Experimental human hookworm infection: a narrative historical review.

In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy.

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.

Soil-transmitted helminth infections among pre-school aged children in Gamo Gofa zone, Southern Ethiopia: Prevalence, intensity and intervention status.

BACKGROUND: Soil-transmitted helminths (STH), i.e., Ascaris lumbricoides, Trichuris trichiura and hookworms are among the most prevalent Neglected Tropical Diseases (NTDs) in Ethiopia. Although pre-school aged children pay a high morbidity toll associated with STH infections, evidence on prevalence, intensity and intervention status is lacking in Ethiopia. This study, therefore, aimed to address these gaps to inform decision made on STH. METHODS: We did a community-based cross-sectional study in five districts of Gamo Gofa zone, Southern Ethiopia; in January 2019. Data were collected using pre-tested questionnaire, and the Kato-Katz technique was used to diagnose parasites eggs in stool. Then, collected data were edited and entered into EpiData 4.4.2, and exported to SPSS software (IBM, version 25) for analysis. RESULTS: A total of 2462 PSAC participated in this study. Overall, the prevalence of STH was 23.5% (578/2462) (95% confidence interval (CI) = 21.8%-25.2%). As caris lumbricoides was the most prevalent (18.6%), followed by Trichuris trichiura (9.2%), and hookworms (3.1%). Of the total, 7.4% PSAC were infected with two STH species. Most of the positive cases with STH showed low infection intensities, while 15.1% ascariasis cases showed moderate infection intensities. The study found that 68.7% of PSAC were treated with albendazole. Also, household's level data showed that 39.4% used water from hand-dug well; 52.5% need to travel ≥30 minutes to collect water; 77.5% did not treat water, and 48.9% had no hand washing facility. In addition, almost 93% care givers achieved less than the mean knowledge and practice score (≤5) on STH prevention. CONCLUSIONS: This study showed that significant proportions of pre-school aged children are suffering from STH infections despite preventive chemotherapy exist at the study area. Also, gaps in the interventions against STH were highlighted. Thus, a call for action is demanding to eliminate STH among PSAC in Ethiopia by 2030.

Anthelmintic Activity of Yeast Particle-Encapsulated Terpenes.

Soil-transmitted nematodes (STN) infect 1-2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many instances of reduced activity. Terpenes are a class of compounds with anthelmintic activity. Thymol, a natural monoterpene phenol, was used to help eradicate hookworms in the U.S. South circa 1910. However, the use of terpenes as anthelmintics was discontinued because of adverse side effects associated with high doses and premature stomach absorption. Furthermore, the dose-response activity of specific terpenes against STNs has been understudied. Here we used hollow, porous yeast particles (YPs) to efficiently encapsulate (>95%) high levels of terpenes (52% w/w) and evaluated their anthelmintic activity on hookworms (Ancylostoma ceylanicum), a rodent parasite (Nippostrongylus brasiliensis), and whipworm (Trichuris muris). We identified YP-terpenes that were effective against all three parasites. Further, YP-terpenes overcame albendazole-resistant Caenorhabditis elegans. These results demonstrate that terpenes are broad-acting anthelmintics. Terpenes are predicted to be extremely difficult for parasites to resist, and YP encapsulation provides water-suspendable terpene materials without surfactants and sustained terpene release that could lead to the development of formulations for oral delivery that overcome fast absorption in the stomach, thus reducing dosage and toxic side effects.

Efficacy evaluation of anthelmintic products against an infection with the canine hookworm (Ancylostoma caninum) isolate Worthy 4.1F3P in dogs.

Ancylostoma caninum is the most prevalent intestinal nematode of dogs, and has a zoonotic potential. Multiple-drug resistance (MDR) has been confirmed in a number of A. caninum isolates, including isolate Worthy 4.1F3P, against all anthelmintic drug classes approved for hookworm treatment in dogs in the United States (US). The cyclooctadepsipeptide emodepside is not registered to use in dogs in the US, but in a number of other countries/regions. The objective of this study was to evaluate the efficacy of emodepside + praziquantel, as well as three commercial products that are commonly used in the US for treatment of hookworms, against a suspected (subsequently confirmed) MDR A. caninum isolate Worthy 4.1F3P. 40 dogs infected on study day (SD) 0 with 300 third-stage larvae, were randomly allocated to one of five treatment groups with eight dogs each: pyrantel pamoate (Nemex®-2), fenbendazole (Panacur® C), milbemycin oxime (Interceptor®), emodepside + praziquantel tablets and non-treated control. Fecal egg counts (FEC) were performed on SDs 19, 20, 22, 27, 31 and 34. All treatments were administered as per label requirements on SD 24 to dogs in Groups 1 through 4. Two additional treatments were administered on SDs 25 and 26 to dogs in Group 2 as per label requirements. Dogs were necropsied on SD 34 and the digestive tract was removed/processed for worm recovery and enumeration. The geometric mean (GM) worm counts for the control group was 97.4, and for the pyrantel pamoate, fenbendazole, milbemycin oxime, and emodepside + praziquantel groups were 74.8, 72.0, 88.9, and 0.4, respectively. These yielded efficacies of 23.2%, 26.1%, and 8.8%, and 99.6%, respectively. These data support previous findings of the MDR status of Worthy 4.1F3P as treatments with pyrantel pamoate, fenbendazole and milbemycin oxime lacked efficacy. In sharp contrast, Worthy 4.1F3P was highly susceptible to treatment with emodepside + praziquantel.

Levels of serum eosinophil cationic protein are associated with hookworm infection and intensity in endemic communities in Ghana.

BACKGROUND: The eosinophil cationic protein (ECP) is a cytotoxic protein mainly secreted by eosinophils granulocytes and plays a role in host defense against parasitic infections. Infection with Necator americanus (hookworm) is traditionally diagnosed by the Kato-Katz method which is inherently tedious, subjective and known to underestimate infection intensity. This study aimed to assess levels of serum ECP in relation to hookworm infection intensity. METHODS: Stool samples from 984 (aged 4 to 80 years) participants in a cross-sectional study conducted in the Kintampo North Municipality of Ghana were examined using the Kato-Katz and formol-ether concentration methods. Serum ECP levels were measured by ECP assay kit and compared between 40 individuals infected with hookworm only, 63 with hookworm- Plasmodium falciparum co-infection, 59 with P. falciparum infection and 36 with no infection. RESULTS: Hookworm infection prevalence was 18.1% (178/984). ECP levels were significantly higher in individuals infected with hookworm only (ß = 2.96, 95%CI = 2.69, 3.23, p<0.001) or co-infected with P. falciparum (ß = 3.15, 95%CI = 2.91, 3.39, p<0.001) compared to the negative control. Levels of ECP were similar between those with only P. falciparum infection and the uninfected control (p>0.05). Increased hookworm intensity was associated with a significant increase in ECP level (ß = 4.45, 95%CI = 2.25, 9.11, rs = 0.193, n = 103, p<0.01). ECP threshold of 84.98ng/ml was associated with a positive predictive value (PPV) of 98% (95% CI = 92, 100), and negative predictive value (NPV) of 76% (95% CI = 62, 87) in classifying hookworm infection status with an AUROC of 96.3%. CONCLUSION: Serum ECP level may be a good biomarker of hookworm infection and intensity and warrant further investigations to help improve current hookworm diagnosis.

Hookworm infection.

Hookworms are soil-transmitted nematode parasites that can reside for many years in the small intestine of their human hosts; Necator americanus is the predominant infecting species. Adult worms feed on the blood of a host and can cause iron deficiency anaemia, especially in high-risk populations (children and women of childbearing age). Almost 500 million people in developing tropical countries are infected, and simulation models estimate that hookworm infection is responsible for >4 million disability-adjusted life years lost annually. Humans mount an immune response to hookworms, but it is mostly unsuccessful at removing adult worms from the bowel. Accordingly, the host switches to an immune-tolerant state that enables hookworms to reside in the gut for many years. Although anthelmintic drugs are available and widely used, their efficacy varies and the drugs do not prevent reinfection. Thus, other control strategies aimed at improving water quality, sanitation and hygiene are needed. In addition, efforts are underway to develop a human hookworm vaccine through public-private partnerships. However, hookworms could also be a resource; as hookworms have the capability to regulate the host's inflammation, researchers are experimentally infecting patients to treat some inflammatory diseases as an approach to discover new anti-inflammatory molecules. This area of endeavour might well yield new biotherapeutics for autoimmune and allergic diseases.

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.

Effect of anthelminthic treatment on helminth infection and related anaemia among school-age children in northwestern Ethiopia.

BACKGROUND: Information about improvements in the health status of population at-risk of helminth infection after anthelminthic treatment helps to evaluate the effectiveness of the large scale deworming program. The objectives of this study were to assess the impact of anthelminthic treatment on the prevalence and intensity of intestinal helminth infection, haemoglobin level and prevalence of anaemia among school-age children. METHODS: A total of 403 children attending Tikur Wuha Elementary School in Jiga, northwestern Ethiopia were enrolled in this study between February and March 2011. Formol-ether concentration and Kato-Katz methods were used to examine stool for intestinal helminth infections at baseline and one month after anthelminthic treatment. Haemoglobin level was measured using Hemocue machine at baseline and one month after anthelminthic treatment. RESULTS: Out of 403 school children examined, 15.4 % were anaemic and 58.3 % were infected with intestinal helminths at baseline. Hookworms (46.9 %), Schistosoma mansoni (24.6 %), Ascaris lumbricoides (4.2 %) and Trichuris trichiura (1.7 %) infections were common. The odds of anaemia was higher among children infected with helminths (adjusted odds ratio (aOR) = 3.83, 95 % CI = 1.92, 7.62) especially in those infected with hookworm (aOR = 2.42, 95 % CI = 1.34, 4.39) or S. mansoni (aOR = 2.67, 95 % CI = 1.46, 4.88) and two or more helminth species (aOR = 7.31, 95 % CI = 3.27, 16.35) than those uninfected with intestinal helminths at baseline. Significant reduction in prevalence of helminth infection (77.0 %) and increment in mean haemoglobin level (+3.65 g/l) of children infected with helminths was observed one month after anthelminthic treatment. The increase in haemoglobin level after anthelminthic treatment was significantly positively associated with the age, but negatively associated with the haemoglobin level at baseline. The change in mean haemoglobin level was significantly higher among undernourished than normal children. Percent reduction in the prevalence of anaemia among children infected with helminths was 25.4 % after anthelminthic treatment. CONCLUSIONS: The present study provides evidence that anthelminthic treatment of school-age children infected with intestinal helminth can improve haemoglobin level in addition to reducing the prevalence and intensity of helminth infections one month after treatment. This suggests that deworming of children may benefit the health of children in sub-Sharan Africa where hookworm and S. mansoni infections are prevalent.

Soil-Transmitted Helminths and Schistosoma mansoni Infections in Ethiopian Orthodox Church Students around Lake Tana, Northwest Ethiopia.

BACKGROUND: Soil-transmitted helminths (STH) and Schistosoma mansoni infections are the major neglected tropical diseases that result in serious consequences on health, education and nutrition in children in developing countries. The Ethiopian Orthodox church students, who are called Yekolotemari in Amharic, live in areas with poor sanitation and hygiene. Moreover, they are not included in the national STH control programs. Thus, STH and S. mansoni infections prevalence is unknown. METHODS: A cross-sectional study was conducted on 384 students in June 2014 to determine STH and S. mansoni infections prevalence. Moreover, the knowledge of students about STH and S. mansoni was assessed. Data on knowledge and clinical symptoms were collected using structured questionnaires via face to face interview. Stool specimens were examined by formol-ether concentration method. RESULTS: The overall prevalence of intestinal helminths infections was 85.9% (95% confidence interval (CI): 82.1-89%). STHs infections prevalence was 65.6% (95% CI: 60.7-70.2%). The prevalence of hookworm, Ascaris lumbricoides and Trichuris trichiura were 31.8% (95% CI: 27.3-36.6%), 29.4% (25-31%) and 3.1% (1.8-5.4%), respectively. On the other hand, S. mansoni prevalence was 14.3% (95% CI: 11.1-18.1%). Majority of students infected with S. mansoni had bloody stool with crud odds-ratio of 2.9 (95% CI: 1.5-5.5). Knowledge assessment showed that 50 (13%) and 18 (4.9%) of the respondents knew about transmission of STH and S. mansoni, respectively. CONCLUSIONS: The prevalence of STH and S. mansoni infections were high thus de-worming program should include the students of Ethiopian Orthodox churches. Furthermore, provision and use of sanitary facilities, health education for students to create awareness of parasitic infections and improved personal hygiene should be in place.

Restoration of hookworm egg development after prolonged storage in stool suspension.

Hookworm infection is still prevalent in southern Thailand despite control measures. Hookworm eggs submerged for an extended period under water from rainfall or in latrines may not survive, but they may recover their ability to develop into infective larvae when exposed to atmospheric air. This study examined the survival of the hookworm eggs in stool suspension and the restoration of development capability after prolonged storage. In stool mass, eggs developed normally and yielded infective filariform larvae (FL) in 7 days. On the contrary, in 1:10 stool suspension, hookworm eggs were found to remain at the 4-8 cell stage; degenerated eggs were observed after 15 days of storage, and the number of degenerated eggs reached 80 % on day 30. Aeration of the suspension, or transferring to a Petri dish or agar plate, restored the capacity of eggs stored for up to 15 days to develop into FL; thereafter, the capacity declined sharply. Retardation of egg development under water or in stool suspension may be due to a lack of atmospheric air. Use of "night soil" from latrines as fertilizer may be one factor in maintaining hookworm transmission, as worm eggs can undergo normal development upon exposure to atmospheric air.

Clinical assessment of coded Unani formulation D-worm and mebandazole for the treatment of hook worm, roundworm and whip worm.

A case control, multicenter, prospective randomized two arm parallel group clinical trials was conducted on 190 patients. The main objective of this study is to provide comparative efficacy results of both trialed medicines. The comparison was done in between herbal medicine D-Worm and Mebandazole allopathic drug for the treatment of helminthiasis. All the rules of GCP (Good Clinical Practices) were followed including clinical history, clinical presentation, examination findings and stool tests. Stool D/R and Parasite antigen tests were performed before and after treatment. The comparison of symptoms were also done including the improvement in abdominal pain, worms in stool, anal itching, nausea and vomiting, loss of appetite, and fatigue etc. The data on clinical proforma was gathered and subjected to statistical analysis. Parasite specific antigen test and stool D/R is considered as gold standard test for the diagnosis and confirmation of helminthes infection. Different parameter i.e. age, sex, and other clinical sign and symptoms were studied and compared between two treatment groups (Control and Test groups) at baseline and end of therapeutic application. Consent of patient was taken at first before the start of examination. Majority of the patients (90%) included in this study group get cured after herbal treatment. The statistical analysis used for the assessment of the effect of the treatment also showed significant improvement after treatment.

Prevalence and Risk Factors of Intestinal Parasites in Cats from China.

The prevalence of intestinal parasites in cats from China was largely unknown prior to this study. The aim of the present study was to investigate the presence of intestinal parasites in cats from central China and also identify risk factors for parasitism. Fecal samples from 360 cats were examined using sugar flotation procedure and fecal smear test by microscope. Cats had mixed two or three kinds of parasites infections. Of the 360 cats feces, intestinal parasites positive feces were 149 (41.39%). 64 (17.78%) were infected with Toxocara cati, 61 (16.94%) with Isospora felis, 41 (11.39%) with Isospora rivolta, 33 (9.17%) with Paragonimus, 23 (6.39%) with hookworms, 11 (3.06%) with Toxoplasma-like oocysts, 10 (2.78%) with Trichuris, 4 (1.11%) with lungworm, 2 (0.56%) with Sarcocystis, and 1 (0.28%) with Trematode. The cats' living outdoor was identified as risk factor by statistical analysis. These results provide relevant basic data for assessing the infection of intestinal parasites in cats from central region of China. In conclusion, there was high prevalence of intestinal parasites in cats from China.

Health assessment of free-ranging endangered Australian sea lion (Neophoca cinerea) pups: effect of haematophagous parasites on haematological parameters.

Evaluation of the health status of free-ranging populations is important for understanding the impact of disease on individuals and on population demography and viability. In this study, haematological reference intervals were developed for free-ranging endangered Australian sea lion (Neophoca cinerea) pups within the context of endemic hookworm (Uncinaria sanguinis) infection and the effects of pathogen, host, and environment factors on the variability of haematological parameters were investigated. Uncinaria sanguinis was identified as an important agent of disease, with infection causing regenerative anaemia, hypoproteinaemia, and a predominantly lymphocytic-eosinophilic systemic inflammatory response. Conversely, the effects of sucking lice (Antarctophthirus microchir) were less apparent and infestation in pups appears unlikely to cause clinical impact. Overall, the effects of U. sanguinis, A. microchir, host factors (standard length, body condition, pup sex, moult status, and presence of lesions), and environment factors (capture-type and year of sampling) accounted for 26-65% of the total variance observed in haematological parameters. Importantly, this study demonstrated that anaemia in neonatal Australian sea lion pups is not solely a benign physiological response to host-environment changes, but largely reflects a significant pathological process. This impact of hookworm infection on pup health has potential implications for the development of foraging and diving behaviour, which would subsequently influence the independent survival of juveniles following weaning. The haematological reference intervals developed in this study can facilitate long-term health surveillance, which is critical for the early recognition of changes in disease impact and to inform conservation management.

Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

Interactions and potential implications of Plasmodium falciparum-hookworm coinfection in different age groups in south-central Côte d'Ivoire.

BACKGROUND: Given the widespread distribution of Plasmodium and helminth infections, and similarities of ecological requirements for disease transmission, coinfection is a common phenomenon in sub-Saharan Africa and elsewhere in the tropics. Interactions of Plasmodium falciparum and soil-transmitted helminths, including immunological responses and clinical outcomes of the host, need further scientific inquiry. Understanding the complex interactions between these parasitic infections is of public health relevance considering that control measures targeting malaria and helminthiases are going to scale. METHODOLOGY: A cross-sectional survey was carried out in April 2010 in infants, young school-aged children, and young non-pregnant women in south-central Côte d'Ivoire. Stool, urine, and blood samples were collected and subjected to standardized, quality-controlled methods. Soil-transmitted helminth infections were identified and quantified in stool. Finger-prick blood samples were used to determine Plasmodium spp. infection, parasitemia, and hemoglobin concentrations. Iron, vitamin A, riboflavin, and inflammation status were measured in venous blood samples. PRINCIPAL FINDINGS: Multivariate regression analysis revealed specific association between infection and demographic, socioeconomic, host inflammatory and nutritional factors. Non-pregnant women infected with P. falciparum had significantly lower odds of hookworm infection, whilst a significant positive association was found between both parasitic infections in 6- to 8-year-old children. Coinfected children had lower odds of anemia and iron deficiency than their counterparts infected with P. falciparum alone. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that interaction between P. falciparum and light-intensity hookworm infections vary with age and, in school-aged children, may benefit the host through preventing iron deficiency anemia. This observation warrants additional investigation to elucidate the mechanisms and consequences of coinfections, as this information could have important implications when implementing integrated control measures against malaria and helminthiases.

Hookworm virulence factors: making the most of the host.

Hookworm disease from Necator americanus and Ancylostoma duodenale affects approximately 700 million people, with N. americanus being the predominant species. Unlike other pathogens (e.g., bacterial infections), where "virulence" is described in regards to acute pathogenesis and case-fatality, hookworms are well-evolved, multicellular parasites that establish long-term infections in their human hosts with a subtle and chronic, but insidious, pathogenesis, usually in the form of iron deficiency anemia from parasite blood feeding that, over time, has devastating effects on the human host especially when it involves children or women of child bearing years. As such, many of the typical terms for "virulence factors" used in other reviews in this special edition cannot be applied to hookworm (e.g., "colonization", "invasion", "or "toxicity"); rather the virulence of hookworm infection comes in terms of their ability to maintain a chronic blood-feeding infection in the lumen of relatively healthy human hosts, an infection that is usually measured in years but can sometimes be measured in decades. In the current manuscript, we describe the routes of invasion hookworms take into their human hosts and the means by which they modulate the human immune system to maintain this long-term parasitism. Little data on hookworm infection comes from actual human infections; instead, much of the data is derived from observations of laboratory animal models, in which hookworms fail to establish this distinctive "chronic infection," either due to physiological or immunological responses of these animal models. Hence, the mode and effects of chronic immunity must be extrapolated from this very different sort of infection to humans. Herein, we aim to synthesize immunological information from both types of models in the context of immune regulation and protection in order to identify future research focuses for the development of new treatment alternatives (i.e. drugs and vaccines).

Molecular mechanisms of hookworm disease: stealth, virulence, and vaccines.

Hookworms produce a vast repertoire of structurally and functionally diverse molecules that mediate their long-term survival and pathogenesis within a human host. Many of these molecules are secreted by the parasite, after which they interact with critical components of host biology, including processes that are key to host survival. The most important of these interactions is the hookworm's interruption of nutrient acquisition by the host through its ingestion and digestion of host blood. This results in iron deficiency and eventually the microcytic hypochromic anemia or iron deficiency anemia that is the clinical hallmark of hookworm infection. Other molecular mechanisms of hookworm infection cause a systematic suppression of the host immune response to both the parasite and to bystander antigens (eg, vaccines or allergens). This is achieved by a series of molecules that assist the parasite in the stealthy evasion of the host immune response. This review will summarize the current knowledge of the molecular mechanisms used by hookworms to survive for extended periods in the human host (up to 7 years or longer) and examine the pivotal contributions of these molecular mechanisms to chronic hookworm parasitism and host clinical outcomes.