealed significant morphostructural variability and cysts grouped into 10 types were characterized, providing useful clinical indications. Only 30 cysts resulted fertile (33.7%), probably due to mean age of sample; 7 of these were "classic" cysts, 1 "septated" and 22 "multivesicular" packed with daughter cysts (DC), of varying turgidity or collapsed. Among the remaining 59 sterile cysts, 52 were degenerated and classified as "hyperlaminated" cysts due to the presence of large convoluted sheets of laminar tissue (SLT) surrounded by varying amounts of caseous (40 specimens), granular (6) or gelatinous (6) matrix. Moreover, "multivesicular", "acephalocyst", "caseous" and "serous" cysts were also recovered among the sterile specimens. Some "multivesicular" cysts (14) appeared as "transitional forms" towards the various types of "hyperlaminated" cysts containing all different forms of DC and large SLT intermingled with a variously degenerated matrix. The comprehensive study allows to hypothesize the train of events leading, over the years, to the gradual transformation and degeneration of the larval form Echinococcus granulosus in the human liver.

Study on immunobiology in endoparasites of public health interest: echinococcosis-hydatidosis.

Cystic echinococcosis caused by Echinococcus granulosus is one of the most widespread zoonoses in the Mediterranean, endemic in some regions such as Sardinia. Some aspects of the research conducted in this area are briefly reviewed for an integrated analysis of both epidemiological and immunobiological knowledge, gained from field observations and experimental studies. Data on epidemiology in intermediate hosts, immunological assessment of exposure in humans, immune response and Th1/Th2 polarization in secondary experimental hydatidosis, kinetics of response in definitive host and cytokine production in experimental models are briefly reported. They confirm the usefulness of an immunobiological approach both in intermediate and definitive hosts and their potential in prevention, monitoring and control of E/H.

Immune response to the cestode Hymenolepis nana: cytokine production during infection with eggs or cysts.

Analysis of cytokine production (IFN-gamma, IL-2, IL-3, IL-4, IL-5) by in vitro Con A-stimulated mesenteric lymph node cells measured daily after egg or cyst infection of mice with Hymenolepis nana showed that cytokine production varies during parasite development and between different host strains (BALB/c and C3H/He mice). Egg infection stimulates a rapid increase in IFN-gamma, independent of mouse strain. In addition, in BALB/c mice a Th2-like response (IL-4, IL-5 secretion) was stimulated 4-5 days p.i., when the parasites are thought to begin their lumenal phase. After infection with cysts significant increases in IFN-gamma, IL-2, IL-4 and IL-5 were observed at the time when autoinfection with eggs is thought to occur. The level of IFN-gamma paralleled that seen after a primary egg infection. This suggests that there is a predominantly Th1-type response during the tissue phase of H. nana development and that, in BALB/c mice, a Th2 polarization occurs during the first few days of the lumenal phase. The cytokine patterns observed are discussed in relation to host responses during chronic helminth infection.

Epidemiology of hydatid disease in the Mediterranean basin with special reference to Italy.

Hydatidosis, caused by dog tapeworms of the genus Echinococcus, is one of the most important cestode infections in man. Of the four species of the genus Echinococcus, only Echinococcus granulosus is widespread in the Mediterranean basin which is still, unfortunately, a major endemic focus. This article critically reviews its diffusion in humans and sheep over the past twenty years. Although most of the available data are scarce, fragmentary, and not homogeneous, they represent the only possibility at present of evaluating the parasitic pressure.

Hydatidosis: a comprehensive view of the Sardinian case.

In Sardinia the close association of sheep, dogs and humans still exists in some parts of the region, so that ideal conditions persist for the perpetuation of the parasite's life cycle. Two factors contribute to the spread of the disease: the practice of slaughtering sheep at home and the proliferation of dogs, mainly strays. This paper reviews the epidemiological picture and the economic consequences of the disease in man and livestock, strongly suggesting that this endemic disease is a major public health problem.

Effect of an intraperitoneal injection with activated Hymenolepis nana and H. diminuta cysticercoids on homologous challenge.

The intraperitoneal injection of excysted-activated cysticercoids of Hymenolepis nana and H. diminuta stimulates a protective immunity in mice and rats against an oral homologous challenge with different levels of effectiveness. The immunizing dose reduced only worm growth in the natural host (i.e. H. nana/mouse and H. diminuta/rat models), while in the unnatural host (i.e. H. diminuta/mouse model) expulsion of the worms from the intestine was accelerated. In mice infected with H. nana the effect appeared about 20 days after injection, but a greater effect was found in both models 40 days later even at low dose (1 cysticercoid). In rats the effect appeared 40 days after injection when a large inoculum (50 or 100 cysticercoids) was used. The induced immunity was slow in developing and only partially effective: this was probably related to host difficulties in processing somatic worm antigens, or to the slow production of metabolites by the worms in the peritoneal cavity.

Immunological memory and lymphoblast-migration in mice infected with Hymenolepis nana.

The presence of small cells carrying memory and lymphoblast migration in C57 Bl/6N inbred mice with the intestinal parasite Hymenolepis nana were investigated. Hymenolepis nana egg-infection stimulated an enhanced accumulation of mesenteric lymphoblasts at days 3, 6 and 9 after infection; lymphoblasts accumulated selectively in the mesenteric nodes (MLN) of mice suggesting a cell-trapping effect. The migration was studied using lymphoblasts from non-infected donors. Spleen cells and MLNC collected from donor mice 30 days after a primary infection and enriched for T cells were able to transfer an adoptive immunity, by contrast unseparated cells were uneffective. This result provides preliminary evidence for the existence of T memory cells in the spleen and in the mesenteric nodes.

[Human hydatidosis in Sardinia. Epidemiologic study of the cases operated on from 1974 to 1981]. / L'idatidosi umana in Sardegna. Studio epidemiologico dei casi operati tra il 1974 e il 1981.

A retrospective survey of surgical cases to obtain baseline data on hydatid disease in Sardinia from 1974 to 1981 revealed an annual mean rate of 11.1/100.000 population. However, real prevalence is obviously higher, since infection is not always synonymous with disease and surgical incidence should be regarded as the figure that counts. Information on sex, age, residence, occupation, cyst location, number of re-operations was collected to assess the public health impact to hydatidosis within the island. The obtained results indicate that not all population is at equal risk, being hydatid disease most prevalent in rural areas and particularly in the districts where sheep-breeding is highly diffused (annual mean rate greater than 20/100.000 population). The highest rate was observed in farmers and shepherds (34.2/100.000) respect to retired (14.1/100.000), housewives (10.9/100.000), employed in services (8.9/100.000) and students (8.3/100.000). Over 55% of the cysts were found in the liver, about 30% in the lung and 15% in other sites. A correlation between age and cyst location and between profession and cyst location was shown. Pulmonary cysts were prevalent in children and young people, hepatic in grown-up people, whereas nearly the same hepatic and pulmonary frequency was observed in shepherds. Comparisons between previous surveyed periods were done and results were discussed, suggesting the need of a continuous and well-planned control programme.

In vitro cellular immune response in mice and rabbits immunized with Trichinella spiralis antigen.

The possibility of using cell mediated immune response as a diagnostic tool has been investigated with T. spiralis laboratory/model. The feasibility of a in vitro microculture method to measure blast cell activity of lymphoblasts in mice experimentally infected with T. spiralis muscle larvae or immunized with soluble crude antigen and the lymphoproliferative response in immunized rabbits was demonstrated. The obtained results suggest that the cell mediated immune response from blood lymphocytes may be very useful to diagnose early parasite infections.

Detection of specific IgE antibodies in sera from patients with hydatidosis.

A simple and sensitive immunoenzymatic assay for detection of specific IgE in hydatid disease is presented. Sera from 43 patients with hydatidosis, eight with schistosomiasis, two with taeniasis, two with cancer and 16 healthy blood donors were tested by both the immunoenzymatic technique and the classical radioallergosorbent test. Data were analysed in terms of different sensitivity and specificity of the two methods. The results indicate that the enzymatic method performed in microplates is as sensitive as the radioimmunological one (77% of positivity for both the tests), but the latter suffers from an higher rate of false positive reactions with sera from patients with other helminthic diseases (80% vs 20%). When the specific IgE evaluation is compared with other classical serological techniques, such as indirect haemagglutination and double diffusion in terms of different sensitivity in revealing an anti-Echinococcus immunological reactivity, the results suggest that specific IgE evaluation represents a useful addition to the classical serodiagnostic tests.