Hookworm infection

INTRODUCTION — Hookworm is a soil-transmitted intestinal helminth (roundworm) infection; it occurs in areas with inadequate access to water, sanitation, and hygiene.

SPECIES — There are two major species of hookworm that cause human infection: Ancylostoma duodenale (in Mediterranean countries, Iran, India, Pakistan, and the Far East) and Necator americanus (in North and South America, Central Africa, Indonesia, islands of the South Pacific, and parts of India).

In addition, a hookworm of dogs and cats, Ancylostoma ceylanicum, has been recognized as a widely prevalent cause of human zoonotic infections in India, Southeast Asia, tropical Australia, and some Melanesian Pacific Islands [1-3]. Moreover, with application of molecular diagnostic techniques [4], human infections with A. ceylanicum are beginning to be recognized in the Americas. A study in Ecuador documented autochthonous human infection with A. ceylanicum [5], and A. ceylanicum has been found in dogs in Grenada, West Indies [6].

EPIDEMIOLOGY AND LIFE CYCLE

Disease burden — Hookworm infections are common in the tropics and subtropics [7-9]. It is estimated that approximately 500 million people are infected with hookworms worldwide [7,8]. Globally, hookworm infections have their major impact not by causing death but rather by contributing to morbidity especially due to anemia, including about 4 million disability-adjusted life years in 2010 [8].

The prevalence of hookworm infection is highest in sub-Saharan Africa, followed by Asia, Latin America, and the Caribbean. Infection is rare in regions with less than 40 inches of rainfall annually.

The prevalence of hookworm infection in rural areas of the southeastern United States in the early 20^th century was high [10]. Extensive control efforts diminished the prevalence within the United States; regions in the southeastern United States that have poor sanitation still are sites of hookworm infection [10-12]. (See 'Prevention and control' below.)

Transmission — Three conditions are important for transmission of hookworm infection: human fecal contamination of soil, favorable soil conditions for larval survival (moisture, warmth, shade), and contact of human skin with contaminated soil. Individuals who walk barefoot or with open footwear in fecally contaminated soil are at risk for infection; risk groups include residents of endemic areas, tourists, and infantry troops [13,14].

Fresh vegetables may be contaminated with infectious forms of soil-transmitted helminths; the impact of food-borne transmission to humans is uncertain [15].

Life cycle — The hookworm life cycle begins with passage of eggs from an adult host into the stool (figure 1). Hookworm eggs hatch in the soil to release rhabditiform larvae that mature into infective filariform larvae. Infection is transmitted by larval penetration into human skin; as few as three larvae are sufficient to produce infection [16]. From the skin, larvae migrate into the blood vessels and are carried to the lungs. Approximately 8 to 21 days following infection, larvae penetrate into the pulmonary alveoli, ascend the bronchial tree to the pharynx, and are swallowed. In addition to percutaneous larval penetration (the principal mode of transmission), A. duodenale infection may also be transmitted by the oral route.

In the small intestine, the larvae mature into adult worms and attach to the intestinal wall with resultant blood loss. A. duodenale larvae may persist within tissues before returning to the intestine, with delay in egg laying [17]. Following fertilization by adult male worms, gravid female adults lay eggs within the bowel. Eggs become detectable in feces about six to eight weeks following infection with N. americanus. Most adult worms are eliminated in one to two years, though infection can persist for many years [18].

Issues related to the relationship between hookworm infection and allergic and autoimmune diseases are discussed separately. (See "Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors".)

CLINICAL MANIFESTATIONS — The potential manifestations reflect the four phases of hookworm infection [14]:

●Dermal penetration by infecting larvae

●Transpulmonary passage

●Acute gastrointestinal symptoms

●Chronic nutritional impairment

Cutaneous manifestations — Dermal penetration of the skin frequently produces a focal pruritic maculopapular eruption at the site of larval penetration (termed "ground itch"). Less often, serpiginous tracks of intracutaneous larval migration can be seen; this is similar to cutaneous larva migrans, which is typically caused by the infective larvae of the animal hookworms. Ground itch generally occurs between the toes and usually resolves within a few days. (See "Hookworm-related cutaneous larva migrans" and "Skin lesions in the returning traveler".)

Transpulmonary passage — Transpulmonary passage is usually asymptomatic. A mild cough and pharyngeal irritation may occur during larval migration in the airways, though eosinophilic pulmonary infiltrates (such as those seen in the setting of Ascaris pulmonary involvement) are rare. (See "Ascariasis".)

Pulmonary symptoms attributable to hookworm have not been observed in experimentally infected volunteers [17]. Furthermore, bronchoalveolar lavage in these individuals has demonstrated only erythema of the bronchial mucosa without prominent eosinophilia in lavage fluids.

Gastrointestinal symptoms — Patients may experience gastrointestinal symptoms at the time of larval migration to the small intestine. Nausea, diarrhea, vomiting, midepigastric pain (usually with postprandial accentuation), and increased flatulence have been observed in individuals with naturally acquired infections [13] and in experimentally infected volunteers [19-21].

Initial infections may be associated with gastrointestinal symptoms (especially mid-epigastric pain) more frequently than subsequent infections. In one individual who was experimentally infected on four occasions, gastrointestinal symptoms and diarrhea were marked with the first infection, mild after the second, and absent after the third and fourth infections [19]. In five subjects given experimental infections with 50 larvae of N. americanus, all experienced abdominal pain, at times moderate to severe [22].

In those with heavy infections, especially in endemic regions, hookworm infections may cause overt gastrointestinal bleeding [23,24].

Gastrointestinal symptoms improve following treatment of hookworm infection [25].

Chronic nutritional impairment — The major impact of hookworm infection is on nutritional status [7,8]. This is particularly important in endemic areas where children and pregnant women may have limited access to adequate nourishment. In addition, maternal hookworm infection is associated with low birthweight.

Hookworms cause blood loss during attachment to the intestinal mucosa by lacerating capillaries and ingesting extravasated blood. This process is facilitated by the production of anticoagulant peptides that inhibit activated factor X and factor VIIa/tissue factor complex [26] and inhibit platelet activation [27]. Each N. americanus and A. duodenale worm consumes about 0.3 mL and 0.5 mL of blood per day, respectively. The daily losses of blood, iron, and albumin can lead to anemia and contribute to impaired nutrition, especially in patients with heavy infections [14,28].

DIAGNOSIS — Clues to the presence of hookworm infection include clinical manifestations as described above, together with history of skin exposure to potentially contaminated soil and/or otherwise unexplained blood eosinophilia.

The diagnosis may be established by stool examination. Molecular diagnostic tests can differentially speciate infecting hookworm species. There are no reliable serologic tests available.

In some cases hookworms may be detected endoscopically, attached to the gastric and small intestinal mucosal [9,24].

Stool examination — Stool examination for the eggs of N. americanus, A. duodenale, or A. ceylanicum is useful for detection of clinically significant hookworm infection (picture 1). Fecal egg excretion becomes detectable about eight weeks after dermal penetration of N. americanus infection and up to 38 weeks after dermal penetration of A. duodenale [17]. Stool examination is not helpful prior to established intestinal tract disease, including during early stages of dermal, pulmonary, or intestinal involvement.

The standard method of diagnosis is with the Kato Katz technique. Other techniques used include the simple sodium nitrate flotation technique (SNF), FLOTAC, and mini-FLOTAC. Microscopic methods of stool examination for detection of hookworm infection vary, but are relatively insensitive especially with low-intensity infections [29], so serial examinations are needed.

Polymerase chain reaction (PCR) tests (including multiplex PCR assays, which can simultaneously detect hookworm, Ascaris lumbricoides, and Trichuris trichiura) have been developed. PCR has superior sensitivity compared with microscopy and has increasing commercial accessibility [30-33]. A PCR assay of human stool can specifically detect A. ceylanicum [34].

The eggs of N. americanus and A. duodenale are morphologically indistinguishable. Speciation is not necessary for clinical purposes and is only possible if adult worms are detected in stool or at endoscopy [35,36].

Eosinophilia — Otherwise, unexplained eosinophilia may be a major clue to the presence of a parasitic infection. Eosinophilia has been attributed to persistent attachment of adult worms to the intestinal mucosa. Among 128 Indochinese refugees with eosinophilia, a diagnosis of intestinal parasitism was made in 95 percent of cases; hookworm and Strongyloides were the most common organisms (55 and 38 percent, respectively) [37]. In one study of immigrants and travelers with eosinophilia in Spain, the most commonly identified parasites were Strongyloides (34 percent), Schistosoma (11 percent), and hookworm (9 percent) [38].

The degree of eosinophilia with hookworm infection is usually mild and varies during the course of the disease. Among experimentally infected volunteers, blood eosinophilia increased progressively after two to three weeks and peaked at five to nine weeks. Peak eosinophil counts ranged from 1350 to 3828 cells/microL [39].

In untreated infections, eosinophilia slowly diminishes in magnitude but can remain elevated for several years [18].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of hookworm depends on the stage of infection:

●Dermal penetration – Cutaneous manifestations of hookworm infection can resemble cutaneous larva migrans (infection with the dog or cat hookworm, Ancylostoma braziliense or Ancylostoma caninum). Hookworm causes focal skin lesions at the site of larval dermal penetration. In rare cases, migration of hookworm larvae elicits a serpiginous migratory track; if so, this occurs shortly after dermal penetration. In contrast, larvae causing cutaneous larva migrans elicit more extensive migratory serpiginous lesions, which last more than a few days and may appear weeks to months following exposure. (See "Hookworm-related cutaneous larva migrans".)

●Transpulmonary passage – Pulmonary manifestations due to hookworm infection can resemble pulmonary infection due to A. lumbricoides or Strongyloides. In some cases, sputum examination may demonstrate diagnostic larvae; otherwise, stool microscopy may be performed, although Ascaris stool eggs may not be detected until three to four weeks following infection. (See "Strongyloidiasis" and "Ascariasis".)

●Acute gastrointestinal symptoms – Gastrointestinal symptoms due to hookworm infections are nonspecific so may be difficult to differentiate from other causes of abdominal pain and flatulence. Infectious etiologies causing similar symptoms include giardiasis, strongyloidiasis, and Dientamoeba fragilis. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Strongyloidiasis" and "Dientamoeba fragilis".)

●Chronic nutritional impairment – The soil-transmitted helminths A. lumbricoides and T. trichiura can also cause growth retardation and malnutrition. In general, iron-deficiency anemia is most strongly associated with hookworm infection. The soil-transmitted helminths may be distinguished based on stool microscopy. (See "Ascariasis" and "Enterobiasis (pinworm) and trichuriasis (whipworm)".)

●Eosinophilia – Consideration of other parasitic and nonparasitic causes of eosinophilia may be warranted. (See "Approach to the patient with unexplained eosinophilia".)

TREATMENT

●Clinical approach

•Preferred treatment – Anthelminthic treatment of hookworm infection consists of albendazole (400 mg once on empty stomach) [40,41].

•Efficacy – The above approach is supported by the following studies:

-In a meta-analysis including 38 studies and more than 7000 individuals, cure rates for albendazole, pyrantel pamoate, and mebendazole were 80, 50, and 32 percent; egg reduction rates were 90, 72, and 61 percent, respectively [41].

-In a randomized trial in China including more than 300 patients age ≥5 years, single-dose albendazole had greater efficacy than single-dose mebendazole (69 and 29 percent cure rates, respectively) [42]. Triple-dose therapy had greater efficacy, with cure rates of 92 and 54 percent, respectively.

-In a randomized trial in Laos including more than 400 children aged 6 to 15 years with hookworm infection treated with either (i) triple therapy with albendazole (400 mg), pyrantel pamoate (20 mg/kg), and oxantel pamoate (20 mg/kg), (ii) albendazole plus oxantel pamoate, or (iii) pyrantel pamoate plus oxantel pamoate, cure rates were 84, 52, and 53 percent, respectively; the egg reduction rates were comparable (99 percent) [43].

•Use of higher albendazole dosing – Data regarding use of higher albendazole doses are limited. In a randomized trial in Cote d’Ivoire including 64 adults with hookworm treated with albendazole (800 or 400 mg single dose), cure rates (based on stool microscopy three weeks after treatment) were higher among those treated with 800 mg (94 versus 53 percent) [44]. No difference in cure rates among 133 school-age children was observed.

●Other regimens

•Acceptable alternative regimens include [40]:

-Mebendazole (100 mg twice daily for three days is more effective than 500 mg single dose)

-Pyrantel pamoate (11 mg/kg per day for three days, not to exceed 1 g/day)

•Emodepside is a cyclooctadepsipeptide drug used in veterinary medicine. In a phase 2a trial including more than 170 adults in Tanzania with hookworm infection (based on demonstration of eggs in stool), patients were randomly assigned to treatment with emodepside, albendazole (400 mg single dose), or placebo [45]. The observed cure rate 14 to 21 days after treatment (assessed by Kato–Katz thick smear technique) among patients treated with emodepside (30 mg) was 95 percent; cure rates among patients treated with albendazole or placebo were 70 percent and 14 percent, respectively. Adverse events associated with emodepside included headache, blurred vision, and dizziness; there were no serious adverse events.

•Tribendimidine, a broad-spectrum anthelmintic agent, also has efficacy against hookworm [45].

•Ivermectin has poor efficacy against hookworm.

●Effect of nutrition - Treatment of hookworm infections in patients with marginal nutrition status has beneficial effects on growth, exercise tolerance, and cognitive function [9]. Even in those without impaired nutrition, anthelminthic therapies can improve hemoglobin levels [46]. Iron replacement alone can lead to restoration of a normal hemoglobin level in individuals with hookworm infection, but anemia recurs unless anthelminthic therapy is given.

PREVENTION AND CONTROL — Preventive measures consist of hygiene measures including drinking safe water, properly cleaning and cooking food, hand washing, and wearing shoes.

Regular deworming of groups at risk, including children, pregnant women, and women of childbearing age, may prevent and reverse malnutrition, iron-deficiency anemia, impaired growth, and poor school performance; uncertainties of the population-level benefits of such approaches remain [9,47,48]. (See "Mass drug administration for control of parasitic infections".)

Development of an effective human vaccine is possible; studies are underway [49].

SUMMARY AND RECOMMENDATIONS

●There are three species of hookworm that cause human infection: Ancylostoma duodenale (in Mediterranean countries, Iran, India, Pakistan, and the Far East), Necator americanus (in North and South America, Central Africa, Indonesia, islands of the South Pacific, and parts of India), and Ancylostoma ceylanicum (principally in India, Southeast Asia, tropical Australia, and some Pacific Islands). Infection is rare in regions with less than 40 inches of rainfall annually. (See 'Introduction' above.)

●The hookworm life cycle begins with passage of eggs from an adult host into the stool (figure 1). Hookworm eggs hatch in the soil to release larvae that mature into infective larvae. Infection is usually transmitted by larval penetration into human skin (A. duodenale infection may also be transmitted by the oral route). From the skin, larvae migrate into the blood vessels and are carried to the lungs, where they penetrate into the pulmonary alveoli, ascend the bronchial tree to the pharynx, and are swallowed. (See 'Epidemiology and life cycle' above.)

●Clinical manifestations include dermal penetration by infecting larvae, transpulmonary passage (usually asymptomatic), acute gastrointestinal symptoms, and chronic nutritional impairment. Hookworms cause blood loss during attachment to the intestinal mucosa by lacerating capillaries and ingesting extravasated blood. The daily losses of blood, iron, and albumin can lead to anemia and contribute to impaired nutrition, especially in patients with heavy infection. (See 'Clinical manifestations' above.)

●The diagnosis is established by stool examination via microscopy or polymerase chain reaction for the eggs of N. americanus or A. duodenale; there are no reliable serologic tests available. Stool examination for detection of hookworm infection is insensitive; serial examinations may be required to make the diagnosis. (See 'Stool examination' above.)

●Otherwise, unexplained eosinophilia may be a major clue to the presence of a parasitic infection. Eosinophilia has been attributed to persistent attachment of adult worms to the intestinal mucosa. (See 'Eosinophilia' above.)

●We suggest albendazole (400 mg once on empty stomach) for treatment of hookworm infection (Grade 2B). Mebendazole and pyrantel pamoate are acceptable but less effective alternative therapies. Iron replacement alone can lead to restoration of a normal hemoglobin level in individuals with hookworm infection, but anemia recurs unless anthelminthic therapy is given. (See 'Treatment' above.)

●Preventive measures consist of hygiene measures including drinking safe water, properly cleaning and cooking food, hand washing, and wearing shoes. Anthelminthic drugs may be administered to populations at risk with the intention of maintaining low individual worm burdens. (See 'Prevention and control' above.)