Worldwide overview of human infections with Hymenolepis diminuta.

Hymenolepis diminuta is a zoonotic cestode parasitizing the small intestine of rodents (definitive hosts). Humans can accidentally enter into the life cycle of this tapeworm via the ingestion of infected insects (intermediate hosts) containing cestode cysticercoids in their body cavity. More than two centuries after the first record in humans, there are no accurate estimates of the number of human cases around the world. In order to have a more precise idea about the number of human cases with H. diminuta and the current status of the disease (hymenolepiasis) worldwide, we conducted a literature review of published records on human infection with H. diminuta. One thousand five hundred and sixty-one published records of infection with H. diminuta from 80 countries were identified. This review presents an estimate of the number of human cases with H. diminuta and a current overview of the prevalence, geographic distribution, symptoms, diagnosis, exposure to infective stages, and therapeutic approaches for this underestimated zoonotic tapeworm.

The immune response to Hymenolepis nana in mice decreases tumorigenesis induced by 7,12 dimethylbenz-anthracene.

BACKGROUND: Cancer is a high-impact disease throughout the world. A negative correlation has been established between the development of cancer and the Th2 immune response. Infection by helminth parasites is characterized by the induction of a strong and long-lasting Th2 response. The aim of this work was to evaluate the effect of the immune response induced by the infection with the helminth Hymenolepis nana, on the tumorigenesis induced by dimethylbenz-anthracene (DMBA) in mice. METHODOLOGY: Four different groups of 14 female BALB/c mice were formed; Group A, dimethyl sulfoxide (DMSO) (vehicle) was administered cutaneously, Group B infected with H. nana, group C, cutaneously DMBA and finally Group D infected with H. nana and cutaneous DMBA. The tumor load was determined in those animals that developed cancerous lesions. In all groups were determined: serum concentration of IgE, IFNγ, IL-10, IL-5 and malondialdehyde (MDA). The inflammatory infiltrate was analyzed from skin samples and the expression of the main eosinophilic protein and myeloperoxidase was determined. RESULTS: The group previously infected with H. nana had a reduced amount of tumors with smaller size, in comparison to the group that received only DMBA; this reduction was associated with lower levels of IFNγ and IL-10, while levels of IgE, IL-5 and MDA were higher. Further, the number of eosinophils and neutrophils was statistically higher in the animals that were previously infected with the helminth and developed less tumors. CONCLUSION: The immune response induced by H. nana infection is associated with the reduction of tumors probably due to the activity of eosinophils and neutrophils.

Malignant Transformation of Hymenolepis nana in a Human Host.

Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer.

Some studies on spontaneous Hymenolepis diminuta infection in laboratory rats.

Hymenolepis diminuta is a tapeworm that occurs worldwide. It is known to be found commonly in areas where large amounts of food grains or other dry feed products, which are the favorite foods for rats. Transmission of disease to human is uncommon; however, it may be a serious threat for population who are living in rural areas which are suffering from excessive rodents. Here, this study had done on spontaneous H. diminuta infection in laboratory rats as a model. Out of thirty five adult laboratory rats investigated for parasitic diseases only nine (25.71%) were diagnosed positive for spontaneous H. diminuta infection. Four of them (44.44%) were found losing of weight and lacking of motility, while the others were normal. On microscopic examination, H. diminuta eggs had been found in their stool. On autopsy, small intestines were found to contain from 5-6 multi-segmented tapeworms in each rat. Histopathologically, intestinal lumen showed varying sections of H. diminuta segments with serrated borders. H. diminuta infection caused multiple mucosal ulcers with absence of intestinal villi from the surface epithelium and excessive mucin. Moreover, inflammatory cells infiltration in the connective tissue core of the villi. Furthermore, the Toluidine blue stain showed that there are Mastiocytosis. Additionally, there were goblet cells hyperplasia on using PAS. Moreover, there were high expression of cyclooxygenase 2 (COX-2), tumor necrosis factor-α (TNF-α) and inducible Nitric-Oxide Synthase (iNOs). This implicate, strong correlation between COX-2, TNF-α and iNOs expression and inflammation induced by H. diminuta.

Murine autoimmune arthritis is exaggerated by infection with the rat tapeworm, Hymenolepis diminuta.

Infection with helminth parasites triggers strong and stereotypic immune responses in humans and mice, which can protect against specific experimentally-induced autoimmune diseases. We have shown that infection with the rat tapeworm, Hymenolepis diminuta, confers a protective effect on FCA-induced joint inflammation. Here, we investigated the effect of a prophylactic infection with H. diminuta on the K/BxN-serum model of polyarthritis in BALB/c mice. Mice were infected with 10 cysticercoids of H. diminuta by oral gavage and 8 days later arthritis was induced by i.p. injection of K/BxN arthritogenic serum. Joint swelling and pain measurements were recorded throughout a 13 day time course. At necropsy, joints and blood serum were collected. K/BxN-treated mice developed joint inflammation in the front paws, hind paws and knees as shown by increased swelling, mechanical allodynia and myeloperoxidase activity. Mice infected with H. diminuta had more severe disease, with increased eosinophil peroxidase activity in their paws and greater inflammatory infiltrate and synovitis in the knee joints. Hymenolepis diminuta-infected mice displayed significant increases in serum levels of C5a and mast cell protease-1 compared with K/BxN-serum only treatment, the latter being indicative of mast cell activation. In contrast to the protective effect of infection with H. diminuta in FCA-induced monoarthritis, infection with this helminth exacerbated K/BxN serum-induced polyarthritis in BALB/c mice. This correlated with increases in C5a and mast cell activation: factors critical in the development of K/BxN-induced arthritis. Thus, while data accumulate from animal models showing that infection with helminth parasites may be beneficial for a variety of auto-inflammatory diseases, our findings demonstrate the potential for helminths to exacerbate disease. Hence care is needed when helminth therapy is translated into a clinical setting.

Exacerbation of oxazolone colitis by infection with the helminth Hymenolepis diminuta: involvement of IL-5 and eosinophils.

Substantial data show that infection with helminth parasites ameliorates colitis; however, oxazolone-induced colitis is exaggerated in mice infected with the tapeworm, Hymenolepis diminuta. We tested the hypothesis that the IL-5 response to helminth infection enhances the severity of oxazolone-induced colitis. Mice were infected with H. diminuta and 8 days later were treated with oxazolone ± anti-IL-5 antibodies. Colitis was assessed 72 hours postoxazolone treatment by disease activity scores, myeloperoxidase activity, and histopathology. Other mice received injections of a replication-deficient adenovirus that carried the IL-5 (Ad.IL-5) gene or a control adenovirus (Ad.delete) ± oxazolone. The effect of H. diminuta+oxazolone in CCL11/CCL22 (eotaxin-1 and 2) knockout (KO) mice was determined. Helminth infection and Ad.IL-5 treatment increased IL-5 and eosinophil numbers. In vivo neutralization of IL-5 significantly reduced the severity of colitis in H. diminuta+oxazolone-treated mice, and H. diminuta did not exaggerate oxazolone-induced colitis in CCL11/CCL22 KO mice. Mice receiving Ad.IL-5 only had no colitis, while oxazolone-induced colitis was more severe in animals cotreated with Ad.IL-5 (Ad.delete + oxazolone was not significantly different from oxazolone only). Thus, while there is much to be gleaned about antiinflammatory mechanisms from rodent-helminth model systems, these data illustrate the caveat that infection with helminth parasites as a therapy could be contraindicated in patients with eosinophilia or elevated IL-5 unless coupled to appropriate measures to block IL-5 and/or eosinophil activity.

Food additives and Hymenolepis nana infection: an experimental study.

The effect of sodium benzoate (SB) on the pathogenesis of Hymenolepis nana (H. nana) and its neurological manifestations was studied in the present work. One hundred and thirty five mice were classified into three groups. GI: received SB alone. GII: received SB before & after infection with H. nana and GIII: infected with H. nana. All groups were subjected to parasitological, histopathological, immunohistochemical and biochemical assays. The results revealed a significant decrease in IL-4 serum level with a significant increase in gamma amino butyric acid (GABA) and decrease in zinc brain levels in GI, while GII showed non significant increase in IL-4 level that resulted in a highly significant increase in the mean number of cysticercoids and adult worms with delayed expulsion as compared to GIII. This was reflected on histopathological and immunohistochemical changes in the brain. Also, there was a highly significant increase in GABA and decrease in zinc brain levels in GII to the degree that induced behavioral changes. This emphasizes the possible synergistic effect of SB on the neurological manifestations of H. nana and could, in part, explain the increased incidence of behavioral changes in children exposed to high doses of SB and unfortunately have H. nana infection.

The findings of capsule endoscopy in patients with common variable immunodeficiency syndrome.

BACKGROUND/AIMS: Common variable immunodeficiency syndrome (CVIS) is a primary immunodeficiency disorder characterized by reduced serum immunoglobulins and heterogeneous clinical features. Parasitic and bacterial infections are very common complications of the syndrome. Capsule endoscopy (CE) represents a new and highly innovative method of demonstrating the small intestinal diseases. We evaluated the practical usefulness and diagnostic yield of CE in three patients with CVIS. METHODOLOGY: Between January 2003 and September 2004 CE was performed in 31 patients for different indications including mostly obscure gastrointestinal bleeding. We particularly evaluated 3 patients with CVIS whose diagnosis was based on serum immunoglobulins levels, clinical features and intestinal biopsy. The three CVIS patients with a median age of 25.6 years (ranged 21-34 years) have been followed-up for a period of 6.3 years (range 3-9 years). After introduction of CE in our medical center, this technique was performed with a Given M2A video capsule system in three patients to explain chronic severe and refractory diarrhea and iron deficiency anemia. RESULTS: All three patients were able to complete the study. In one of the three patients, CE demonstrated unlimited sessile and sometimes pedunculated polyp-like lesions of 2 to 6mm in diameter starting from antrum of the stomach to terminal ileum without escaping fashion and a parasite, Hymenolepsis nana that was located in the ileum of the patient. Biopsy obtained by conventional endoscopy from small intestine and antrum demonstrated typical nodular lymphoid hyperplasia. In the second patient, the same capsule endoscopic and histological findings were found on the mucosa of the duodenum and jejunum but not ileum and the stomach. In the third patient in whom the follow-up period was 3 years, CE revealed no abnormality through the small intestine. CONCLUSIONS: Our data indicated that CE may be necessary for the patients with CVIS to evaluate not only the complications but also extension of the small intestinal involvement.

Ileal mucosal mast cell, eosinophil, and goblet cell populations during Hymenolepis diminuta infection of the rat.

The population dynamics in the enteric connective tissues of eosinophils, mucosal mast cells (MMC), and in the mucosal epithelium of goblet cells were examined morphometrically in fixed ileal tissue of outbred Sprague Dawley rats during the first 32 days of infection with the tapeworm Hymenolepis diminuta. MMC and eosinophils were present in the lamina propria and submucosa; however, only eosinophils were also present in the muscularis externa. Eosinophilic infiltrate was first observed in the lamina propria at 15 days postinfection (dpi) and the numbers of eosinophils remained elevated through 32 dpi. Initial mucosal mastocytosis was detected on 6 dpi and MMC numbers continued to rise over the study period without reaching a plateau. Goblet cell hyperplasia occurred only at 32 dpi. In contrast to some intestinal nematode infections where these same 3 cell types are associated with the host's expulsion responses, H. diminuta is not lost by a rapid host response in the outbred Sprague Dawley rat strain used in these experiments. We suggest that either the induction of hyperplasia of these host effector cells in ileum tissue during H. diminuta infection is not capable of triggering parasite rejection mechanisms, or the function of the induced hyperplasia is necessary for some as yet unassociated physiological or tissue architecture change in the host's intestine.

Hymenolepis diminuta: praziquantel removal of adult tapeworms is followed by apoptotic down-regulation of mucosal mastocytosis.

The rat tapeworm, Hymenolepis diminuta, induces mastocytosis, hypertrophy of enteric smooth muscle, alteration of enteric myoelectric activity, and slowed enteric transit of the rat host's intestine. This report examines the resolution of both tapeworm-induced mastocytosis and tissue changes during the period following removal of the tapeworm with Praziquantel (PZQ). The dynamics of the mucosal mast cell (MMC) population following removal of the tapeworms was assessed by histochemical identification of MMC and morphometric techniques. As a possible mechanism of MMC population regulation, MMC apoptosis was examined over the same experimental period using the in situ nick end labeling of fragmented DNA (TUNEL). Shifts in MMC numbers were correlated with functional and morphological changes of the intestine following removal of the adult-stage tapeworm. Ileal tissues from rats infected 32 days with H. diminuta (the beginning of plateau phase of tapeworm-induced chronic mastocytosis) were harvested 1, 2, 3, and 4 weeks after the PZQ treatment. Control ilea were obtained either from rats which were never infected and never treated with PZQ or from rats infected with H. diminuta for 32 days but not treated with PZQ. In order to detect MMC and apoptosis, tissue sections of ileum were doubled stained sequentially with Astra blue for MMC granules followed by a modification of the TUNEL technique. No alteration in MMC numbers were observed in PZQ-treated animals until 3 weeks after the removal of the tapeworms. The decline of MMC occurred in the mucosa and submucosa. MMC numbers first approached uninfected control levels at 4 weeks posttreatment. Coincident with the decline in mucosal MMC numbers, the rate of MMC entering apoptosis also declined. Simultaneously, ileal smooth muscle layers, hypertrophied by infection, and mucosal structures began the process of involution and atrophy. Apoptosis of MMC in the submucosa and muscularis mucosa was not detected. In conclusion, H. diminuta-elicited mastocytosis and increased thickness of both mucosa and muscularis externa do not begin a decline toward control values until 3 weeks after the parasites are gone and normal intestinal motility is restored. These data are consistent with the lack of MMC mediation of altered motility, and the decline in the rate of MMC apoptosis at 3 weeks post-PZQ suggests that apoptosis may play an important role in the involution of tapeworm-induced mastocytosis.

Hymenolepsis diminuta: mucosal mastocytosis and intestinal smooth muscle hypertrophy occur in tapeworm-infected rats.

The mechanisms mediating motility changes during noninvasive tapeworm infection have not been characterized. In contrast, host intestinal motility changes during invasive nematode infection are mediated by mucosal mast cells (MMC). The purpose of this study was to examine and the correlate onset of myoelectric alterations 8 days after initial tapeworm infection with changes in intestinal morphology, MMC numbers, and MMC secretory activity. Segments of the small intestine, the tapeworms normal habitat, along with stomach, colon, and bladder were taken from tapeworm-infected and control rats. Tissues were fixed and stained to identify MMC and for morphologic measurement. Tapeworm-infected and uninfected rats with chronically implanted intestinal electrodes were treated with ketotifen, a mast cell stabilizer, and in vivo myoelectric activity monitored. In tapeworm-infected rats, the muscularis externa, on day 20 postinfection, and crypts of Lieberkuhn, on day 26 postinfection, from the entire small intestine appeared thickened or deeper, respectively. Increased muscularis thickness was due to smooth muscle hypertrophy in both the circular and the longitudinal muscle layers. Mucosal mastocytosis was first observed on day 26 postinfection and occurred only in the ileum of tapeworm-infected rats. Pharmacologic stabilization of mast cells with ketotifen did not prevent onset of enteric myoelectric alterations during tapeworm infection. Stomach, colon, and bladder MMC numbers and tissue dimensions were not different between Hymenolepis diminuta-infected rats and uninfected controls. Initiation of myoelectric alterations 8 days after infection precedes and may be a contributing factor to the onset of both smooth muscle hypertrophy and mucosal mastocytosis. Taken together, our data indicate that mast cells are not an initiating factor nor chronic stimulus maintaining intestinal myoelectric alterations during H. diminuta infection.

Inflammatory responses in the intestine during tapeworm infections. Mucosal mast cells and mucosal mast cell proteases in Sprague-Dawley rats infected with Hymenolepis diminuta.

Comparative studies were made of two populations of Sprague-Dawley rats infected with Hymenolepis diminuta. The time course of infection, the development of mucosal mastocytosis and the levels of rat mucosal mast cell (MMC) protease (RMCP II) in serum and in jejunal mucosal tissues were monitored at intervals after infection with 40 cysticercoids of the tapeworm. Worm expulsion patterns differed markedly between the two populations, rats of New Zealand origin showing an abrupt and clear-cut loss of worms, rats of English origin showing a more gradual decline over a longer time period. In both populations, however, numbers of MMC and levels of tissue RMCP II were positively correlated with time after infection and negatively correlated with worm numbers. In only one of the three experiments (using English strain rats over a short time period) did levels of serum RMCP II change with time. In the other two experiments, in which English-strain and New Zealand-strain rats were used, there were no correlations between serum RMCP II and time, numbers of MMC, numbers of worms or levels of tissue RMCP II. The absence of correlation between serum RMCP II and worm loss in these experiments implies that MMC have no direct role in expulsion of H. diminuta. The data do show, nevertheless, that this purely luminal tapeworm is fully capable of activating the mucosal T lymphocyte-MMC precursor axis to elicit a mucosal mastocytosis.

Pathological and immunopathological changes in albino mice experimentally infected with Hymenolepis nana.

The pathological and immunopathological effects of H. nana on experimentally infected albino mice were studied, sacrificed one, three and five months post egg inoculation. The results showed that most of the mice had diarrhoea, loss of appetite and were inactive. On the other hand, the liver and spleen showed some pathological changes and cysticercoids were seen particularly in the liver. The kidneys showed cloudy swelling (3/90). The brain showed oedema (15/90) and glyosis (15/90). Intestinal atrophy and ulceration were very marked (30/90) with negative reaction to PAS and Alcian blue stain. Cysticercoids were seen in intestinal villi. The immunoglobulins in sections of the S. intestine changed from moderate to negative (IgA) or to mild (IgM) or from mild to marked (IgG). The whole results were discussed.

Hymenolepis diminuta: changes in intestinal morphology and the enterochromaffin cell population associated with infection in male C57 mice.

Mean villus height, crypt depth and the number of 5-HT-positive enterochromaffin (EC) cells have been examined in two regions of the small intestine (20-30% and 60-70% distance from the pylorus) of male, 6 to 8-week-old, C57 mice following a 5-cysticercoid infection of the rat tapeworm, Hymenolepis diminuta. Test mice and sham-infected controls were autopsied 0, 4, 8, 10, 14 and 28 days post-primary infection (p-1 degree-i) and 2, 4, 5, 7 and 14 days post-secondary infection (p-2 degrees-i), administered 28 days p-1 degree-i. Morphometric analysis revealed a statistically significant increase in crypt depth in the 60-70% intestine region in infected mice during both primary and secondary infections; no significant deviation from the control was observed for villus height in infected mice. Statistical analysis showed a significant increase in the number of 5-HT-positive EC cells in infected mice. This response occurred in the lower portion of the intestine on days 10-p-1 degree-i and 5-p-2 degrees-i, and was not due to increased mucosal surface area in this region. Results are discussed with reference to murine cestode rejection and the possible involvement therein of the neuroendocrine system.

Hymenolepis diminuta: intestinal goblet cell response to infection in male C57 mice.

Intestinal goblet cell numbers in two regions of the small intestine (20-30% and 60-70% distance form the pylorus) of male, 6- to 8-week-old C57 mice have been monitored following a 5-cysticercoid infection of the rat tapeworm, Hymenolepis diminuta. Test and sham-infected control mice were autopsied 0, 4, 8, 10, 14, and 28 days postprimary infection (p-1 degree-i) and 2, 4, 5, 7, and 14 days postsecondary infection (p-2 degree-i), administered 28 days p-1 degree-i. Results show a statistically significant increase in the number of mucus-containing goblet cells in both regions of the intestine during primary and secondary infections. Peak goblet cell numbers occurred on Day 8 p-1 degree-i and Day 5 p-2 degree-i in the 20-30% region and on Day 10 p-1 degree-i and Day 5 p-2 degree-i in the 60-70% region. In both regions, cell numbers declined to control levels by Day 14 p-1 degree-i, but remained significantly above control values 14 days p-2 degree-i. The increase in cell numbers correlated with an increase in goblet cell theca size and observable amounts of luminal mucus. The same infection regime in mice treated with cortisone elicited no goblet cell response. Male Wistar rats given a 10-cysticercoid infection and autopsied on Day 0, Day 10, and 15 months p-i showed a statistically significant increase in mucus-containing goblet cells only in the 60-70% region of intestine 10 days p-i; however, the worm burden was not eliminated. The functional significance of these results is discussed in relation to host immunity and murine cestode rejection.