Hookworm: Ancylostoma duodenale and Necator americanus

Noelle Pineda and Elizabeth Yang

Humbio 153 Parasites and Pestilence

 

Introduction

Hookworm infection is caused by the blood-feeding nematode parasites of the species Ancylostoma duodenale and Necator americanus.  Together, the hookworms infect an estimated 576-740 million individuals today of which 80 million are severely infected.  The morbidity associated with severe infection includes intestinal blood loss, anemia, and protein malnutrition.  The burden of infection is concentrated mostly among the world’s poorest who live on less than $2 a day.  A particularly vulnerable population is children in low and middle income countries as infection with hookworm can stunt growth and physical fitness and impair and intellectual and cognitive development.  The tragic irony of the situation is that there are readily available and cheap resources for treatment which often cost less than 2 cents per pill. 

 

Throughout this paper, we will explore the biological, epidemiological, and public health concepts associated with hookworm.  Each section lays an important foundation for the next.  For example, it is imperative to understand the lifecycle of hookworm not just for the sake of knowing it but to understand critical points of intervention with treatment, vaccination, and public health campaigns.  Together, the sections all build towards the final goal of elimination of hookworm from many parts of the world.          

 

Agent

Kingdom: Animalia

Phylum: Nematoda

Class: Secernentea

Order: Strongiloidae

Family: Ancylostomatidae

Genus: Necator/Ancylostoma

Species: Necator americanus and Ancylostoma duodenale

 

Synonyms

Hookworm infection has numerous synonyms including acanthocheilonemiasis, ancylostomiasis, necatoriasis, and uncinariasis [1].

 

History of Discovery

Documentation of hookworm dates as early as the third-century B.C. when the authors of the Hippocratic Corpus referred to a disease characterized by intestinal distress, a yellow-green complexion, and a tendency to eat dirt.  The first definitive observations of hookworm, however, were not made until 1838 when Angelo Dubini discovered hookworm during an autopsy.  Dubini was responsible for naming the parasite Ancylostoma duodenale and also described the hookworm’s teeth in great detail.  Reports of hookworm then began to increase throughout the world, first in Egypt in 1846 and then in Brazil in 1865.  By 1878, Giovanni B. Grassi and his colleagues had announced a method of diagnosis via microscopic examination of the feces for hookworm eggs. 

 

In 1880, Edoardo Perroncito first noted the correlation between hookworms and anemia among miners digging the St. Gottard tunnel in the Alps.  Soon thereafter in 1881, the first antihelminthic drug, Thymol, was developed and used as the drug of choice until the 1920’s.  In 1898, Arthur Looss determined the life cycle of hookworm while Charles W. Stiles identified Necator americanus as another species of hookworm that infected humans.  It was Stiles who convinced the Rockefeller Foundation to initiate its $1 million campaign against hookworm in the United States using treatment, education, and latrine-building programs.  Although the campaign was unsuccessful in eliminating hookworm from the United States, the campaign has become a significant model in the history of hookworm elimination for its goal and size [2].

 

Clinical Presentation in Humans

Hookworm infection is generally considered to be asymptomatic, but as Norman Stoll described in 1962, hookworm is an extremely dangerous infection because its damage is “silent and insidious” [3].  There are general symptoms that an individual may experience soon after infection. Ground-itch, which is an allergic reaction at the site of parasitic penetration and entry, is common in patients infected with N. americanus [4].  Additionally, cough and pneumonitis may result as the larvae begin to break into the alveoli and travel up the trachea. Once the larvae reach the small intestine of the host and begin to mature, the infected individual may suffer from diarrhea and other gastrointestinal discomfort [5].  However, the “silent and insidious” symptoms referred to by Stoll are really only related to chronic, heavy-intensity hookworm infections. Major morbidity associated with hookworm is caused by intestinal blood loss, iron deficiency anemia, and protein malnutrition [6].  They result mainly from adult hookworms in the small intestine ingesting blood, rupturing erythrocytes, and degrading hemoglobin in the host [7].  This long-term blood loss can manifest itself physically through facial and peripheral edema; eosinophilia and pica caused by iron deficiency anemia are also experienced by some hookworm-infected patients [8].  Recently, more attention has been given to other important outcomes of hookworm infection that play a large role in public health.  It is now widely accepted that children who suffer from chronic hookworm infection can suffer from growth retardation as well as intellectual and cognitive impairments [9].  Additionally, recent research has focused on the potential of adverse maternal-fetal outcomes when the mother is infected with hookworm during pregnancy.

 

Transmission

Necator can only be transmitted through penetration of the skin whereas Ancylostoma can be transmitted percutaneously, orally, and probably transplacentally.  When A. duodenale is transmitted orally, the early migrations of the larvae cause Wakana disease which is characterized by nausea, vomiting, pharyngeal irritation, cough, dyspnea, and hoarseness [10].  

 

Reservoir and Vector

Humans are the definitive hosts for both Necator americanus and Ancylostoma duodenale.  Ancylostoma caninum primarily infects dogs, but humans can be dead-end hosts that prevent the larvae from completing their life cycle [11].

           

Incubation Period

 

The incubation period can vary between a few weeks to many months and is largely dependent on the number of hookworm parasites with which an individual is infected [12].

 

Morphology

Adult A. duodenale worms are grayish white or pinkish with the head slightly bent in relation to the rest of the body.  This bend forms a definitive hook shape at the anterior end for which hookworms are named.  They possess well developed mouths with two pairs of teeth (Figure 1).  While males measure approximately one centimeter by 0.5 millimeter, the females are often longer and stouter.  Additionally, males can be distinguished from females based on the presence of a prominent posterior copulatory bursa [13]. 

 

N. americanus is very similar in morphology to A. duodenale.  N. americanus is generally smaller than A. duodenale with males usually 5 to 9 mm long and females about 1 cm long.  Whereas A. duodenale possess two pairs of teeth, N. americanus possesses a pair of cutting plates in the buccal capsule (Figure 1).  Additionally, the hook shape is much more defined in Necator than in Ancylostoma [14].  

 

 

Figure 1. Teeth of Ancylostoma on the left and cutting plates of Necator on the right.

John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis: Saunders Elsevier, 2006.

Hotez, Peter J., Simon Brooker, Jeffrey M. Bethony, et al. “Current concepts: hookworm infection.” The NewEngland Journal of Medicine 351 (2004): 799-807.

 

 

Life Cycle

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Figure 2. Hookworm Life Cycle

Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”. PLoS Med 2(3): e67

 

N. Americanus and A. duodenale eggs can be found in warm, moist soil where they will eventually hatch into first stage larvae, or L1. L1, the feeding non-infective rhabditoform stage, will feed on soil microbes and eventually molt into second stage larvae, L2. L2, which is also in the rhabditoform stage, will feed for approximately 7 days and then molt into the third stage larvae, or L3. L3 is the filariform stage of the parasite, that is, the non-feeding infective form of the larvae. The L3 larvae are extremely motile and will seek higher ground to increase their chances of penetrating the skin of a human host. The L3 larvae can survive up to 2 weeks without finding a host. It is important to note that while N. americanus larvae only infect through penetration of skin, A. duodenale can infect both through penetration as well as orally. 

 

After the L3 larvae have successfully entered the host, the larvae then travel through the subcutaneous venules and lymphatic vessels of the human host. Eventually, the L3 larvae enter the lungs through the pulmonary capillaries and break out into the alveoli. They will then travel up the trachea to be coughed and swallowed by the host. After being swallowed, the L3 larvae are then found in the small intestine where they molt into the L4, or adult worm stage. The entire process from skin penetration to adult development takes about 5-9 weeks. The female adult worms will release eggs (N. Americanus about 9,000-10,000 eggs/day and A. duodenale 25,000-30,000 eggs/day) which are passed in the feces of the human host. These eggs will hatch in the environment within several days and the cycle with start anew [15].

 

Diagnostics

Diagnostics of hookworm relies mainly on the recovery of the eggs from the stools.  The egg is unsegmented or in an early segmentation stage when passed, but sometimes when specimens have been allowed to stand at room temperature for a long period of time, a larva may be observed within the egg.  It is rare that eggs hatch and that free larvae are found in the stool.  If this were to occur, however, the free larvae would have to be distinguished from the larva of Strongyloides.  This can be done based on the length of the buccal cavity, the space between the oral opening and the esophagus: hookworm rhabditoform larvae have long buccal cavities whereas Strongyloides rhabditoform larvae have short buccal cavities [16]. 

 

Recent research has focused on the development of DNA-based tools for diagnosis of infection, specific identification of hookworm, and analysis of genetic variability within hookworm populations [17].  Because hookworm eggs are often indistinguishable from other parasitic eggs, PCR assays could serve as a molecular approach for accurate diagnosis of hookworm in the feces [18, 19].   

 

Management and Therapy

 

           

Figure 3. Suggested Drug Treatments for Hookworm

Bethony, Brooker, Albonico, Geiger, Loukas, Diemert and Hotez, (2006) Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm, Lancet 367:1521–1532.

 

The most common treatment for hookworm are Benzimidazoles (BZAs), specifically albendazole and mebendazole.  BZAs kill adult worms by binding to the nematode’s beta-tubulin and subsequently inhibiting microtubule polymerization within the parasite [20].  In certain circumstances, levamisole and pyrantel pamoate may be used [21].  The 2008 study by Keiser and Utzinger, “Efficacy of Current Drugs Against Soil-Transmitted Helminth Infections: Systematic Review and Meta-analysis,” examined the relative efficacies of different drug treatments.  They found that the efficacy of single-dose treatments for Hookworm infections were as follows: 72% for albendazole, 15% for mebendazole, and 31% for pyrantel pamoate [22]. This substantiates prior claims that albendazole is much more effective than mebendazole for Hookworm infections. Also noteworthy is that the World Health Organization recommends anthelmintic treatment in pregnant women after the first trimester [23].  It is also recommended that if the patient also suffers from anemia ferrous sulfate (200mg) be administered three times daily at the same time as anthelmintic treatment; this should be continued until hemoglobin values return to normal which could take up to 3 months [24].

 

Other important issues related to the treatment of hookworm are reinfection and drug resistance.  It has been show that reinfection after treatment can be extremely high. Some studies even show that 80% of pretreatment hookworm infection rates can be seen in treated communities within 30-36 months [25].  While reinfection may occur, it is still recommended that regular treatments be conducted as it will minimize the occurrence of chronic outcomes.  There are also increasing concerns about the issue of drug resistance.  Drug resistance has appeared in front-line anthelmintics used for livestock nematodes.  Generally human nematodes are less likely to develop resistance due to longer reproducing times, less frequent treatment, and more targeted treatment.  Nonetheless, the global community must be careful to maintain the effectiveness of current anthelmintic as no new anthelmintic drugs are in the late-stage development [26].

 

Epidemiology

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Figure 4. Map of Global Hookworm Prevalence

Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”. PLoS Med 2(3): e67

 

It is estimated that 576-740 million individuals are infected with Hookworm today [27].  Of these infected individuals, about 80 million are severely affected [28].  The major etiology of Hookworm infection is N. Americanus which is found the Americas, sub-Saharan Africa, and Asia [29].  A. duodenale is found in more scattered focal environments, namely Europe and the Mediterranean [30].  Most infected individuals are concentrated in sub-Saharan Africa and East Asia/the Pacific Islands with each region having estimates of 198 million and 149 million infected individuals, respectively.  Other affected regions include: South Asia (50 million), Latin America and the Caribbean (50 million), South Asia (59 million), Middle East/North Africa (10 million) [31].  A majority of these infected individuals live in poverty-stricken areas with poor sanitation. Hookworm infection is most concentrated among the world’s poorest who live on less than $2 a day [32]. 

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Figure 5. Hookworm Prevalence vs. Human Development Index

Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”. PLoS Med 2(3): e67

 

Many of the numbers regarding the prevalence of Hookworm infection are estimates as there is no international surveillance mechanism currently in place to determine prevalence and global distribution [33].  Some prevalence rates have been measured through survey data in endemic regions around the world. The following are some of the most recent findings on prevalence rates in regions endemic with hookworm:

 

Darjeeling, Hooghly District, West Bengal, India (Pal et al. 2007) [34]

 

Xiulongkan Village, Hainan Province, China (Gandhi et al. 2001) [35]

 

Hoa Binh, Northwest Vietnam (Verle et al. 2003) [36]

 

Minas Gerais, Brazil (Fleming et al. 2006) [37]

 

KwaZulu-Natal, South Africa (Mabaso et al. 2004) [38]

 

There have also been recent technological developments that will hopefully facilitate more accurate mapping of Hookworm prevalence. Some researchers have begun to use geographical information systems (GIS) and remote sensing (RS) to examine helminth ecology and epidemiology. Brooker et al. utilized this technology to create helminth distribution maps of sub-Saharan Africa.  By relating satellite derived environmental data with prevalence data from school-based surveys, they were able to create detailed prevalence maps.  

 

 

Figure 6. Predicted prevalence of hookworm based on relationships between AVHRR satellite data and surveyed prevalence of school-aged children

Brooker, Clements, Bundy (2007) Global epidemiology, ecology and control of soil-transmitted helminth infections. Adv Parasitol 62:221-261 

 

The study focused on a wide range of helminths, but interesting conclusions about Hookworm specifically were found. Compared to other helminths, hookworm is able to survive in much hotter conditions are were highly prevalent throughout the upper end of the thermal range. Hopefully this information along with more detailed prevalence maps can lead to more effective public health measures [39].

 

Public Health and Prevention Strategies

With an estimated 740 million individuals infected, hookworm is a major public health concern in our world today. While hookworm infection may not directly lead to mortality, its effects on morbidity demand immediate attention. When considering disability-adjusted-life-years (DALYs), neglected tropical diseases, including hookworm, rank among diarrheal diseases, ischemic heart disease, malaria, and tubercolosis as one of the most important health problems of the developing world [40].  It has been estimated that as many as 22.1 million DALYs have been lost due to hookworm [41].  Recently, there has been increasing interest to address the public health concerns associated with hookworm.  For example, the Bill and Melinda Gate Foundation recently donated $34 million to fight Neglected Tropical Diseases including hookworm infection [42].  Former President Clinton also announced a mega-commitment at the Clinton Global Initiative (CGI) 2008 Annual Meeting to de-worm 10 million children [43]. 

 

Most of these public health concerns have focused on children who are infected with hookworm. This focus on children is largely due to the large body of evidence that has demonstrated strong associations between hookworm infection and impaired learning, increased absences from school, and decreased future economic productivity [44].  In 2001, the 54th World Health Assembly passed a resolution demanding member states to attain a minimum target of regular deworming of at least 75% of all at-risk school children by the year 2010 [45].  A 2008 World Health Organization publication reported on these efforts to treat at-risk school children. Some of the interesting statistics were as follows: 1) only 9 out of 130 endemic countries were able to reach the 75% target goal; and 2) less than 77 million school-aged children (of the total 878 million at risk) were reached which means that only 8.78% of at-risk children are being treated for hookworm infection [46].  While there is progress being made, these numbers also remind us of how much work is still to be done.

 

School-based mass deworming programs have been the most popular strategy to address the issue of hookworm infection in children.  School-based programs are extremely cost effective as schools already have an available, extensive, and sustained infrastructure with a skilled workforce that has a close relationship with the community [47].  With little training from a local healthy system, teachers can easily administer the drugs which often cost less than $0.50 per child per year [48].

 

Figure 7. School-aged child being treated in Nepal. "Action Against Worms." WHO Newsletter (Feb. 2007).

 

Recently, many people have begun to question if the school-based programs are necessarily the most effective approach.  An important concern with school-based programs is that they often do not reach children who do not attend school, thus ignoring a large amount of at-risk children.  A 2008 study by Massa et al. continued the debate regarding school-based programs.  They examined the effects of community-directed treatments versus school-based treatments in the Tanga Region of Tanzania. A major conclusion was that the mean infection intensity of hookworm was significantly lower in the villages employing the community-directed treatment approach than the school-based approach [49]. The community-directed treatment model used in this specific study allowed villagers to take control of the child’s treatment by having villagers select their own community drug distributors to administer the antihelminthic drugs.  Additionally, villagers organized and implemented their own methods for distributing the drugs to all children.  The positive results associated with this new model highlight the need for large-scale community involvement in deworming campaigns.

 

Many mass deworming programs also combine their efforts with a public health education. These health education programs often stress important preventative techniques such as: always wearing shoes, washing your hands before eating, and staying away from water/area contaminated by human feces. But while these may seem like simple tasks, they raise important public health challenges.  The fact is that most infected populations are from poverty-stricken areas with very poor sanitation.  Thus, it is most likely that at-risk children cannot afford shoes to wear, do not have access to clean water to wash their hands, and live in environments with no proper sanitation infrastructure.  Health education, therefore, must address preventive measures in ways that are both feasible and sustainable in the context of resource-limited settings.  

 

Figure 8. Child health education material for soil transmitted helminths

Global Materials. WHO. <http://www.who.int/wormcontrol/education_materials/global/en/ spanish_flipchartforchildren.pdf>.

 

 

Evaluation of numerous public health interventions have generally shown that improvement in each individual component ordinarily attributed to poverty (for example, sanitation, health education, footwear, and underlying nutrition status) often have minimal impact on transmission.  For example, one study found that the introduction of latrines into a resource-limited community only reduced the prevalence of hookworm by four percent [50].  Another study in Salvador, Brazil found that improved drainage and sewerage had minimal impact of the prevalence and no impact at all on the intensity of hookworm [51].  This seems to suggest that environmental control alone has minimal effect on the transmission of hookworm.  It is imperative, therefore, that more research be performed to understand the efficacy and sustainability of integrate programs that combine numerous preventive methods including education, sanitation, and treatment.   

 

Vaccines

While annual or semi-annual mass antihelminthic administration is a critical aspect of any public health intervention, many have begun to realize how unsustainable it is due to aspects such as poverty, high rates of re-infection, and diminished efficacy of drugs with repeated use.  Current research, therefore, has focused on the development of a vaccine that could be integrated into existing control programs.  The goal of vaccine development is not necessarily to create a vaccine with sterilizing immunity or complete protection against immunity.  A vaccine that reduces the likelihood of vaccinated individuals developing severe infections and thus reduced blood and nutrient levels could still have a significant impact on the high burden of disease throughout the world. 

 

Current research focuses on targeting two stages in the development of the worm: the larval stage and the adult stage.  Research on larval antigens has focused on proteins that are members of the pathogenesis-related protein superfamily, Ancylostoma Secreted Proteins [52].  Although they were first described in Anyclostoma, these proteins have also been successfully isolated from the secreted product of N. americanus.  N. americanus ASP-2 (Na-ASP-2) is currently the leading larval-stage hookworm vaccine candidate.  A randomized, double-blind, placebo-controlled study has already been performed; 36 healthy adults without a history of hookworm infection were given three intramuscular injections of three different concentrations of Na-ASP-2 and observed for six months after the final vaccination [53].  The vaccine induced significant anti-Na-ASP-2 IgG and cellular immune responses.  In addition, it was safe and produced no debilitating side effects.  The vaccine is now in a phase one trial; healthy adult volunteers with documented evidence of previous infection in Brazil are being given the same dose concentration on the same schedule used in the initial study [54].  If this study is successful, the next step would be to conduct a phase two trial to assess the rate and intensity of hookworm infection among vaccinated persons.  Because the Na-ASP-2 vaccine only targets the larval stage, it is critical that all subjects enrolled in the study be treated with antihelminthic drugs to eliminate adult worms prior to vaccination. 

 

Adult hookworm antigens have also been identified as potential candidates for vaccines.  When adult worms attach to the intestinal mucosa of the human host, erythrocytes are ruptured in the worm’s digestive tract which causes the release of free hemoglobin which is subsequently degraded by a proteolytic cascade.  Several of these proteins that are responsible for this proteolytic cascade are also essential for the worm’s nutrition and survival [55].  Therefore, a vaccine that could induce antibodies for these antigens could interfere with the hookworm’s digestive pathway and impair the worm’s survival.  Three proteins have been identified: the aspartic protease-hemoglobinase APR-1, the cysteine protease-hemoglobinase CP-2, and a glutathione S-transferase [56, 57, 58].  Vaccination with APR-1 and CP-2 led to reduced host blood loss and fecal egg counts in dogs [56, 57].  With APR-1, vaccination even led to reduced worm burden [56].  Research is currently stymied at the development of at least one of these antigens as a recombinant protein for testing in clinical trials. 

 

Figure 9. Table of candidates for hookworm vaccine.

Diemert, David J., Jeffrey M. Bethony, and Peter J. Hotez. “Hookworm Vaccines.” Vaccines 46 (2008): 282-288.

 

 

New Research

 

Hookworm-Related Anemia in Pregnancy

Consider these statistics: one third of all pregnant women in developing countries are infected with Hookworm, 56% of all pregnant women in developing countries suffer from anemia, and 20% of all maternal deaths are either directly or indirectly related to anemia [59]. Numbers like this have led to an increased interest in the topic of hookworm-related anemia during pregnancy. With the understanding that chronic hookworm infection can often lead to anemia, many people are now questioning if the treatment of hookworm could decrease severe anemia rates and thus change maternal and child health as well.  Most evidence suggests that the effect of hookworm on maternal anemia merits that all women of child-bearing age living in endemic areas be subject to periodic anthelmintic treatment.  The World Health Organization even recommends that infected pregnant women be treated after their first trimester [60].  Despite these suggestions, only Madagascar, Nepal and Sri Lanka have added deworming to their antenatal care programs [61].

 

This lack of deworming of pregnant women is explained by the fact that most individuals still fear that anthelmintic treatment will result in adverse birth outcomes.  However, a 2006 study by Gyorkos et al. may assuage these fears.  The study found that when comparing a group of pregnant women treated with mebendazole with a control placebo group, both groups illustrated rather similar rates in adverse birth outcomes.  The treated group demonstrated 5.6% adverse birth outcomes, while the control group had 6.25% adverse birth outcomes [62].  Furthermore, Larocque et al. illustrated that treatment for hookworm infection actually led to positive health results in the infant.  This study concluded that treatment with mebendazole and iron supplements during antenatal care significantly reduced the proportion of very low birth weight infants when compared to a placebo control group [63].  So far, studies have validated recommendations to treat infected pregnant women for hookworm infection during pregnancy.

 

Further research on the topic is merited. The intensity of hookworm infection as well as the species of hookworm have yet to be studied as they relate to hookworm-related anemia during pregnancy. Additionally, more research must be done in different regions of the world to see if trends noted in completed studies persist. 

 

Hookworm and Malaria Co-infection

Co-infection with hookworm and Plasmodium falciparum is fairly ubiquitous throughout Africa due to spatial congruence (Figure 10) [64].  Although exact numbers are unknown, preliminary analyses estimate that as many as a quarter of African schoolchildren (17.8-32.1 million children aged 5-14 years) may be coincidentally at-risk for both P. falciparum and hookworm [65].  While original hypotheses stated that co-infection with multiple parasites would impair the host’s immune response to a single parasite and increase susceptibility to clinical disease, studies have yielded contrasting results.  For example, one study in Senegal showed that the risk of clinical malaria infection was increased in helminth-infected children in comparison to helminth-free children while other studies have failed to reproduce such results [66].  Some hypotheses and studies even suggest that helminth infections may protect against cerebral malaria due to the possible modulation of pro-inflammatory and anti-inflammatory cytokines responses [67].

 

 

 

Figure 10. Co-infection distribution of malaria and hookworm in sub-Saharan Africa

Brooker, Simon, Archie CA Clements, Peter J. Hotez, et al. “The co-distribution of Plasmodium falciparum and hookworm among African schoolchildren.” Malaria Journal 5 (2006): 99-107.

 

Furthermore, the mechanisms underlying this supposed increased susceptibility to disease are unwknown.  For example, it is known that helminth infections cause potent and highly polarized immune response characterized by increased T-helper cell type 2 (Th2) cytokine and Immunoglobulin(Ig)E production [68].  However, the effect of such responses on the human immune response is unknown.  Additionally, both malaria and helminth infection can cause anemia, but the effect of co-infection and possible enhancement of anemia is poorly understood.

 

 

 

Hookworms and the Hygiene Hypothesis

The hygiene hypothesis states that infants and children who lack exposure to infectious agents are more susceptible to allergic diseases via modulation of immune system development.  As Mary Ruebush writes in her book Why Dirt is Good, “what a child is doing when he puts things in his mouth is allowing his immune response to explore his environment.  Not only does this allow for ‘practice’ of immune responses, which will be necessary for protection, but it also plays a critical role in teaching the immature immune response what is best ignored” [69].  The theory was first proposed by David P. Strachan who noted that hay fever and eczema were less common in children who belonged to large families [70].  Since then, some monumental studies have noted the effect of gastrointestinal worms on the development of allergies in the developing world.  For example, a study in Gambia found that eradication of worms in some villages led to increased skin reactions to allergies among children [71].  

 

Although the exact mechanism is unknown, scientists hypothesize that the helper T cells are key players.  Allergic diseases, which are immunological responses to normally harmless antigens, are driven by a TH2-mediated immune response.  Bacteria, viruses, and parasites, on the other hand, elicit a TH1-mediated immune response which inhibits or down-regulates the TH2 response [72].  TH1 also inhibits the activity of TH17 which is heightened in numerous inflammatory diseases including multiple sclerosis and asthma [73].  More research is currently being performed to better understand the possible mechanism for the hygiene hypothesis. 

 

Useful links

 

References

1. “Disease information for Hookworm (Ancylostomiasis) disease.” DiagnosisPro. http://en.diagnosispro.com/disease_information-for/hookworm-ancylostomiasis-disease/14925.html

2. Power, Helen J. “History of hookworm.” Encyclopedia of Life Sciences. John Wiley & Sons, Ltd., 2002. 

3. Stoll NR (1962) On endemic hookworm, where do we stand today? Exp Parasitol 12:241-252.

4. John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

5. Ibid.

6. Bethony, Brooker, Albonico, Geiger, Loukas, Diemert and Hotez, (2006) Soil-transmitted helminth infections:

ascariasis, trichuriasis, and hookworm, Lancet 367:1521–1532.

7. Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”.

            PLoS Med 2(3): e67

8. John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

9. Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”.

PLoS Med 2(3): e67

10. Hotez, Peter J., Simon Brooker, Jeffrey M. Bethony, et al. “Current concepts: hookworm infection.” The New

England Journal of Medicine 351 (2004): 799-807.

11. John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

12. "Hookworms." The Center for Food Security and Public Health. May 2005. Iowa State University

13. John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

14. Ibid.

15. Hawdon, Hotez, (1996) Hookworm: developmental biology of the infectious process  Current Opinion in

Genetics and Development 6(5):618-623.

Bethony, Brooker, Albonico, Geiger, Loukas, Diemert and Hotez, (2006) Soil-transmitted helminth infections:

ascariasis, trichuriasis, and hookworm, Lancet 367:1521–1532.

Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”. PLoS

Med 2(3): e67

John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

16. John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology: Ninth Edition. St. Louis:

Saunders Elsevier, 2006. 

17. Gasser, Robin B., Cinzia Catacessi, and Bronwyn E. Campbell. “Improved molecular diagnostic tools for human

hookworms.” Expert Reviews 9 (2009): 17-21.

18. Ibid.

19. Yong, Tai-Soon, Jong-Ho Lee, Seobo Sim, et al. “Differential diagnosis of Trichostrongylus and hookworm

            eggs via PCR using ITS-1 sequence.” Korean Journal of Parasitology 45 (2007): 69-74.

20. Bethony, Brooker, Albonico, Geiger, Loukas, Diemert and Hotez, (2006) Soil-transmitted helminth infections:

ascariasis, trichuriasis, and hookworm, Lancet 367:1521–1532.

21. Hotez P, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The Great Infection of Mankind”.

            PLoS Med 2(3): e67

22. Keiser, Utzinger. (2008) Efficacy of Current Drugs Against Soil-Transmitted Helminth Infections. JAMA

299(16):1937-1948

23. Bethony, Brooker, Albonico, Geiger, Loukas, Diemert and Hotez, (2006) Soil-transmitted helminth infections:

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