Immunopathology and modulation induced by hookworms: From understanding to intervention.

Hookworm infection is considered the most prevalent human soil-transmitted helminth infection affecting approximately 500 million people and accounting for 3.2 million disability-adjusted life years lost annually. As with many other neglected tropical diseases, no international surveillance mechanisms that show accurate data on the prevalence of hookworm infection are in place, thus hindering strategies to control parasite transmission. In this review, we unravel the current knowledge in immunopathology and immunoregulation of hookworm infection and present discoveries in drug therapies based on the capability of hookworms to regulate inflammation to treat allergic, inflammatory and metabolic diseases. Additionally, we highlight potential vaccine development and treatments and propose avenues for further inquiry.

Exploring Tropical Infections: A Focus on Cutaneous Larva Migrans.

GENERAL PURPOSE: To provide information about infection with cutaneous larva migrans (CLM). TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, NPs, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Distinguish the clinical features, diagnosis, and management of CLM.2. Explain the epidemiology of CLM. ABSTRACT: Cutaneous larva migrans is a hookworm infection and one of the most common skin diseases of tourists in tropical countries. Most commonly, the infection is transmitted by contact with feces of dogs and cats containing hookworm eggs. This case-based review explores the epidemiology, diagnosis, clinical features, and management of cutaneous larva migrans infection.

Cutaneous larva migrans is a hookworm infection and one of the most common skin diseases of tourists in tropical countries. Most commonly, the infection is transmitted by contact with feces of dogs and cats containing hookworm eggs. This case-based review explores the epidemiology, diagnosis, clinical features, and management of cutaneous larva migrans infection.

Hookworm-related cutaneous larva migrans of the penis successfully treated with topical ivermectin.

Hookworm-related cutaneous larva migrans is an infestation of the skin caused by nematodes. Involvement of genitals is extremely rare. We report the case of a child with this infestation on the penis who cleared rapidly with topical ivermectin.

Hookworm Infection: A Neglected Cause of Overt Obscure Gastrointestinal Bleeding.

Hookworm infections are widely prevalent in tropical and subtropical areas, especially in low income regions. In the body, hookworms parasitize the proximal small intestine, leading to chronic intestinal hemorrhage and iron deficiency anemia. Occasionally, hookworms can cause overt gastrointestinal bleeding, but this is often ignored in heavily burdened individuals from endemic infectious areas. A total of 424 patients with overt obscure gastrointestinal bleeding were diagnosed by numerous blood tests or stool examinations as well as esophagogastroduodenoscopy, colonoscopy, capsule endoscopy or double-balloon enteroscopy. All of the patients lived in hookworm endemic areas and were not screened for hookworm infection using sensitive tests before the final diagnosis. The patients recovered after albendazole treatment, blood transfusion, and iron replacement, and none of the patients experienced recurrent bleeding in the follow-up. All the 31 patients were diagnosed with hookworm infections without other concomitant bleeding lesions, a rate of 7.3% (31/424). Seventeen out of 227 patients were diagnosed with hookworm infections in the capsule endoscopy (CE), and 14 out of 197 patients were diagnosed with hookworm infections in the double balloon enteroscopy (DBE). Hookworm infections can cause overt gastrointestinal bleeding and should be screened in patients with overt obscure gastrointestinal bleeding (OGIB) in endemic infectious areas with sensitive methods. Specifically, the examination of stool specimens is clinically warranted for most patients, and the proper examination for stool eggs relies on staff's communication.

An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection.

Hookworms digest hemoglobin from erythrocytes via a proteolytic cascade that begins with the aspartic protease, APR-1. Ac-APR-1 from the dog hookworm, Ancylostoma caninum, protects dogs against hookworm infection via antibodies that neutralize enzymatic activity and interrupt blood-feeding. Toward developing a human hookworm vaccine, we expressed both wild-type (Na-APR-1(wt)) and mutant (Na-APR-1(mut)-mutagenesis of the catalytic aspartic acids) forms of Na-APR-1 from the human hookworm, Necator americanus. Refolded Na-APR-1(wt) was catalytically active, and Na-APR-1(mut) was catalytically inactive but still bound substrates. Vaccination of canines with Na-APR-1(mut) and heterologous challenge with A. caninum resulted in significantly reduced parasite egg burdens (P=0.034) and weight loss (P=0.022). Vaccinated dogs also had less gut pathology, fewer adult worms, and reduced blood loss compared to controls but these did not reach statistical significance. Vaccination with Na-APR-1(mut) induced antibodies that bound the native enzyme in the parasite gut and neutralized enzymatic activity of Na-APR-1(wt) and APR-1 orthologues from three other hookworm species that infect humans. IgG1 against Na-APR-1(mut) was the most prominently detected antibody in sera from people resident in high-transmission areas for N. americanus, indicating that natural boosting may occur in exposed humans. Na-APR-1(mut) is now a lead antigen for the development of an antihematophagy vaccine for human hookworm disease.

Twenty-five-year research progress in hookworm excretory/secretory products.

Hookworm infection is a major public health problem that threatens about 500 million people throughout tropical areas of the world. Adult hookworms survive for many years in the host intestine, where they suck blood, causing iron deficiency anemia and malnutrition. Numerous molecules, named excretory/secretory (ES) products, are secreted by hookworm adults and/or larvae to aid in parasite survival and pathobiology. Although the molecular cloning and characterization of hookworm ES products began 25 years ago, the biological role and molecular nature of many of them are still unclear. Hookworm ES products, with distinct structures and functions, have been linked to many essential events in the disease pathogenesis. These events include host invasion and tissue migration, parasite nourishment and reproduction, and immune modulation. Several of these products represent promising vaccine targets for controlling hookworm disease and therapeutic targets for many inflammatory diseases. This review aims to summarize our present knowledge about hookworm ES products, including their role in parasite biology, host-parasite interactions, and as vaccine and pharmaceutical targets and to identify research gaps and future research directions in this field.

Exploiting Old Pathogens to Create New Therapeutics.

Intestinal worms are well known for their potent immuno-modulatory capacity. In a recent study, Navarro et al. (2016) identify a secreted hookworm protein that can suppress allergic responses in both mice and humans. This represents an exciting strategy for treating chronic inflammatory disorders such as allergy.

Intestinal parasites and pregnancy.

Intestinal parasites and pregnancy commonly coexist. Environmental, nutritional, and immunologic factors influence the clinical manifestations and determine the need for treatment of intestinal parasitism during pregnancy. No serious medical or obstetric problems attributable to intestinal parasites developed among 147 parasitized pregnant refugees living and delivering in a refugee camp in Southeast Thailand. These patients received adequate nutrition, careful prenatal monitoring, and no antiparasitic drug therapy. During pregnancy chemotherapy for intestinal parasites should not be used unless required for appropriate clinical and public health reasons.

The epidemiology and control of hookworm infection in the Burma Valley area of Zimbabwe.

An integrated hookworm control programme, involving mass chemotherapy and improvements in public health, was conducted in the Burma Valley and Vumba areas of Zimbabwe between 1985 and 1990. Three sequential annual mass chemotherapy programmes were implemented. Infection status was monitored annually throughout. Initial observations indicated asymptotic age prevalence and intensity profiles, with peak infection levels in adults. Mass chemotherapy was shown to have immediate and medium term benefits for community health. Reinfection was slow to develop, and average intensity had not returned to pre-intervention levels 39 months after the cessation of chemotherapy. The results support the existence of age-dependency in reinfection. Despite a marked increase in the number of sanitation units, no relationship was found between latrine availability and reinfection intensity on individual farms. This result is consistent with observations that the effect of sanitation is slow to develop, and indicates that repeated anthelmintic intervention should be maintained until sanitation has an impact on transmission.

Natural history of intestinal parasites in asymptomatic adults.

The need to treat asymptomatic adults who have intestinal parasites should be based on considerations of potential pathogenicity and transmission risk, but such data are sparse in general and unavailable for countries such as the United States, where reinfection is rare. Opinions of North American physicians about the natural history and treatment of 12 parasites detectable by stool examination were assessed using the Delphi technique. In response to the first questionnaire, majority agreement on pathogenic potential was achieved for only 3 of 12 parasites. When the more expert group was queried a second time, majority agreement was achieved for 8 of 12 parasites. Nevertheless, the predicted risk of subsequent disease still varied widely, from 1:10 to 1:1,000 for most parasites, and was unrelated to the perceived need for treatment. Almost all respondents thought asymptomatic adults with any intestinal parasites should always be treated. Transmission risk was judged to be low and was generally appropriate to the life cycle of the parasite.

Weekly iron-folic acid supplementation with regular deworming is cost-effective in preventing anaemia in women of reproductive age in Vietnam.

BACKGROUND: To estimate the cost and cost-effectiveness of a project administering de-worming and weekly iron-folic acid supplementation to control anaemia in women of reproductive age in Yen Bai province, Vietnam. METHODS AND FINDINGS: Cost effectiveness was evaluated using data on programmatic costs based on two surveys in 2006 and 2009 and impact on anaemia and iron status collected in 2006, 2007, and 2008. Data on initial costs for training and educational materials were obtained from the records of the National Institute of Malariology, Parasitology and Entomology and the Yen Bai Malaria Control Program. Structured questionnaires for health workers at district, commune and village level were used to collect ongoing distribution and monitoring costs, and for participants to collect transport and loss of earnings costs. The cost per woman treated (defined as consuming at least 75% of the recommended intake) was USD0.76 per annum. This estimate includes financial costs (for supplies, training), and costs of health care workers' time. Prevalence of anaemia fell from 38% at baseline, to 20% after 12 months. Thus, the cost-effectiveness of the project is assessed at USD 4.24 per anaemia case prevented per year. Based on estimated productivity gains for adult women, the benefit:cost ratio is 6.7∶1. Cost of the supplements and anthelminthics was 47% of the total, while costs of training, monitoring, and health workers' time accounted for 53%. CONCLUSION: The study shows that weekly iron-folic acid supplementation and regular de-worming is a low-cost and cost-effective intervention and would be appropriate for population-based introduction in settings with a high prevalence of anaemia and iron deficiency and low malaria infection rates.

Long-term weekly iron-folic acid and de-worming is associated with stabilised haemoglobin and increasing iron stores in non-pregnant women in Vietnam.

BACKGROUND: The prevalence of anaemia and iron deficiency in women remains high worldwide. WHO recommends weekly iron-folic acid supplementation where anaemia rates in non-pregnant women of reproductive age are higher than 20%. In 2006, a demonstration project consisting of weekly iron-folic acid supplementation and regular de-worming was set up in two districts in a northern province in Vietnam where anaemia and hookworm rates were 38% and 76% respectively. In 2008 the project was expanded to all districts in the province, targeting some 250,000 women. The objectives of this study were to: 1) examine changes in haemoglobin, iron stores and soil transmitted helminth infection prevalence over three years and 2) assess women's access to and compliance with the intervention. METHODS AND FINDINGS: The study was a semi-cross-sectional, semi-longitudinal panel design with a baseline survey, three impact surveys at three-, twelve- and thirty months after commencement of the intervention, and three compliance surveys after ten weeks, eighteen and thirty six months. RESULTS: After thirty months, mean haemoglobin stabilised at 130.3 g/L, an increase of 8.2 g/L from baseline, and mean serum ferritin rose from 23.9 µg/L to 52 µg/L. Hookworm prevalence fell from 76% to 22% over the same period. After thirty six months, 81% of the target population were receiving supplements and 87% were taking 75% or more of the supplements they received. CONCLUSIONS: Weekly iron-folic acid supplementation and regular de-worming was effective in significantly and sustainably reducing the prevalence of anaemia and soil transmitted helminth infections and high compliance rates were maintained over three years.

Intraperitoneal blood transfusion in African adults with hookworm anaemia.

Twenty-nine patients were given an intraperitoneal transfusion of blood. The procedure was found to be free of serious complications. Study of the absorption of an (51)Cr-labelled cells from the peritoneum in 14 patients showed that between 35 and 100% of the blood was absorbed intact in 6 to 10 days. Intraperitoneal transfusion may be indicated as an alternative or as an addition to exchange transfusion in severe hookworm anaemia.