Human hookworm disease is a common helminth infection that is predominantly caused by the nematode parasites Necator americanus and Ancylostoma duodenale; organisms that play a lesser role include Ancylostoma ceylonicum, Ancylostoma braziliense, and Ancylostoma caninum. Hookworm infection is acquired through skin exposure to larvae in soil contaminated by human feces (see the image below). Soil becomes infectious about 9 days after contamination and remains so for weeks, depending on conditions.
Worldwide, hookworms infect an estimated 440 million people. Although most of those affected are asymptomatic, [1, 2] approximately 10% experience anemia. Hookworms may persist for many years in the host and impair the physical and intellectual development of children and the economic development of communities.
Historically, hookworm infection has disproportionately affected the poorest among the least-developed nations, largely as a consequence of inadequate access to clean water, sanitation, and health education. The frequent absence of symptoms notwithstanding, hookworm disease substantially contributes to the incidence of anemia and malnutrition in developing nations.  It occurs most commonly in the rural tropical and subtropical areas of Asia, sub-Saharan Africa, and Latin America. 
Individual hookworm treatment consists of iron replacement and anthelmintic therapy. Community eradication has proven difficult, even with intensive, yearly, school-based programs. Despite this, successful control and eradication of hookworms is a worthy goal for new methods that would offer huge economic and social benefits to much of Africa and Asia.
See Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.
Hookworm life cycle
Each day in the intestine, a mature female A duodenale worm produces about 10,000-30,000 eggs, and a mature female N americanus worm produces 5000-10,000 eggs (see the image below). After deposition onto soil and under appropriate conditions, each egg develops into an infective larva. These larvae are developmentally arrested and nonfeeding. If they are unable to infect a new host, they die when their metabolic reserves are exhausted, usually in about 6 weeks.
Larval growth is most proliferative in favorable soil that is sandy and moist, with an optimal temperature of 20-30°C. Under these conditions, the larvae hatch in 1 or 2 days to become rhabditiform larvae, also known as L1 (see the image below).
The rhabditiform larvae feed on the feces and undergo 2 successive molts; after 5-10 days, they become infective filariform larvae, or L3 (see the image below). These L3 go through developmental arrest and can survive in damp soil for as long as 2 years. However, they quickly become desiccated if exposed to direct sunlight, drying, or salt water. L3 live in the top 2.5 cm of soil and move vertically toward moisture and oxygen.
The L3 larvae are 500-700 µm long (barely visible to the naked eye) and are capable of rapid penetration into normal skin, most commonly on the hands or feet. Transmission occurs after 5 or more minutes of skin contact with soil that contains viable larvae. The skin penetration may cause a local pruritic dermatitis, also known as ground itch. Ground itch at the site of penetration is more common with Ancylostoma than with Necator.
The larvae migrate through the dermis, entering the bloodstream and moving to the lungs within 10 days. Once in the lungs, they break into alveoli, causing a mild and usually asymptomatic alveolitis with eosinophilia. (Hookworms are among the causes of the pulmonary infiltrates and eosinophilia [PIE] syndrome, along with Ascaris and Strongyloides species.)
Having penetrated the alveoli, the larvae are carried to the glottis by means of the ciliary action of the respiratory tract. During pulmonary migration, the host may develop a mild reactive cough, sore throat, and fever that resolve after the worm migrates into the intestines. At the glottis, the larvae are swallowed and carried to their final destination, the small intestine.
During this part of the migration, the larvae undergo 2 further molts, developing a buccal capsule and attaining their adult form. The buccal capsule of an adult A duodenale has teeth to facilitate attachment to mucosa, whereas an adult N americanus has cutting plates instead. A muscular esophagus creates suction in the buccal capsule.
Using their buccal capsule, the adult worms attach themselves to the mucosal layer of the proximal small intestine, including the lower part of the duodenum, jejunum, and proximal ileum (see the image below). In so doing, they rupture the arterioles and venules along the luminal surface of the intestine.
The adult worms release hyaluronidase, which degrades intestinal mucosa and erodes blood vessels, resulting in blood extravasation. They also ingest some blood. An anticoagulant facilitates blood flow by blocking the activity of factors Xa and VIIa. Adult worms also elaborate factors (eg, neutrophil inhibitory factor) that protect them from host defenses.
In 3-5 weeks, the adults become sexually mature, and the female worms begin to produce eggs that appear in the feces of the host.
Although N americanus infects only percutaneously, A duodenale can also infect by means of ingestion; however, in su Ancylostoma may also lie dormant in tissues and later be transmitted through breast milk. This ability to enter dormancy in the human host may be an adaptive response evolved to increase the chances of propagation. If all larvae were to mature promptly during dry seasons of the year, females would release eggs onto inhospitable soil. Eggs produced and released during the wet season have a much greater chance of encountering optimal soil conditions for further development.
Neither Necator nor Ancylostoma multiplies within the host. If the host is not reexposed, the infection disappears after the worm dies. The natural life span for an adult A duodenale is about 1 year, and that for an adult N americanus is 3-5 years.
Types of hookworm disease
Hookworm infection gives rise to the following 3 clinical entities in humans:
Classic hookworm disease - This is a gastrointestinal (GI) infection characterized by chronic blood loss that leads to iron-deficiency anemia and protein malnutrition; it is caused primarily by N americanus and A duodenale and less commonly by the zoonotic species A ceylonicum
Cutaneous larva migrans - This is an infection whose manifestations are limited to the skin; it is most commonly caused by A braziliense, whose definitive hosts include dogs and cats
Eosinophilic enteritis - This is a GI infection characterized by abdominal pain but no blood loss; it is caused by the dog hookworm A caninum
In cutaneous larva migrans, the infective larvae of zoonotic species such as A braziliense do not elaborate sufficient concentrations of hydrolytic enzymes to penetrate the junction of the dermis and epidermis. The larvae thus remain trapped superficial to this layer, where they migrate laterally at a rate of 1-2 cm/day and create the pathognomonic serpiginous tunnels associated with this condition. Larvae can survive in the skin for about 10 days before dying.
In eosinophilic enteritis, A caninum larvae typically enter a human host by penetrating the skin, though infection by oral ingestion is also possible. These larvae probably remain dormant in skeletal muscles and create no symptoms. In some individuals, larvae may reach the gut and mature into adult worms.
Why some individuals sustain A caninum development and then respond with a severe localized allergic reaction is unknown. Adult worms secrete various potential allergens into the intestinal mucosa. Some patients have been reported to experience increasingly severe recurrent abdominal pain, which may be analogous to a response to repeated insect stings.
Intestinal blood loss secondary is the major clinical manifestation of hookworm infection.  In fact, hookworm disease historically refers to the childhood syndrome of iron deficiency anemia, protein malnutrition, growth and mental retardation with lethargy resulting from chronic intestinal blood loss secondary to hookworm infection in the face of an iron deficient diet.
Hookworms ingest and digested some of the blood from the injured mucosa by means of a multienzyme cascade of metallohemoglobinases. Each Necator worm ingests 0.03 mL of blood daily, whereas each Ancylostoma worm ingests 0.15-0.2 mL of blood daily. Inhibited host coagulation due to a series of anticoagulants directed against factor Xa and the factor VIIa–tissue factor (TF) complex, as well as against platelet aggregation, further exacerbates blood loss.
The amount of blood loss and the degree of anemia are positively correlated with the worm burden, whereas hemoglobin, serum ferritin, protoporphyrin levels are significantly and negatively correlated with the number of worms.  Threshold worm loads for anemia differ nationally, with as few as 40 worms producing anemia in countries with low iron consumption.
Generally, the extent of hookworm infection may be categorized as follows:
Light (< 100 worms)
Moderate (100-500 worms)
Heavy (500-1000 worms)
People who develop an initial heavy infection seem to reacquire heavy infection, and individuals who are lightly infected reacquire light infections. Since each adult worm is the molt of a single infective larva, this suggests continuing exposure to highly contaminated environments with little amnestic immunity in the host. Individuals with light infection have minimal blood loss and may have infection but not disease, especially if iron intake or reserves are adequate to compensate for the blood loss. Moderate-to-heavy infections cause iron-deficiency anemia.
In addition, because A duodenale consumes more blood per worm than N americanus does, the severity of anemia may differ as a factor of the hookworm species that is causing the infection. Severe anemia affects intellectual and physical development in children and cardiovascular performance in adults.
Because of the clinically significant blood loss and the worm's ingestion of serum proteins, hypoproteinemia may also develop, which is clinically manifested as weight-loss, anasarca, and edema.
This is the result of a protein-losing enteropathy, with immunoglobulins among the proteins lost as a result of worm digestion. This results in stunted growth, as well as an increased susceptibility to infections such as malaria and gastrointestinal infections with enteric bacteria, viruses, and protozoa. This protein-losing enteropathy can also contribute to a more rapid progression of an HIV infection. In patients with high enough iron intake, enteropathy may occur independent of anemia.
Hookworms appear to evade or inhibit effective human immune responses. The persistence of hookworm infection supports the theory that the worms have evolved adaptive molecular mechanisms to achieve a homeostatic balance with the host immune response. [6, 7, 8, 9]
Little is known about the innate immune response to metazoan in general and hookworms in particular.  Hookworm-derived pathogen-associated molecular patterns (PAMPS) of molecules are thought to react with receptors on dentritic cells or basophiles to stimulate interleukin (IL)–4 and initiate an immunological cascade resulting in a type 2 regulatory response from Th2 helper cells. This may be augmented by “alarmins” such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 released from epithelial cells damaged by worms. These activate newly described innate lymphoid type-2 cells (ILC2) that provide early rise in protective TH2 cytokines IL-5 and IL-13.
Meanwhile, worm products inhibit IL-12 and TSLP induces basophil production of IL-4, both promoting differentiation of Th2 cells. The antiparasite Th2 cells produce more IL-4, IL-5, and IL-13, which cause B cell immunoglobulin G type 1 (IgG1) and immunoglobulin E (IgE) class switching. Antiworm IgE binds the parasite and actives mast cells, which release inflammatory molecules, while IL-5 promotes eosinophil expansion and activation and M2 macrophage differentiation, which damage and produce granulomas, respectively. Other effector molecules include transforming growth factor-beta (TGF-b), resistinlike molecule (RELM)–alpha, chitinases, and matrix metalloproteases, all of which damage or limit the parasite.
At the same time, this intense Th2 immune response must be regulated by the host to avoid immunopathology, and by the parasite to allow survival. Helminths enhance expression of T cell co-inhibitory molecules that include PD-1 and CTLA-4, and promote differentiation of tolerogenic dentric cells and T regulatory cells. T regulatory cells produce anti-inflammatory cytokines IL-10 and TGF-b. Hookworms also appear to secrete an inhibitor of natural killer cells, thereby suppressing production of interferon gamma and the Th2 response that would be expected to clear the parasite.
Since 1989 with David Strachan’s observation of a correlation between incidence of hay fever in children and low family size, the hygiene hypothesis has excited investigators as to a possible inverse relationship between helminth infections and allergic and autoimmune disease.
The increased prevalence of atopy, asthma, and food allergy in areas free of worm infestation has been cited as supportive of the hygiene hypothesis and has even prompted investigation of worms or worm products as therapy for such diseases. Similarly, areas of high hookworm endemicity have low rates of reaction to dust mite antigens. It is thought that worm-activated regulatory and counter-regulatory processes involving Th2 and T regulatory cells and cell products may paradoxically inhibit Th2 responses that in the absence of worms, cause reactions to potential allergens.
In the search for possible vaccine targets, investigators have focused on hookworm molecular inhibitors of coagulation factors Xa and VIIa-TF and metalloproteases that degrade hemoglobin and intestinal mucosal cells. The Sabin Vaccine Institute has developed a 2 antigen human hookworm vaccine comprising recombinant Necator antigens Na- GST-1 and Na- APR-1, each of which is required for hookworm use of host blood.  Another antigen, Ancylostoma -secreted protein 2 (ASP-2), appears necessary for chemokine receptor binding and invasion and has shown some promise in animal vaccine trials. The 3-dimensional structure of Na-ASP-2 has recently been reported and identified as a conserved tandem histidine motif necessary for catalytic or proteolytic activity.  Unfortunately, this vaccine produced urticarial reactions among previously infected recipients, and its development was halted. 
Organisms that have been shown to cause hookworm disease include the following:
N americanus is the globally predominant human hookworm and is the only member of its genus known to infect humans.  It is a small, cylindrical, off-white worm; adult males measure 7-9 mm, and adult females measure 9-11 mm. 
A duodenale is more geographically restricted than N americanus and is one of several anthropophilic members of the genus Ancylostoma. It primarily infects humans and is responsible for classic hookworm disease. A duodenale resembles N americanus in appearance but is somewhat larger, with adult males measuring 8-11 mm and adult females measuring 10-13 mm.
On microscopy, N americanus can be differentiated from A duodenale on the basis of the cutting plates that it possesses in place of teeth (see the images below). 
A ceylonicum primarily infects canines and felines but can cause milder classic hookworm disease in humans. A braziliense is a canine and feline hookworm that, in humans, causes cutaneous larva migrans, or creeping eruption, a self-limiting condition characterized by serpiginous burrows formed as the larvae migrate through the epidermis. A caninum is a canine hookworm that mainly causes eosinophilic enteritis in humans (though it also causes cutaneous larva migrans in a minority of cases).
Poor sanitation, limited access to clean water, and low income are well-documented risk factors for hookworm infection. High-risk populations include international travelers, refugees, international adoptees, and recent immigrants. 
Favorable environmental conditions conduce to the development of hookworm disease. Optimal conditions for eggs include ambient temperatures of 20-30°C and warm, moist, well-aerated soil that is shielded from sunlight. These conditions occur during cultivation of numerous agricultural products; hence, hookworm infections occur primarily in rural areas. Larvae fail to develop in temperatures below 13°C and are destroyed by temperatures below 0°C and above 45°C. They are also killed by drying and direct sunlight.
United States statistics
Although hookworm infection is now thought to be rare in the United States, hookworm played an important role in the impoverishment of the southeastern region of the country until the 1930s. Studies performed in the early 1970s indicated prevalences as high as 14.8% among schoolchildren from rural Kentucky and as high as 12% among schoolchildren from rural coastal Georgia. A low prevalence of classic hookworm infection, mainly due to N americanus, is still found in pockets of the southeastern United States.
Hookworm infection and disease are now most likely to be found in immigrants, refugees, and adoptees from tropical countries. Occasionally, people returning from travel abroad present with acute watery diarrhea with eosinophilia upon their return to the United States.
Cutaneous larva migrans is endemic in the southeastern states and Puerto Rico. The canine hookworm A caninum has reportedly caused eosinophilic enteritis in Australia and the United States.
Human infection with A duodenale or N americanus is estimated to affect approximately 439 million people worldwide.  These parasites drain the equivalent of all the blood from approximately 1.5 million people every day.
Infection is most prevalent in tropical and subtropical zones, roughly between the latitudes of 45°N and 30°S; in some communities, prevalence may be as high as 90%. The disease flourishes in rural communities with moist shaded soil and inadequate latrines. Agricultural laborers have traditionally been at high risk. Improper disposal of human feces and the common habit of walking barefoot are key epidemiologic features. However, the use of footwear has not been shown to affect hookworm prevalence, in that the larvae can invade through any skin surface.
In 2010, it was estimated that 117 million individuals in sub-Saharan Africa were infected with hookworms, as well as 64 million in East Asia, 140 million in South Asia, 77 million in Southeast Asia, 30 million in Latin America and the Caribbean, 10 million in Oceania, and 4.6 million in the Middle East and North Africa. Oceania has the highest prevalence (49%), followed by sub-Saharan Africa (13%), Southeast Asia (12.6%), South Asia (8.6%), East Asia (5%), and Latin America/Caribbean (5%). (ref16). These represent approximately 20% decreases in prevalence from 2005 WHO estimates.
Infection is closely associated with poverty; inadequate sanitation, poor housing construction, and lack of access to essential medications are major factors in this relationship. Studies performed in Brazil indicate that the prevalence and intensity of infection is higher among poorer households. Similar studies in Uganda indicate that in comparison with the spotty geographic prevalence of ascariasis and trichuriasis, hookworm disease is more homogeneously distributed. 
As countries develop, the factors conducing to hookworm disease are mitigated, and hookworm infestation decreases.  In developed countries, infection is most commonly encountered in travelers, immigrants, and adoptees from developing countries.
Both Necator and Ancylostoma species have worldwide distribution. A duodenale predominates in the Mediterranean region, in northern regions of India and China, and in North Africa. A ceylonicum is found in focally endemic areas in southern Asia. N americanus predominates in southern China, Southeast Asia, the Americas, most of Africa, and parts of Australia. This differential distribution is not absolute, and mixed infections may occur in individual patients. Coinfection with Ascaris or Trichuris is common in many parts of the world.
Age- and sex-related demographics
In endemic areas, the highest prevalences are reported among school-aged children and adolescents, possibly because of age-related changes in exposure and the acquisition of immunity.  Once infected, children are more vulnerable to developing morbidity because dietary intake often fails to compensate for intestinal losses of iron and protein, especially in developing countries. A fulminant form of acute GI hemorrhage associated with acute Ancylostoma infection has been described in newborns.
Although children bear a large disease burden, hookworm infection appears to have an atypical age distribution. Unlike other soil-transmitted helminth infections, such as ascariasis and trichuriasis (for which the incidence peaks in childhood), hookworm infection appears to increase throughout childhood until it reaches a plateau in adulthood.  Studies from China and Brazil indicate a consistently increasing prevalence, from 15% at age 10 years to 60% at age 70 years and older. Egg counts in stool also increase in a similar pattern.
Although adults carry larger worm burdens than children do and are generally more subject to disease, the relationship is nonlinear and depends on diet and activity thresholds. The increasing prevalence of hookworm disease and higher worm burden among adults in many infected communities, especially in China, suggests that hookworm is immunosuppressive.
Males and females are equally susceptible to hookworm infection.
With proper treatment, the prognosis is excellent. Mortality is low, though those hookworm-related deaths that do occur are probably underrecognized as a consequence of the insidious nature of the disease.
In classic hookworm disease, appropriate anthelmintic treatment and iron and diet therapy typically result in complete recovery from anemia and malnutrition, though some deficits in intellectual function may persist. In endemic areas, reinfection is very likely: Most patients become reinfected within months unless they are relocated to an area of significantly improved sanitation.
In cutaneous larva migrans, the larvae die even when no treatment is provided, and symptoms resolve within a few weeks to several months. Eosinophilic enteritis promptly responds to mebendazole therapy.
Anemia remains the most significant clinical consequence of hookworm infection. Hookworms are the leading cause of iron-deficiency anemia in developing countries. Severe anemia retards childhood development and intellectual performance and can cause significant disability in heavily infected communities. Vigorous labor is possible only with hemoglobin levels higher than 7 g/dL.
The timing of anemia onset depends on the patient’s preexisting iron stores. In a study involving 492 children, the prevalence of anemia and the prevalence of ferritin levels lower than 12 μg/L were 60.5% and 33.1%, respectively, in those with N americanus infection, compared with 80.6% and 58.9%, respectively, in those with A duodenale infection. 
Young women, especially those who are pregnant, and laborers are most susceptible to symptomatic anemia. Adolescent girls and women of child-bearing age are at particular risk for poor outcomes such as increased maternal mortality, prematurity, low birth weight, and impaired lactation. As many as 30-54% of cases of moderate-to-severe anemia among African and Asian women are attributable to hookworm.
Malabsorption may occur. Heavy infections can cause significant protein loss as the host loses RBCs and plasma. Adult hookworms also secrete a potent inhibitor of digestive enzymes, which may contribute to malabsorption. Malabsorption leads to hypoproteinemia, which aggravates malnutrition. Malabsorption is more common in children than in adults. Anemia and protein malnutrition occur together in as many as 25% of infected individuals.
Patient education focuses on preventive measures. Walking barefoot outdoors in endemic areas should generally be discouraged; however, the effect of wearing proper footwear on hookworm transmission is likely to be overestimated. Inadequate sanitation remains a primary risk factor for hookworm infection. [23, 24] Public health education about proper hygiene and improved sanitation may considerably reduce the risk of infection.
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