Experimental hookworm infection: a randomized placebo-controlled trial in asthma.

BACKGROUND: Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma. OBJECTIVES: To determine the effects of experimental hookworm infection in asthma. METHODS: Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD(20)AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects. RESULTS: Mean PD(20)AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: -1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated. CONCLUSIONS: Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken.

Metabolic alterations in the hamster co-infected with Schistosoma japonicum and Necator americanus.

Co-infection with hookworm and schistosomes is a common phenomenon in sub-Saharan Africa, as well as in parts of South America and southeast Asia. As a first step towards understanding the metabolic response of a hookworm-schistosome co-infection in humans, we investigated the metabolic consequences of co-infection in an animal model, using a nuclear magnetic resonance (NMR)-based metabolic profiling technique, combined with multivariate statistical analysis. Urine and serum samples were obtained from hamsters experimentally infected with 250 Necator americanus infective L(3) and 100 Schistosoma japonicum cercariae simultaneously. In the co-infection model, similar worm burdens were observed as reported for single infection models, whereas metabolic profiles of co-infection represented a combination of the altered metabolite profiles induced by single infections with these two parasites. Consistent differences in metabolic profiles between the co-infected and non-infected control hamsters were observed from 4 weeks p.i. onwards. The predominant metabolic alterations in co-infected hamsters consisted of depletion of amino acids, tricarboxylic acid cycle intermediates (e.g. citrate and succinate) and glucose. Moreover, alterations of a series of gut microbial-related metabolites, such as decreased levels of hippurate, 3-hydroxyphenylpropionic acid, 4-hydroxyphenylpropionic acid and trimethylamine-N-oxide, and increased concentrations of 4-cresol glucuronide and phenylacetylglycine were associated with co-infection. Our results provide a first step towards understanding the metabolic response of an animal host to multiple parasitic infections.

Systems metabolic effects of a necator americanus infection in Syrian hamster.

Hookworms (Ancylostoma duodenale and Necator americanus) are blood-feeding intestinal nematodes that infect approximately 700 million people worldwide. To further our understanding of the systems metabolic response of the mammalian host to hookworm infection, we employed a metabolic profiling strategy involving the combination of (1)H NMR spectroscopic analysis of urine and serum and multivariate data analysis techniques to investigate the biochemical consequences of a N. americanus infection in the hamster. The infection was characterized by altered energy metabolism, consistent with hookworm-induced anemia. Additionally, disturbance of gut microbiotal activity was associated with a N. americanus infection, manifested in the alterations of microbial-mammalian cometabolites, including phenylacetylglycine, p-cresol glucuronide, 4-hydroxy-3-methyl-phenylpropionic acid, hippurate, 4-hydroxyphenylactate, and dimethylamine. The correlation between worm burden and metabolite concentrations also reflected a changed energy metabolism and gut microbial state. Furthermore, elevated levels of urinary 2-aminoadipate was a characteristic feature of the infection, which may be associated with the documented neurological consequences of hookworm infection.

Coinfections with Schistosoma haematobium, Necator americanus, and Entamoeba histolytica/Entamoeba dispar in children: chemokine and cytokine responses and changes after antiparasite treatment.

The effect of polyparasite infections on cytokine and chemokine responses as well as the effect of antiparasite treatment was studied in children without parasite infection (the G0 group), in children singly infected with Schistosoma haematobium (the G1 group), and in children multiply infected with S. haematobium/Schistosoma mansoni, Entamoeba histolytica/Entamoeba dispar, and Necator americanus (the G3+ group). Linear regression analysis disclosed a significant risk for coinfection with hookworm and Schistosoma species. Polyparasite infections detected in 23% of children before treatment were present in 5% at 15 months after treatment. Chemokine responses to S. mansoni adult worm antigen (SmAg) diminished after treatment for macrophage inflammatory chemokine (MIP)-1alpha/chemokine (C-C motif) ligand (CCL)-3 (among G3+ children, by a factor of 200 [95% confidence interval {CI}, 33-1111]) and for MIP-1beta/CCL-4 (among G3+ children, by a factor of 26 [95% CI, 6-117]) but were enhanced for thymus- and activation-regulated chemokine/CCL-17 (among G3+ children, by a factor of 10 [95% CI, 3-32]) (P < .001 for all). In response to E. histolytica antigen, interleukin (IL)-13 levels increased after treatment among G1 children by a factor of 138 (95% CI, 12-1569) and among G3+ children by a factor of 21 (95% CI, 7-64) (P < .001 for both). Cellular production of interferon (IFN)-gamma in response to SmAg decreased 4 weeks after treatment among G3+ children, whereas T helper cell type 2 (Th2) IL-13 production was enhanced among G1 and G3+ children. In summary, polyparasite infections with S. haematobium/S. mansoni, E. histolytica/E. dispar, and N. americanus generated prominent proinflammatory cytokine and chemokine responses, and, after antihelminth treatment, the inflammatory chemokine response lessened as the Th2 responsiveness in coinfected children increased.

A study on the prevalence of hookworm infection in four districts of West Bengal and its linkage with anaemia.

Stool samples collected from the districts of Darjeeling, Jalpaiguri, Hooghly and Calcutta in West Bengal were examined for hookworm and associated parasites. It was found that maximum prevalence of hookworm was in Hooghly district (24.8%). N. americanus appeared to be more prevalent species in all the districts studied. The load ofhookworm infection appeared to be mostly in the mild range. Ascaris lumbricoides appeared to the most common accompanying infection. In the affected population, the degree of anaemia was mostly mild.

Onchocerca volvulus-specific antibody and cytokine responses in onchocerciasis patients after 16 years of repeated ivermectin therapy.

The recommended control option against onchocerciasis is repeated ivermectin treatment, which will need to be implemented for decades, and it remains unknown how repeated ivermectin therapy might affect immunity against Onchocerca volvulus in the long term. O. volvulus-specific antibody reactivity and cellular cytokine production were investigated in onchocerciasis patients receiving ivermectin (150 microg/kg) annually for 16 years. In treated patients, the T helper type 2 (Th2) cytokine interleukin (IL)-5 and T regulatory IL-10 in response to O. volvulus antigen (OvAg) and bacteria-derived Streptolysin O (SL-O) diminished to levels found in infection-free endemic controls; also, cellular release of Th1-type interferon (IFN)-gamma at 16 years post initial ivermectin treatment (p.i.t.) approached control levels. In ivermectin-treated onchocerciasis patients, IL-5 production in responses to the mitogen phytohaemagglutinin (PHA) decreased, but IL-10 in response PHA increased, and neither attained the cytokine production levels of endemic controls. At 16 years p.i.t., O. volvulus-specific IgG1 and IgG4 subclass reactivity still persisted at higher levels in onchocerciasis patients than in O. volvulus exposed but microfilariae-free endemic controls. In addition, cytokine responses remained depressed in onchocerciasis patients infected concurrently with Mansonella perstans and Necator americanus or Entamoeba histolytica/dispar. Thus, long-term ivermectin therapy of onchocerciasis may not suffice to re-establish fully a balanced Th1 and Th2 immune responsiveness in O. volvulus microfilariae-negative individuals. Such deficient reconstitution of immune competence may be due to an as yet continuing and uncontrolled reinfection with O. volvulus, but parasite co-infections can also bias and may prevent the development of such immunity.

Eosinofilia en inmigrante africano asintomático / Asymptomatic eosinophilia in an African immigrant

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Functional significance of low-intensity polyparasite helminth infections in anemia.

BACKGROUND: We wanted to quantify the impact that polyparasite infections, including multiple concurrent low-intensity infections, have on anemia. METHODS: Three stool samples were collected and read in duplicate by the Kato-Katz method in a cross-sectional sample of 507 children from Leyte, The Philippines. The number of eggs per gram of stool was used to define 3 infection intensity categories--uninfected, low, and moderate/high (M+)--for 3 geohelminth species and Schistosomiasis japonicum. Four polyparasite infection profiles were defined in addition to a reference profile that consisted of either no infections or low-intensity infection with only 1 parasite. Logistic regression models were used to quantify the effect that polyparasitism has on anemia (hemoglobin level <11 g/dL). RESULTS: The odds of having anemia in children with low-intensity polyparasite infections were nearly 5-fold higher (P = .052) than those in children with the reference profile. The odds of having anemia in children infected with 3 or 4 parasite species at M+ intensity were 8-fold greater than those in children with the reference profile (P < .001). CONCLUSION: Low-intensity polyparasite infections were associated with increased odds of having anemia. In most parts of the developing world, concurrent infection with multiple parasite species is more common than single-species infections. This study suggests that concurrent low-intensity infections with multiple parasite species result in clinically significant morbidity.

[Transmission of schistosomiasis in an urban population and prevalence of intestinal helminthiasis in Bamako, Mali ]. / Transmission de la schistosomose urbaine et prévalence des helminthoses intestinales à Bamako, Mali.

Parasitological, malacological and anthropological studies were performed to assess the prevalence of Schistosoma haematobium and S. mansoni in schoolchildren living in the suburban area of Bamako. A total of 1017 schoolchildren aged 6-14 years were selected in two different areas between September 1997 and December 1999. In Djikoroni, the prevalence of S. haematobium and S. mansoni was 80.7% (339/420) and 22.8% (85/372) respectively. There was no significant difference of prevalence and intensity of infection with S. haematobium between schools, gender and age (p > 0.05), whereas, those of S. mansoni were higher in the vicinity of (+/- 100 m from) major sites where infected Biomphalaria pfeifferi were found (p < 0.001). In Niomirambougou, S. haematobium was prevalent in 46.7% (279/597) and S. mansoni in 28.2% (134/475). Boys and children aged 11-14 years were more infected (p < 0.001). Associated intestinal helminths (Hymenolepis nana, Necator americanus and Ascaris lumbricoides) were relatively scarce (prevalence < 1%). The prevalences of schistosome infected snails intermediate host were relatively high, 49.3% (100/203) in B. pfeifferi, 20.6% (88/138) in B. truncatus and 24.1% (7/29) in B. globosus. We recorded a total of 2514 water contacts about which 1130 in December and 1384 in January. Most of the children, 42.9% (1077/2511) were attracted to water bodies for bathing, swimming and playing, suggesting the lack of recreational facilities in these areas. Developing local control programmes in schools located in the vicinity of water bodies would contribute to break the parasite transmission cycle in Bamako.

Innate and cognate mechanisms of pulmonary eosinophilia in helminth infection.

Passage of helminth larvae through the lungs can cause pulmonary eosinophilia that may have evolved as a means of parasite attrition. If allergic responses represent a misdirected activation of this arm of the immune system, then mechanisms governing eosinophil recruitment during infection would be expected to be closely related to those seen in allergy. We studied primary Necator americanus infection and compared this to multiply-infected or vaccinated mice. The arrival of larvae in the lungs triggered rapid eosinophil recruitment, which was greatly enhanced in previously sensitized mice. Interestingly, the presence of larvae in the lung was sufficient to trigger eosinophil chemoattractant production, including the chemokines eotaxin and MIP-1alpha, and was not enhanced by prior exposure to the parasites. Infection stimulated IL-5 production in all groups; however, this and IgE production were greatly enhanced in sensitized animals. Elevated IL-5 increased bone marrow production of eosinophils, and eosinophilia was abrogated by treatment with anti-IL-5 antibody. Therefore, trapping of larvae in the pulmonary vasculature is sufficient to trigger eosinophil recruitment, by induction of chemokines and IL-5. Primed cognate Th2 immunity does not increase local chemokine production, but does increase IL-5 production, which greatly enhances the availability of eosinophils for recruitment to the lung.

Parasite-specific antibody and cellular immune responses in human infected with Necator americanus and Oesophagostomum bifurcum.

In this study parasite-specific antibody, cellular reactivity and Thl-type or Th2-type cytokine responses were investigated in humans concurrently infected with Necator americanus and Oesophagostomum bifurcum. The prospects for O. bifurcum-specific serodiagnosis based on IgG4 and IgE were evaluated. IgG4 showed low specificity for O. bifurcum due to antigen cross-reactivity with N. americanus, while IgE specifically distinguished between hookworm and O. bifurcum, and, in doubly infected patients, levels of O. bifurcum-specific as well as N. americanus-specific IgE were significantly elevated compared to those with N. americanus mono-infections. Cellular immunity was not strictly dominated by a Thl- or Th2- type reactivity. In co-infected patients cellular unresponsiveness to parasite antigens was observed, while cellular production of tumour necrosis factor alpha (TNF-alpha) and gamma-interferon (IFN-gamma) was greater in those doubly infected. Th2-type cytokines (interleukin-5 and interleukin-10) were produced in equal amounts by peripheral blood mononuclear cells from individuals with mono- and coinfections. Such mixed Thl-type and Th2-type immune responsiveness associated with persisting gastrointestinal parasitic nematodes may reflect a state of infection at which parasite-induced inflammatory and enteropathogenic responses co-exist, and furthermore, helminth coinfection will not only suppress parasite-specific cellular responsiveness but may also direct cytokine production towards a "permissive Th1-type cytokine profile" that favours parasite persistence.