Hookworm

Background:

Human hookworm infection is a common soil-transmitted helminth infection that is caused by the nematode parasites, Necator americanus and Ancylostoma duodenale. Worldwide, hookworm infects an estimated 740 million people, most of whom are asymptomatic. Despite this lack of symptoms, hookworm substantially contributes to the incidence of anemia and malnutrition in developing nations. The greatest number of cases occurs in the rural tropical and subtropical areas of China and sub-Saharan Africa, followed in number by India, South Asia, and Latin America.

The importance of hookworm infection has historically been undermined by the disproportionate number of impoverished people affected and by the insidious nature of the infection. However, this trend has slowly reversed. At the 54th World Health Assembly in 2001, a resolution was passed to encourage antihelmintic treatment in at-risk school-aged children by 2010 in an attempt to control morbidity. At present, new international efforts are ongoing to reduce the impact of this parasitic infection, with promising progress being made, particularly in the development of a new chemotherapeutics and an effective vaccine.

Pathophysiology:

N americanus is the globally predominant human hookworm and the only member of its genus known to infect humans. A duodenale is more geographically restricted than N americanus but one of several anthropophilic members of the genus Ancylostoma. Ancylostoma ceylanicum infects canines and felines, and it causes mild human intestinal illness. Ancylostoma caninum is the canine hookworm and causes eosinophilic enteritis in humans. Ancylostoma braziliense is a canine and feline hookworm that causes cutaneous larva migrans in humans, or creeping eruption, a self-limiting condition characterized by serpiginous burrows as the larvae migrate through the epidermis. Unlike N americanus or A duodenale, these organisms that cause zoonotic infections tend to lead only to mild disease in humans.

N americanus is a small, cylindrical, off-white worm with a life expectancy of 3-10 years. One worm can cause 0.03 mL of intestinal blood loss per day. The adult male worm measures 7-9 mm with the female worm measuring 9-11 mm and laying 3000-6000 eggs per day. A duodenale resembles N americanus in appearance, but its adult life expectancy is only 1-3 years. A duodenale is the larger of the 2 species, with male worms measuring 8-11 mm and adult female worms measuring 10-13 mm. Female members of this species lay upwards of 10,000-30,000 eggs per day. A duodenale also consumes more blood than N americanus does, ingesting 0.15 mL per worm per day. Although N americanus infects only percutaneously, A duodenale can infect by means of ingestion, and lactogenic transmission during breastfeeding has been proposed.

On microscopy, N americanus can be differentiated from A duodenale on the basis of its cutting plates instead of teeth.

The life cycle of hookworms begins with the passing of hookworm eggs in human feces and their deposition into the soil (see Image 1 for the hookworm life cycle). 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.

The rhabditiform larvae feed on the feces and undergo 2 successive molts, such that, after 5-10 days, they become infective filariform larvae, or L3. 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. Infection of the human host is established when filariform larvae penetrate the skin, typically on the hands or feet. This penetration may cause a local pruritic dermatitis, also known as ground itch. The larvae migrate through the dermis, entering the bloodstream and moving to the lungs within 10 days.

Once in the lungs, the hookworms penetrate the alveoli and 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. Using this buccal capsule, the worms attach themselves to the mucosal layer of the proximal small intestine, including the lower part of the duodenum, jejunum, and proximal ileum. In 3-5 weeks, the adults become sexually mature, and the female worms begin to produce eggs that appear in the person's feces.

Intestinal blood loss secondary to infection is the major clinical manifestation of hookworm infection. In fact, hookworm disease historically refers to the clinically significant hypochromic, microcytic anemia and the depletion of iron stores resulting from chronic intestinal blood loss secondary to hookworm infection. Attaching to the mucosal layer and using their mouth parts, hookworms rupture the arterioles and venules along the luminal surface of the intestine. The worms ingested and digested some of the blood from the injured mucosa by means of a multienzyme cascade of metallohemoglobinases. Inhibited host coagulation due to a series of anticoagulants directed against factor Xa and the factor VIIa–tissue factor complex, as well as again platelet aggregation, further exacerbate blood loss.

The amount of blood loss and degree of anemia is positively correlated with the worm burden, whereas hemoglobin, serum ferritin, protoporphyrin levels are significantly and negatively correlated with the number of worms. 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. Because of the clinically significant blood loss and the ingestion of serum proteins, hypoproteinemia may also develop, which clinically manifests as weight-loss, anasarca, and edema.

Despite their small size, large number, and apparent anatomic simplicity, hookworms continue to evade lasting human immune responses. As part of recent public health efforts to reduce rates of hookworm infection, the evoked immune response has been extensively investigated in both human and animal models. Although hookworm infection stimulates a helper T-cell type-2 response, the role of this response in maintaining or deterring ongoing infection is debated. Levels of immunoglobulin G (IgG) detectably increase in the 2-8 weeks after the primary infection. In addition, in naturally infected populations, levels of all 5 subtypes of immunoglobulins appear elevated, with substantial upregulation of polyclonal immunoglobulin E (IgE). Eosinophilia is commonly observed, peaking at 35-65 days after infection. Hookworm infection also appears to cause upregulation of the cytokine interleukin (IL)-10 and is a proposed mechanism of proinflammatory cytokine suppression.

The persistent nature of hookworm infection supports the theory that hookworms have evolved adaptive molecular mechanisms to achieve a homeostatic balance with the host immune response. Identified components of the hookworm response include calreticulin, antioxidants, and eotaxin metalloproteinase among others. This modulation of the human immune response by hookworms has also been postulated to reduce the allergenic response of the host, a theory known as the hygiene hypothesis.

Frequency:

· In the US: Once endemic in the southeast United States, hookworm infection is now rare except in high-risk populations, such as international travelers, refugees, international adoptees, and recent immigrants.

· Internationally: The absolute number of hookworm infections is highest in China with 203 million followed by sub-Saharan Africa with 198 million. When prevalences are compared, sub-Saharan Africa is highest with 29% of the population infected followed by East Asia, which has a prevalence of 26%. India, South Asia, and Latin America have slightly decreased but still notable infection rates.

Mortality/Morbidity:

· The mortality rate is low and likely underrecognized because of its insidious nature.

· Anemia remains the most significant clinical implication of hookworm disease. Because of chronic reinfection, hypoproteinemia, weight-loss, edema, and anasarca may also occur.

· See also Special Concerns.

Age:

Although children bear a large disease burden, hookworm infection appears to have an atypical distribution of infection by age. Unlike other soil-transmitted helminth infections, such as those due to Ascaris or Trichuris organisms, for which the incidence peaks in childhood, hookworm infection appears to continue to increase throughout childhood until it reaches a plateau in adulthood.
History:

· Most infected individuals are asymptomatic.

· During the first 1-2 weeks after a cutaneous infection, hookworm produces an intensely pruritic dermatitis at the site of infection termed ground itch.

· Wakana syndrome occurs in people who have been infected with a large burden of A duodenale by means of oral ingestion. This syndrome is similar to an immediate-type hypersensitivity reaction characterized by pharyngeal itching, hoarseness, nausea, vomiting, cough, dyspnea, and eosinophilia.

· Mild cough, dysphagia, and fever may occur during pulmonary migration.

· Loeffler syndrome is rare during pulmonary infection. It is characterized by paroxysmal attacks of cough, dyspnea, pleurisy, little or no fever, and eosinophilic pulmonary infiltrates that last several weeks after the initial infection.

· After the worm migrates into the intestines, patients may have nausea, abdominal pain, and flatulence. These symptoms peak 30-45 days after infection.

· Patients with severe anemia may have fatigue, syncope, or exertional dyspnea. They may also have a history of perverted taste and pica.

Physical:

· Stunted growth may be observed in children with severe infection.

· An erythematous, pruritic, papulovesicular rash on the palms and soles at the site of initial infection may persist for 1-2 weeks after initial infection.

· During pulmonary migration, cough, fever, and a reactive bronchoconstriction may be observed, with wheezing heard on auscultation.

· Abdominal examination may reveal midepigastric pain on palpation during the period of intestinal involvement.

· Hypoproteinemia may lead to anasarca and peripheral edema.

· Tachycardia, hypothermia, and pallor may be present due to anemia.

· Stools may be bloody or melanotic.

Causes: Poor sanitation and poverty are well-documented risk factors for hookworm infection. High-risk populations include international travelers, refugees, international adoptees, and recent immigrants.

Lab Studies:

· Anemia is confirmed by evaluating the CBC, and microscopy reveals hypochromic, microcytic RBCs.

· Eosinophilia may also be present during the initial phases of infection, peaking at 30-65 days.

· The diagnosis is confirmed with microscopic analysis of fecal samples to verify the presence of hookworm eggs. The specimen is fixed in formalin and prepared as a wet mount.

o During the initial stages of infection, results of stool studies may be normal.

o In rare cases, the worm or larvae may be present in the fecal sample.

o Although hookworm eggs are easily distinguished from the eggs of other helminth, rhabditiform larvae are occasionally seen in old stool specimens. Differentiating hookworm larvae from those of Strongyloides organisms requires attention to the unique morphologic features, particularly the relatively short buccal cavity and prominent genital primordium of Strongyloides larvae.

o Under basic light microscopy, the eggs of N americanus and A duodenale appear morphologically similar. During clinical evaluation, this distinction is not necessary because the management remains the same for both.

o The worm burden may be estimated by counting the number of eggs per gram of stool, by multiplying by the daily stool weight, and by dividing the result by 25,000. A worm burden of <25 is generally subclinical. However, >500 worms is clinically significant.

Medical Care:

· In the United States, chemotherapeutics available for treatment of hookworm disease include the benzimidazoles, mebendazole and albendazole, and pyrantel pamoate. Benzimidazoles are an effective chemotherapeutic option with cure rates greater than 90% after a full course of treatment. However, reinfection remains a notable problem because exposure to the hookworm does not confer long-term immunity.

· Iron supplements improve motor and language development in infected children.

· Nutritional support, including folate supplementation, may also be beneficial, especially if the patient is malnourished.

In the past, treatment of pregnant or lactating women was discouraged because of concerns about potential teratogenicity. These populations are now recognized as being at high risk in endemic regions, and treatment may be warranted after careful clinical consideration of the risks and benefits. Treatment may be indicated because of the high neonatal and maternal morbidity and mortality rates.

Published reports about the use of albendazole or mebendazole in children younger than 6 years are limited. To the authors' knowledge, no randomized controlled trials of benzimidazoles for the treatment of hookworm infection in a pediatric population have been performed. The US Food and Drug Administration (FDA) has approved mebendazole for the treatment of hookworm in children older than 2 years. Albendazole is used off-label for hookworm treatment and is not advised for use in children younger than 6 years. Given this information, the following section represents treatment recommendations. The potential benefits and risks must be considered before treatment is started.

Drug Category: Antihelmintics -- Parasitic biochemical pathways differ from those in the human host. Therefore, toxicity is directed to the parasite, egg, or larvae. Mechanisms of action vary in the drug class. Antiparasitic actions may include the following:

1. Inhibition of microtubules, which irreversibly blocks glucose uptake

2. Inhibition of tubulin polymerization

3. Depolarizing neuromuscular blockade

4. Inhibition of cholinesterase

5. Increased permeability of the cell membrane resulting in intracellular calcium loss

6. Vacuolization of the schistosome tegument

7. Increased permeability of the cell membrane to chloride ions due to alteration of chloride channels

Drug Name


Albendazole (Albenza) -- Benzimidazole carbamate that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. Decreases production of adenosine triphosphate (ATP) in the worm, causing its energy depletion, immobilization, and finally death. Converted in liver to its primary metabolite, albendazole sulfoxide. Less than 1% of primary metabolite excreted in urine. Plasma level substantially rises (as much as 5-fold) when ingested after high-fat meal.

Adult Dose


Classic hookworm disease and eosinophilic enteritis: 400 mg PO once
Cutaneous larva migrans: 400 mg PO qd for 3 d

Pediatric Dose


<6 years: Not established
>6 years: Administer as in adults

Contraindications


Documented hypersensitivity

Interactions


Coadministration with carbamazepine may decrease efficacy; dexamethasone, cimetidine, and praziquantel may increase toxicity

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Discontinue use if results of liver function tests (LFTs) increase substantially (resume when levels decrease to pretest values); abdominal pain, nausea, vomiting, diarrhea, dizziness, vertigo, fever, increased intracranial pressure, and alopecia may occur



Drug Name


Mebendazole (Vermox) -- Recommended for treatment of eosinophilic enteritis; inhibits microtubule polymerization by binding to cytoplasmic b-tubulin; by affecting intestinal cells of parasite, prevents its use of nutrients and essentially starves it to death; dose below selectively toxic to parasites because binds to parasite b-tubulin at concentrations lower than those needed to bind mammalian protein; because acts locally on worms in GI tract, systemic drug concentration does not dictate action.
Repeat stool examination with a concentration technique recommended after 2 wk. Retreatment indicated if results positive. No fasting or purging required. Tab may be chewed, swallowed, or crushed and mixed with food.

Adult Dose


100 mg PO bid for 3 d or 500 mg PO once; in some studies, cure rates best with multidose regimen

Pediatric Dose


<2 years: Not established
>2 years: Administer as in adults

Contraindications


Documented hypersensitivity

Interactions


Carbamazepine and phenytoin may decrease effects; cimetidine may increase levels

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Adjust dose in hepatic impairment



Drug Name


Pyrantel pamoate (Antiminth, Pin-Rid, Pin-X) -- FDA approved but considered investigational for this condition. Depolarizing neuromuscular blocking agent that inhibits cholinesterases, resulting in spastic paralysis of worm.

Adult Dose


11 mg/kg (5 mg/lb) PO qd for 3 d, not to exceed 1 g/dose, may administer without regard to ingestion of food or time of day

Pediatric Dose


<2 years: Not established
>2 years: Administer as in adults

Contraindications


Documented hypersensitivity; hepatic disease

Interactions


In ascariasis, pyrantel and piperazine mutually antagonistic and should not be used concomitantly; in pediatric patients, theophylline serum levels may increase

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Caution in liver impairment, anemia, and malnutrition



Further Inpatient Care:

· Repeat the stool examination 2 weeks after treatment is started.

· If the results remain positive, the course of therapy should be repeated.

Further Outpatient Care:

· Iron supplements and nutritional support to include folate supplementation may be necessary in patients with anemia and malnutrition.

Deterrence/Prevention:

· Although walking barefoot outdoors in endemic areas should be discouraged, the effect of wearing proper footwear on hookworm transmission is likely to be overestimated.

· Public health education about proper hygiene and sanitation considerably reduces the risk of infection.

· In 2001, the World Health Assembly passed a resolution to encourage antihelmintic treatment in at least 75% of at-risk school-aged children by 2010 to control morbidity.

· School-based deworming programs are unlikely to adequately control the prevalence of hookworm infection. However, they are likely to substantially affect children's nutritional status, cognitive development, and productivity. Children with hookworm anemia have notably decreased scores on cognitive function tests and delayed acquisition of language and motor skills. With treatment of the infection and anemia, their educational performance and productivity improve.

· As our understanding of the immunoepidemiology and of the molecular pathogenesis of hookworm infection improves, the development of a safe and effective vaccine remains a high priority. Ancylostoma-secreted proteins (ASPs) have been of particular interest with regard to vaccine development. In hamster and canine models, statistically significant reductions in hookworm burden were observed with an ASP-derived vaccine. This vaccine is currently undergoing human testing.

Prognosis:

· With proper treatment, the prognosis is excellent.

· In endemic areas, reinfection occurs frequently.

Medical/Legal Pitfalls:

· Failure to recognize, diagnosis, and properly treat hookworm disease in any patient having traveled from or through endemic regions is a pitfall.

Special Concerns:

· Severe anemia disproportionately affects pregnant women and children because of their low preexisting iron stores.

o Anemic pregnant women are at increased risk of having premature and low-birth weight infants, in addition to being at risk of having impaired lactation after delivery.

o Both mother and the baby have high perinatal mortality rates.

o Although rare, neonatal infection with A duodenale contracted by means of breastfeeding may lead to fulminant GI hemorrhage.

o An effect more common that fulminant GI hemorrhage is worsened school performance and productivity among children with chronic infection. The etiology of this cognitive impairment is likely multifactorial, secondary to both chronic iron-deficiency anemia and missed learning opportunities.

o In physical terms, children with chronic infection also have linear growth retardation.

· The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the National Naval Medical Center, Walter Reed Army Medical Center, Uniformed Services University of Health Sciences, Department of the Navy, Department of the Army, or of the Department of Defense.