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Hookworm and Strongyloides Infections
113 Hookworm and Strongyloides Infections
113
Taryn N. Clark, Robert H. Gilman
KEY FEATURES • Hookworm and Strongyloides are intestinal nematodes that penetrate exposed skin (feet, hands, buttocks, and legs) to establish infection. • Hookworm infection leads to intestinal blood loss and iron-deficiency anemia, especially in Africa, Asia, and Latin America. Infection results in developmental and cognitive delays in children, as well as reductions in future wage earning. • Hookworm is common in pregnant women in low-income countries, resulting in poor birth outcomes. • Deworming with benzimidazole anti-helminthics is the therapeutic approach to reduce the number of hookworms in the intestine and improve anemia. For severe anemia, especially in pregnant women, additional iron supplementation may be necessary. • Strongyloides stercoralis infection leads to diarrhea, and without treatment can cause chronic infection lasting decades. • Infection is difficult to diagnose because of the paucity of larvae detected in feces. • Hyperinfection with Strongyloides is linked to exogenous steroid use or other immune dysregulation and is associated with high mortality. • Deworming with ivermectin is the therapeutic approach for Strongyloides. In hyperinfection, prolonged treatment may be required, along with management of secondary bacteremias and bacterial meningitis.
HOOKWORM INFECTIONS Introduction Human hookworm infection is a global cause of anemia and malnutrition.1 Approximately 85% of cases are caused by Necator americanus, followed by Ancylostoma duodenale. A. ceylanicum, which infects a number of animals, is occasionally found in humans in restricted geographic areas. A. braziliense is a cause of cutaneous larva migrans, and A. caninum is a rare cause of eosinophilic enteritis. The hallmark of hookworm disease resulting from moderate and heavy infections is iron-deficiency anemia (IDA) due to parasite blood feeding and chronic blood loss.1 Because hookworms are responsible for a significant proportion of IDA in low- and middleincome countries, global disease burden studies estimate that hookworm infection is one of the most important parasitic diseases. During the first few decades of the 20th century, hookworm infection was common in the rural southeastern United States, but it has been eliminated as a public health problem after urbanization, consistent shoe-wearing, and economic development.
Epidemiology Approximately 800 million people are infected worldwide, with the largest number of cases in sub-Saharan Africa, Asia, and tropical regions of the Americas.2 Hookworm is soil-transmitted and
acquired when infective larvae in the soil penetrate exposed human skin. Environmental factors favoring hookworm transmission are extreme rural poverty; poor sanitation; soil conditions that include sandy or loamy soils that facilitate the migration of hookworm larvae; high temperatures; and adequate moisture, rainfall, and shade. In most endemic areas, as with other soil-transmitted helminthiases, the prevalence of hookworm rises sharply in the first few years of life and then reaches a plateau. However, unlike ascariasis and trichuriasis, hookworm intensity often rises in adulthood. These observations partly explain the high intensity of hookworm infection found in women of reproductive age and some elderly populations.3
Natural History, Pathogenesis, and Pathology Hookworm ova are passed in the feces and develop in the soil (Fig. 113.1). Under optimal conditions, each egg liberates a rhabditiform larva, which gradually doubles in size and molts twice to become a slender, non-feeding, infective, third-stage larva (L3). L3 larvae live in the top one-half inch of soil, with their ends projecting upward from the surface. When contact is made with human skin, they penetrate the skin (commonly feet, hands, buttocks, and legs) by releasing proteases and other hydrolytic enzymes. A. duodenale L3 larvae are also orally infective. Larval migration in the skin is associated with immediate hypersensitivity. After skin penetration, the larvae access the venous circulation and are carried to the lungs, where they migrate through the respiratory tree to the pharynx. Larvae are coughed up, swallowed, pass through the esophagus and stomach, and arrive in the small intestine before molting to become adults. Eosinophilia typically begins shortly after larvae enter the gut. Eggs appear in the stool 5 or more weeks after invasion of the skin by larvae. Almost all pathology is caused by the adult stages, which are small, cylindrical, creamy-white nematodes roughly 1 cm in length (Figs. 113.1 and 113.2). At the site of parasite attachment in the gut, hookworms lacerate capillaries in the mucosa or arterioles in the submucosa and bleeding ensues after secretion of hookworm anti-coagulants (Figs. 113.2 and 113.3). Hookworms ingest blood, lyse red cells, and then degrade hemoglobin through an ordered cascade of hemoglobin-digesting proteases. It has been estimated that 25 adult N. americanus hookworms will cause 1 mL of blood loss per day, which contains roughly 0.5 mg of iron. This amount is equivalent to the daily iron intake of a child.4
Clinical Features The clinical features of hookworm infection correspond to its life cycle and the intensity of infection.1
Ground Itch and Cutaneous Larva Migrans Associated with the penetration of the skin by L3 larvae, there is intense itching, and in some instances, erythematous, pruritic papules at the site of penetration. Cutaneous larva migrans is a related condition caused by skin penetration of animal hookworms, classically A. braziliense, and results in raised, reddened, serpiginous tracks that mark the migration of the worm. They are most frequently seen on the lower extremities, followed by the buttocks and anogenital area, although the trunk and upper extremities may be affected.
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Swallowed Pharynx Attached to small intestine
Trachea
Lungs
Circulation
4HU Adults in small intestine
Penetrates skin
Eggs in feces (diagnostic stage) Filariform larva (infective stage)
,_[LYUHSLU]PYVUTLU[
Rhabditiform larva hatches Rhabditiform larva in soil (occasionally in old feces) Fig. 113.1 Life cycle of hookworm. (Redrawn from Melvin DM, Brooke MM, Sadun EH. Common intestinal helminths of man. Atlanta, GA: Centers for Disease Control, DHEW Publication No. (CDC) 75–8286, 1964.)
Pulmonary Manifestations As larvae pass through the lungs, patients may complain of cough and wheezing. In a small percentage, eosinophilic infiltrates can be seen on chest film.
Gastrointestinal Manifestations Epigastric pain and tenderness occur early in the intestinal phase. Abdominal pain can be severe and suggests peptic ulcer disease.
Iron-Deficiency Anemia The hallmark of chronic hookworm disease is a microcytic, hypochromic IDA. The development of IDA depends on the number and species of infecting hookworm, the iron reserves and requirements of the host, and the availability of iron in the diet. Lassitude, weakness, apathy, and depression are characteristic of anemia. On physical examination, the mucous membranes, conjunctivae, and skin appear pale. Iron deficiency has also been associated with koilonychia and angular stomatitis. A yellowishgreen hue (chlorosis) that results in a sallow complexion can be seen in heavy infections. Anemia is often accompanied by eosinophilia, and, in severe cases, protein loss and hypoalbuminemia. In children, chronic hookworm infection and disease lead to deficits
in growth and physical fitness, as well as reductions in intelligence, cognition, and reduced school performance. IDA from chronic hookworm infection in pregnancy is associated with increased maternal morbidity, as well as low birth weight and prematurity. Severe cases of hookworm anemia and hypoalbuminemia are accompanied by cardiovascular changes.
Patient Evaluation, Diagnosis, and Differential Diagnosis Hookworm disease should be considered in any patient from an endemic area who presents with anemia, eosinophilia, or both. The diagnosis is confirmed by identifying hookworm ova in the stool (see Fig. 113.1). The eggs of N. americanus and A. duodenale are almost indistinguishable, and both are eliminated in feces in two- to eight-celled stages of cleavage. A clear space is present between the cells and the shell (see Fig. 113.1). Direct fecal examination in saline or an iodine solution detects persons with more than 1200 eggs per gram of stool. Zinc sulfate flotation or formalin–ether concentration techniques can identify persons with lighter infections. For epidemiologic studies, it may be necessary to perform quantitative fecal egg counts, which roughly correlate with the number of hookworms in the intestine. FLOTAC and mini-FLOTAC can also be used. The Kato–Katz quantitative method is used widely, but the method requires immediate
CHAPTER 113 Hookworm and Strongyloides Infections
847
113
A
B
C
D Fig. 113.2 (A) Mouthparts of Necator americanus with two pairs of chitinized cutting plates. (B) Mouthparts of Ancylostoma duodenale with two large pairs of teeth, with each of the medial pair bearing a small accessory process. (C) Mouthparts of A. braziliense with two pairs of teeth: a large outer pair and a small inner pair without accessory processes. (D) Mouthparts of A. caninum with three well-developed pairs of teeth.
evaluation, as the technique can selectively destroy hookworm eggs over time, leaving only Ascaris, Trichuris, and schistosome eggs in areas of co-endemicity.
Treatment The therapy of hookworm disease is treatment with an oral antihelminthic agent. In resource-poor countries where hookworm is endemic, the drugs are usually administered as part of mass treatment programs, either on child health days or through schoolbased deworming programs on an annual or more frequent basis.5 Deworming improves physical and intellectual development and hemoglobin levels. Benzimidazole agents, albendazole or
mebendazole, have been first-line treatments. However, in a systematic review and meta-analysis, the cure rate of single-dose oral albendazole (400 mg) was 72% compared with 15% for single-dose mebendazole (500 mg).6 Therefore for single-dose mass drug administration, albendazole is likely the only acceptable agent. Triple-dose therapy with either agent is more effective than single dose, with albendazole providing higher cure rates than mebendazole.7 Pyrantel pamoate can be administered as a dose of 11 mg/kg (max. 1 g) for 3 days. Benzimidazoles are teratogenic and embryotoxic in high doses in laboratory animals. Therefore in children older than 1 year but under 2 years, albendazole should be given at one-half the dose (200 mg). For women in their second and third trimesters of
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infection is widespread, the prevalence is typically low (<10%). Prevalence is reportedly elevated in older HTLV-1–infected patients in regions where this virus is endemic (e.g., Japan, Caribbean). Immigrants, travelers, or military veterans from endemic areas (e.g., southern Asia) can have prolonged infections. The latter are usually older males; veterans who have lived in endemic tropical areas; and those with underlying malignant, metabolic, pulmonary or renal disease. They have mild to moderate chronically relapsing symptoms. Military personnel who were infected in the South Pacific in World War II, the Korean War, or the Vietnam War can remain infected and are at risk for episodic symptoms of chronic infection or overwhelming hyperinfection, especially if they receive corticosteroid therapy.
Natural History, Pathogenesis, and Pathology
Fig. 113.3 Longitudinal section through hookworm attached to intestinal mucosa. (Courtesy, Dr. Pedro Morera, Facultad de Microbiologia, Universidad de Costa Rica.)
pregnancy, treatment has proven benefits of reduced maternal and perinatal morbidity and mortality.3 However, no anti-helminthic treatment should be administered during the first trimester. During pregnancy, treating the anemia of hookworm disease with both anti-helminthic drugs and iron therapy is superior to either treatment alone. An experimental vaccine to prevent hookworm infection and re-infection is under development.8,9
STRONGYLOIDES INFECTIONS Introduction Strongyloidiasis—threadworm infection—results from infection by Strongyloides stercoralis. Infection has been recognized since 1876, when Normand described the larvae in stools of French soldiers in Southeast Asia with Cochin–China diarrhea. S. stercoralis has a complex life cycle of penetrating the skin, migrating through the lungs, and residing in the small bowel (Fig. 113.4), similar to the hookworm. It is unusual among helminths in its ability to multiply within the host and maintain a persistent infection for years (autoinfection). This capacity allows S. stercoralis to overwhelm immunocompromised hosts with hyperinfection. There is a link between strongyloidiasis and co-infection with human T-cell lymphotropic virus type 1 (HTLV-1).10,11 Although almost all Strongyloides infections are with S. stercoralis, the primate parasite S. fulleborni is recognized in humans in Africa and in Papua New Guinea, where it is a cause of “swollen belly syndrome,” particularly among infants and young children.
Epidemiology Strongyloidiasis has a patchy, widespread distribution through warm, wet, tropical, and sub-tropical areas. In temperate regions, it is encountered in institutions where sanitary facilities are poor or in moist conditions. Some have estimated that 30 to 100 million people are infected. The difficulties in diagnosing strongyloidiasis have contributed to a limited understanding of the global prevalence and disease burden.10,11 Strongyloidiasis is endemic in tropical Asia, Africa, and Latin America, as well as rural Appalachia in the United States and parts of southern and eastern Europe. Although
The life cycle of S. stercoralis is complex (see Fig. 113.4). Like other intestinal nematodes, it can involve host and soil stages. However, the life cycle can occur completely in the soil (free-living cycle) or completely in the host (internal or external autoinfection). Autoinfection is the basis of persistent infection and hyperinfection in patients receiving corticosteroids. Human infection begins with exposure of the skin to L3 larvae that reside in fecally contaminated, moist soil (see Fig. 113.4). These larvae have slender bodies and notched tails that distinguish them from hookworm larvae. The L3 migrate through the lungs and ascend the airways to the trachea and epiglottis before being swallowed to complete their life cycle in the small intestine. There, after two molts, adult females (2.2 mm long) penetrate and reside in the superficial mucosa of the duodenum and jejunum. The evidence for the existence of male worms is controversial. In the intestine, adult female worms, eggs, and larvae are found in the superficial sub-mucosa and in the mucosal crypts, causing mechanical trauma, mucous discharge, and microscopic ulceration but usually minimal inflammation. Progressive involvement may lead to edema; flattened villi; malabsorption; and even ulceration, enteritis, and secondary bacterial invasion. Nearly 1 month after infection, the adult female lays oval, thin-shelled, embryonated eggs that closely resemble hookworm eggs but are usually not seen because they rapidly hatch in the intestinal mucosa to produce first-stage, non-infectious rhabditiform larvae (Fig. 113.5). It is this larval stage that is characteristically found in the stool or the upper small bowel. Under favorable soil conditions, rhabditiform larvae transform into infective L3 within 24 hours after fecal passage. L3 larvae can survive for several weeks under moist conditions and develop into adult male and female worms (see Fig. 113.4). Alternatively, autoinfection can occur by rapid transformation of rhabditiform larvae to infectious L3 in the gut lumen, where they penetrate the intestinal mucosa (internal autoinfection) to proceed via the lungs to maintain infection (see Fig. 113.4). Under selected conditions, the autoinfective process may become dysregulated, leading to a large number of L3 penetrating the gut, cycling through the lungs, and re-entering the intestine, leading to hyperinfection, secondary bacteremias, and bacterial meningitis. Immunosuppressive drug therapies, especially corticosteroids, are associated with hyperinfection. Other conditions are hematologic malignancies, solid organ transplantations, and autoimmune disorders, although corticosteroids are used for treatment of many of these. Infection with HTLV-1 (as well as co-infections with tuberculosis, leprosy, or syphilis) is another risk factor; however, the basis for this has not been established. In some patients with hyperinfection, the migrating larvae can develop to adult worms in ectopic sites (e.g., the lung and central nervous system). This condition is known as disseminated strongyloidiasis. In external autoinfection, L3 larvae can develop in the colorectal area and penetrate the perianal skin, resulting in pruritic creeping eruption, or larva currens and external autoinfection.
CHAPTER 113 Hookworm and Strongyloides Infections
Trachea
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Pharynx
113 Swallowed
Lungs
Adult in mucosa of small intestine
Circulation Penetrates intestine or perianal skin
Man
Penetrates skin
Egg in mucosa (occasionally in feces) Filariform larva Filariform larva (infective stage)
(diagnostic stage)
Rhabditiform larva in feces
Direct development External environment Free-living adults in soil
Indirect development Rhabditiform larva in soil Eggs in soil Fig. 113.4 Life cycle of Strongyloides stercoralis. (Redrawn from Melvin DM, Brooke MM, Sadun EH. Common intestinal helminths of man. Atlanta, GA: Centers for Disease Control, DHEW Publication No. (CDC) 75–8286, 1964.)
Clinical Features The clinical manifestations of S. stercoralis infection are acute infection, chronic persisting infection, and the hyperinfection syndrome.10,11
Acute Infection One-third or more of individuals are asymptomatic. Cough, shortness of breath, wheezing, fever, transient pulmonary infiltrates, and eosinophilia are infrequent but may be encountered with the migration of larvae through the lungs. When adult worms develop and penetrate the mucosa in the small bowel, non-specific aching or epigastric abdominal pain and diarrhea can develop. With heavy infections, vomiting, malabsorption, steatorrhea, weight loss, edema, or a paralytic ileus with edema in the small bowel wall may be seen. In external autoinfection, there is a pruritic maculopapular rash or rapidly migrating linear urticaria called larva currens that is usually seen on the buttocks.
in the South Pacific. The classically recognized triad of symptoms is larva currens, abdominal pain, and diarrhea. There is an endemic focus in southeastern Kentucky and in Appalachia, where most patients are usually white, male, older than 50 years, and from lower socioeconomic backgrounds. HTLV-1 infection is an important risk factor for chronic, persisting infection.
Hyperinfection Syndrome Gastrointestinal signs and symptoms are common; they include crampy abdominal pain, bloating, watery diarrhea, and constipation. Patients can develop an ileus and small bowel obstruction, with diffuse tenderness and hypoactive bowel sounds. Pulmonary manifestations are variable, and larva currens is common. There is a high mortality, often with gram-negative enteric bacterial infection secondary to extensive larval spread from the intestine. Sepsis, meningitis, peritonitis, and endocarditis are commonly documented.10,11
Chronic, Persisting Infection
Patient Evaluation, Diagnosis, and Differential Diagnosis
This condition probably occurs as a result of internal autoinfection and is best described in military veterans or in former prisoners of war who have returned from endemic tropical areas in Asia or
Any individual from a strongyloidiasis-endemic area who is diagnosed with HTLV-1 infection or who is expected to take corticosteroids (including doses as low as 1 mg of dexamethasone
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bc
bc
es
bc es
immunosorbent assay tests also give high specificity and sensitivity, particularly if combined with Western blot. All immunodiagnostic methods can cross-react with other nematode helminth infections. Sensitivity may decrease in co-infection with HTLV-1. S. stercoralis antigen is not widely available for diagnostic use.
bc es
es mb
nr nr c
nr
nr
c
c c
mg
mg
mg
mg
gp
gp
gp
gp
a
a
a a
Treatment All individuals who are infected with S. stercoralis should be treated. The first-line treatment for acute or chronic infection is oral ivermectin, 200 µg/kg per day, on 2 successive days. The safety of ivermectin in young children (<15 kg) and in pregnancy has not been established. Albendazole at 400 mg orally twice daily for 7 days is an alternative. Albendazole should be taken with a fatty meal to promote absorption; ivermectin should be taken on an empty stomach and with water. Patients with HTLV-1 should be treated until their stools are negative for larvae or until they become seronegative. Immunocompromised patients with hyperinfection syndrome should be treated until clinical signs resolve. Because the autoinfective life cycle requires at least 2 weeks, some investigators recommend that treatment and screening should continue until fecal cultures have been negative for 2 weeks. For patients who cannot take or absorb oral medications, a veterinary parenteral formulation of ivermectin has been used. In disseminated strongyloidiasis, combination therapy with albendazole and ivermectin has been recommended, although there are no controlled clinical trials to support this. In hyperinfection, patients with co-infection with enteric bacteria, bacteremia, and bacterial meningitis should be treated with parenteral antibiotics. Patients with Strongyloides hyperinfection are infectious and may require isolation. After treatment for hyperinfection, some clinicians choose to keep patients on chronic suppressive therapy with anti-helminthic agents. REFERENCES
A
B
C
cb
D
Fig. 113.5 Figures of typical rhabditiform larval stages of (A) Strongyloides, (B) hookworm, (C) Trichostrongylus, and (D) Rhabditis (ca. ×400). Explanation of labels: a, anus; bc, buccal chamber; c, cardiac bulb of esophagus; cb, beadlike swelling of caudal tip; es, esophagus; gp, genital primordia; mb, midesophageal bulb; mg, midgut; nr, nerve ring. (Redrawn from Beaver PC, Jung RC, Cupp EW. Clinical parasitology, 9th ed. Philadelphia: Lea & Febiger, 1984.)
daily), should be screened for strongyloidiasis. There should be a high index of suspicion for Strongyloides in patients with an exposure history and characteristic skin and intestinal symptoms. It is important to diligently search fecal specimens for characteristic rhabditiform larvae (see Fig. 113.5). Amplifying the indirect life cycle in vitro is a technique to improve the likelihood of finding Strongyloides larvae. Fecal samples are placed on nutrient agar that is examined for tracks of bacteria from migrating larvae. The Baermann funnel gauze concentration method and Harada Mori cultures on vertical strips of damp filter paper (where the larvae migrate down) are also used. Although serology has lacked sensitivity and specificity, there is an improved immunofluorescence antibody assay using Strongyloides antigen. Newer enzyme-linked
1. Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med 2004;351:799–807. 2. Pullan RL, Smith JL, Jasrasaria R, Brooker SJ. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit Vectors 2014;7:37. 3. Brooker S, Hotez PJ, Bundy DAP. Hookworm-related anaemia among pregnant women: a systematic review. PLoS Negl Trop Dis 2008;2:e291. 4. Crompton DW. The public health importance of hookworm parasitology. Parasitology 2000;121(Suppl.):S39–50. 5. Hotez PJ. Mass drug administration and the integrated control of the world’s high prevalence neglected tropical diseases. Clin Pharmacol Ther 2009;85:649–64. 6. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA 2008;299:1937–48. 7. Steinmann P, Utzinger J, Du ZW, et al. Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: a randomized controlled trial. PLoS ONE 2011;6:e25003. 8. Diemert D, Bethony J, Hotez PJ. Hookworm vaccines. Clin Infect Dis 2008;46:282–8. 9. Hotez PJ, Bethony JM, Diemart DJ, et al. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol 2010;8(11):814–26. 10. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208–17. 11. Ramanathan R, Nutman T. Strongyloides stercoralis infection in the immunocompromised host. Curr Infect Dis Rep 2008;10:105–10.
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Taryn N. Clark, Robert H. Gilman
KEY FEATURES • Hookworm and Strongyloides are intestinal nematodes that penetrate exposed skin (feet, hands, buttocks, and legs) to establish infection. • Hookworm infection leads to intestinal blood loss and iron-deficiency anemia, especially in Africa, Asia, and Latin America. Infection results in developmental and cognitive delays in children, as well as reductions in future wage earning. • Hookworm is common in pregnant women in low-income countries, resulting in poor birth outcomes. • Deworming with benzimidazole anti-helminthics is the therapeutic approach to reduce the number of hookworms in the intestine and improve anemia. For severe anemia, especially in pregnant women, additional iron supplementation may be necessary. • Strongyloides stercoralis infection leads to diarrhea, and without treatment can cause chronic infection lasting decades. • Infection is difficult to diagnose because of the paucity of larvae detected in feces. • Hyperinfection with Strongyloides is linked to exogenous steroid use or other immune dysregulation and is associated with high mortality. • Deworming with ivermectin is the therapeutic approach for Strongyloides. In hyperinfection, prolonged treatment may be required, along with management of secondary bacteremias and bacterial meningitis.
HOOKWORM INFECTIONS Introduction Human hookworm infection is a global cause of anemia and malnutrition.1 Approximately 85% of cases are caused by Necator americanus, followed by Ancylostoma duodenale. A. ceylanicum, which infects a number of animals, is occasionally found in humans in restricted geographic areas. A. braziliense is a cause of cutaneous larva migrans, and A. caninum is a rare cause of eosinophilic enteritis. The hallmark of hookworm disease resulting from moderate and heavy infections is iron-deficiency anemia (IDA) due to parasite blood feeding and chronic blood loss.1 Because hookworms are responsible for a significant proportion of IDA in low- and middleincome countries, global disease burden studies estimate that hookworm infection is one of the most important parasitic diseases. During the first few decades of the 20th century, hookworm infection was common in the rural southeastern United States, but it has been eliminated as a public health problem after urbanization, consistent shoe-wearing, and economic development.
Epidemiology Approximately 800 million people are infected worldwide, with the largest number of cases in sub-Saharan Africa, Asia, and tropical regions of the Americas.2 Hookworm is soil-transmitted and
acquired when infective larvae in the soil penetrate exposed human skin. Environmental factors favoring hookworm transmission are extreme rural poverty; poor sanitation; soil conditions that include sandy or loamy soils that facilitate the migration of hookworm larvae; high temperatures; and adequate moisture, rainfall, and shade. In most endemic areas, as with other soil-transmitted helminthiases, the prevalence of hookworm rises sharply in the first few years of life and then reaches a plateau. However, unlike ascariasis and trichuriasis, hookworm intensity often rises in adulthood. These observations partly explain the high intensity of hookworm infection found in women of reproductive age and some elderly populations.3
Natural History, Pathogenesis, and Pathology Hookworm ova are passed in the feces and develop in the soil (Fig. 113.1). Under optimal conditions, each egg liberates a rhabditiform larva, which gradually doubles in size and molts twice to become a slender, non-feeding, infective, third-stage larva (L3). L3 larvae live in the top one-half inch of soil, with their ends projecting upward from the surface. When contact is made with human skin, they penetrate the skin (commonly feet, hands, buttocks, and legs) by releasing proteases and other hydrolytic enzymes. A. duodenale L3 larvae are also orally infective. Larval migration in the skin is associated with immediate hypersensitivity. After skin penetration, the larvae access the venous circulation and are carried to the lungs, where they migrate through the respiratory tree to the pharynx. Larvae are coughed up, swallowed, pass through the esophagus and stomach, and arrive in the small intestine before molting to become adults. Eosinophilia typically begins shortly after larvae enter the gut. Eggs appear in the stool 5 or more weeks after invasion of the skin by larvae. Almost all pathology is caused by the adult stages, which are small, cylindrical, creamy-white nematodes roughly 1 cm in length (Figs. 113.1 and 113.2). At the site of parasite attachment in the gut, hookworms lacerate capillaries in the mucosa or arterioles in the submucosa and bleeding ensues after secretion of hookworm anti-coagulants (Figs. 113.2 and 113.3). Hookworms ingest blood, lyse red cells, and then degrade hemoglobin through an ordered cascade of hemoglobin-digesting proteases. It has been estimated that 25 adult N. americanus hookworms will cause 1 mL of blood loss per day, which contains roughly 0.5 mg of iron. This amount is equivalent to the daily iron intake of a child.4
Clinical Features The clinical features of hookworm infection correspond to its life cycle and the intensity of infection.1
Ground Itch and Cutaneous Larva Migrans Associated with the penetration of the skin by L3 larvae, there is intense itching, and in some instances, erythematous, pruritic papules at the site of penetration. Cutaneous larva migrans is a related condition caused by skin penetration of animal hookworms, classically A. braziliense, and results in raised, reddened, serpiginous tracks that mark the migration of the worm. They are most frequently seen on the lower extremities, followed by the buttocks and anogenital area, although the trunk and upper extremities may be affected.
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PART 6 Helminthic Infections
Swallowed Pharynx Attached to small intestine
Trachea
Lungs
Circulation
4HU Adults in small intestine
Penetrates skin
Eggs in feces (diagnostic stage) Filariform larva (infective stage)
,_[LYUHSLU]PYVUTLU[
Rhabditiform larva hatches Rhabditiform larva in soil (occasionally in old feces) Fig. 113.1 Life cycle of hookworm. (Redrawn from Melvin DM, Brooke MM, Sadun EH. Common intestinal helminths of man. Atlanta, GA: Centers for Disease Control, DHEW Publication No. (CDC) 75–8286, 1964.)
Pulmonary Manifestations As larvae pass through the lungs, patients may complain of cough and wheezing. In a small percentage, eosinophilic infiltrates can be seen on chest film.
Gastrointestinal Manifestations Epigastric pain and tenderness occur early in the intestinal phase. Abdominal pain can be severe and suggests peptic ulcer disease.
Iron-Deficiency Anemia The hallmark of chronic hookworm disease is a microcytic, hypochromic IDA. The development of IDA depends on the number and species of infecting hookworm, the iron reserves and requirements of the host, and the availability of iron in the diet. Lassitude, weakness, apathy, and depression are characteristic of anemia. On physical examination, the mucous membranes, conjunctivae, and skin appear pale. Iron deficiency has also been associated with koilonychia and angular stomatitis. A yellowishgreen hue (chlorosis) that results in a sallow complexion can be seen in heavy infections. Anemia is often accompanied by eosinophilia, and, in severe cases, protein loss and hypoalbuminemia. In children, chronic hookworm infection and disease lead to deficits
in growth and physical fitness, as well as reductions in intelligence, cognition, and reduced school performance. IDA from chronic hookworm infection in pregnancy is associated with increased maternal morbidity, as well as low birth weight and prematurity. Severe cases of hookworm anemia and hypoalbuminemia are accompanied by cardiovascular changes.
Patient Evaluation, Diagnosis, and Differential Diagnosis Hookworm disease should be considered in any patient from an endemic area who presents with anemia, eosinophilia, or both. The diagnosis is confirmed by identifying hookworm ova in the stool (see Fig. 113.1). The eggs of N. americanus and A. duodenale are almost indistinguishable, and both are eliminated in feces in two- to eight-celled stages of cleavage. A clear space is present between the cells and the shell (see Fig. 113.1). Direct fecal examination in saline or an iodine solution detects persons with more than 1200 eggs per gram of stool. Zinc sulfate flotation or formalin–ether concentration techniques can identify persons with lighter infections. For epidemiologic studies, it may be necessary to perform quantitative fecal egg counts, which roughly correlate with the number of hookworms in the intestine. FLOTAC and mini-FLOTAC can also be used. The Kato–Katz quantitative method is used widely, but the method requires immediate
CHAPTER 113 Hookworm and Strongyloides Infections
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113
A
B
C
D Fig. 113.2 (A) Mouthparts of Necator americanus with two pairs of chitinized cutting plates. (B) Mouthparts of Ancylostoma duodenale with two large pairs of teeth, with each of the medial pair bearing a small accessory process. (C) Mouthparts of A. braziliense with two pairs of teeth: a large outer pair and a small inner pair without accessory processes. (D) Mouthparts of A. caninum with three well-developed pairs of teeth.
evaluation, as the technique can selectively destroy hookworm eggs over time, leaving only Ascaris, Trichuris, and schistosome eggs in areas of co-endemicity.
Treatment The therapy of hookworm disease is treatment with an oral antihelminthic agent. In resource-poor countries where hookworm is endemic, the drugs are usually administered as part of mass treatment programs, either on child health days or through schoolbased deworming programs on an annual or more frequent basis.5 Deworming improves physical and intellectual development and hemoglobin levels. Benzimidazole agents, albendazole or
mebendazole, have been first-line treatments. However, in a systematic review and meta-analysis, the cure rate of single-dose oral albendazole (400 mg) was 72% compared with 15% for single-dose mebendazole (500 mg).6 Therefore for single-dose mass drug administration, albendazole is likely the only acceptable agent. Triple-dose therapy with either agent is more effective than single dose, with albendazole providing higher cure rates than mebendazole.7 Pyrantel pamoate can be administered as a dose of 11 mg/kg (max. 1 g) for 3 days. Benzimidazoles are teratogenic and embryotoxic in high doses in laboratory animals. Therefore in children older than 1 year but under 2 years, albendazole should be given at one-half the dose (200 mg). For women in their second and third trimesters of
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infection is widespread, the prevalence is typically low (<10%). Prevalence is reportedly elevated in older HTLV-1–infected patients in regions where this virus is endemic (e.g., Japan, Caribbean). Immigrants, travelers, or military veterans from endemic areas (e.g., southern Asia) can have prolonged infections. The latter are usually older males; veterans who have lived in endemic tropical areas; and those with underlying malignant, metabolic, pulmonary or renal disease. They have mild to moderate chronically relapsing symptoms. Military personnel who were infected in the South Pacific in World War II, the Korean War, or the Vietnam War can remain infected and are at risk for episodic symptoms of chronic infection or overwhelming hyperinfection, especially if they receive corticosteroid therapy.
Natural History, Pathogenesis, and Pathology
Fig. 113.3 Longitudinal section through hookworm attached to intestinal mucosa. (Courtesy, Dr. Pedro Morera, Facultad de Microbiologia, Universidad de Costa Rica.)
pregnancy, treatment has proven benefits of reduced maternal and perinatal morbidity and mortality.3 However, no anti-helminthic treatment should be administered during the first trimester. During pregnancy, treating the anemia of hookworm disease with both anti-helminthic drugs and iron therapy is superior to either treatment alone. An experimental vaccine to prevent hookworm infection and re-infection is under development.8,9
STRONGYLOIDES INFECTIONS Introduction Strongyloidiasis—threadworm infection—results from infection by Strongyloides stercoralis. Infection has been recognized since 1876, when Normand described the larvae in stools of French soldiers in Southeast Asia with Cochin–China diarrhea. S. stercoralis has a complex life cycle of penetrating the skin, migrating through the lungs, and residing in the small bowel (Fig. 113.4), similar to the hookworm. It is unusual among helminths in its ability to multiply within the host and maintain a persistent infection for years (autoinfection). This capacity allows S. stercoralis to overwhelm immunocompromised hosts with hyperinfection. There is a link between strongyloidiasis and co-infection with human T-cell lymphotropic virus type 1 (HTLV-1).10,11 Although almost all Strongyloides infections are with S. stercoralis, the primate parasite S. fulleborni is recognized in humans in Africa and in Papua New Guinea, where it is a cause of “swollen belly syndrome,” particularly among infants and young children.
Epidemiology Strongyloidiasis has a patchy, widespread distribution through warm, wet, tropical, and sub-tropical areas. In temperate regions, it is encountered in institutions where sanitary facilities are poor or in moist conditions. Some have estimated that 30 to 100 million people are infected. The difficulties in diagnosing strongyloidiasis have contributed to a limited understanding of the global prevalence and disease burden.10,11 Strongyloidiasis is endemic in tropical Asia, Africa, and Latin America, as well as rural Appalachia in the United States and parts of southern and eastern Europe. Although
The life cycle of S. stercoralis is complex (see Fig. 113.4). Like other intestinal nematodes, it can involve host and soil stages. However, the life cycle can occur completely in the soil (free-living cycle) or completely in the host (internal or external autoinfection). Autoinfection is the basis of persistent infection and hyperinfection in patients receiving corticosteroids. Human infection begins with exposure of the skin to L3 larvae that reside in fecally contaminated, moist soil (see Fig. 113.4). These larvae have slender bodies and notched tails that distinguish them from hookworm larvae. The L3 migrate through the lungs and ascend the airways to the trachea and epiglottis before being swallowed to complete their life cycle in the small intestine. There, after two molts, adult females (2.2 mm long) penetrate and reside in the superficial mucosa of the duodenum and jejunum. The evidence for the existence of male worms is controversial. In the intestine, adult female worms, eggs, and larvae are found in the superficial sub-mucosa and in the mucosal crypts, causing mechanical trauma, mucous discharge, and microscopic ulceration but usually minimal inflammation. Progressive involvement may lead to edema; flattened villi; malabsorption; and even ulceration, enteritis, and secondary bacterial invasion. Nearly 1 month after infection, the adult female lays oval, thin-shelled, embryonated eggs that closely resemble hookworm eggs but are usually not seen because they rapidly hatch in the intestinal mucosa to produce first-stage, non-infectious rhabditiform larvae (Fig. 113.5). It is this larval stage that is characteristically found in the stool or the upper small bowel. Under favorable soil conditions, rhabditiform larvae transform into infective L3 within 24 hours after fecal passage. L3 larvae can survive for several weeks under moist conditions and develop into adult male and female worms (see Fig. 113.4). Alternatively, autoinfection can occur by rapid transformation of rhabditiform larvae to infectious L3 in the gut lumen, where they penetrate the intestinal mucosa (internal autoinfection) to proceed via the lungs to maintain infection (see Fig. 113.4). Under selected conditions, the autoinfective process may become dysregulated, leading to a large number of L3 penetrating the gut, cycling through the lungs, and re-entering the intestine, leading to hyperinfection, secondary bacteremias, and bacterial meningitis. Immunosuppressive drug therapies, especially corticosteroids, are associated with hyperinfection. Other conditions are hematologic malignancies, solid organ transplantations, and autoimmune disorders, although corticosteroids are used for treatment of many of these. Infection with HTLV-1 (as well as co-infections with tuberculosis, leprosy, or syphilis) is another risk factor; however, the basis for this has not been established. In some patients with hyperinfection, the migrating larvae can develop to adult worms in ectopic sites (e.g., the lung and central nervous system). This condition is known as disseminated strongyloidiasis. In external autoinfection, L3 larvae can develop in the colorectal area and penetrate the perianal skin, resulting in pruritic creeping eruption, or larva currens and external autoinfection.
CHAPTER 113 Hookworm and Strongyloides Infections
Trachea
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Pharynx
113 Swallowed
Lungs
Adult in mucosa of small intestine
Circulation Penetrates intestine or perianal skin
Man
Penetrates skin
Egg in mucosa (occasionally in feces) Filariform larva Filariform larva (infective stage)
(diagnostic stage)
Rhabditiform larva in feces
Direct development External environment Free-living adults in soil
Indirect development Rhabditiform larva in soil Eggs in soil Fig. 113.4 Life cycle of Strongyloides stercoralis. (Redrawn from Melvin DM, Brooke MM, Sadun EH. Common intestinal helminths of man. Atlanta, GA: Centers for Disease Control, DHEW Publication No. (CDC) 75–8286, 1964.)
Clinical Features The clinical manifestations of S. stercoralis infection are acute infection, chronic persisting infection, and the hyperinfection syndrome.10,11
Acute Infection One-third or more of individuals are asymptomatic. Cough, shortness of breath, wheezing, fever, transient pulmonary infiltrates, and eosinophilia are infrequent but may be encountered with the migration of larvae through the lungs. When adult worms develop and penetrate the mucosa in the small bowel, non-specific aching or epigastric abdominal pain and diarrhea can develop. With heavy infections, vomiting, malabsorption, steatorrhea, weight loss, edema, or a paralytic ileus with edema in the small bowel wall may be seen. In external autoinfection, there is a pruritic maculopapular rash or rapidly migrating linear urticaria called larva currens that is usually seen on the buttocks.
in the South Pacific. The classically recognized triad of symptoms is larva currens, abdominal pain, and diarrhea. There is an endemic focus in southeastern Kentucky and in Appalachia, where most patients are usually white, male, older than 50 years, and from lower socioeconomic backgrounds. HTLV-1 infection is an important risk factor for chronic, persisting infection.
Hyperinfection Syndrome Gastrointestinal signs and symptoms are common; they include crampy abdominal pain, bloating, watery diarrhea, and constipation. Patients can develop an ileus and small bowel obstruction, with diffuse tenderness and hypoactive bowel sounds. Pulmonary manifestations are variable, and larva currens is common. There is a high mortality, often with gram-negative enteric bacterial infection secondary to extensive larval spread from the intestine. Sepsis, meningitis, peritonitis, and endocarditis are commonly documented.10,11
Chronic, Persisting Infection
Patient Evaluation, Diagnosis, and Differential Diagnosis
This condition probably occurs as a result of internal autoinfection and is best described in military veterans or in former prisoners of war who have returned from endemic tropical areas in Asia or
Any individual from a strongyloidiasis-endemic area who is diagnosed with HTLV-1 infection or who is expected to take corticosteroids (including doses as low as 1 mg of dexamethasone
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bc
bc
es
bc es
immunosorbent assay tests also give high specificity and sensitivity, particularly if combined with Western blot. All immunodiagnostic methods can cross-react with other nematode helminth infections. Sensitivity may decrease in co-infection with HTLV-1. S. stercoralis antigen is not widely available for diagnostic use.
bc es
es mb
nr nr c
nr
nr
c
c c
mg
mg
mg
mg
gp
gp
gp
gp
a
a
a a
Treatment All individuals who are infected with S. stercoralis should be treated. The first-line treatment for acute or chronic infection is oral ivermectin, 200 µg/kg per day, on 2 successive days. The safety of ivermectin in young children (<15 kg) and in pregnancy has not been established. Albendazole at 400 mg orally twice daily for 7 days is an alternative. Albendazole should be taken with a fatty meal to promote absorption; ivermectin should be taken on an empty stomach and with water. Patients with HTLV-1 should be treated until their stools are negative for larvae or until they become seronegative. Immunocompromised patients with hyperinfection syndrome should be treated until clinical signs resolve. Because the autoinfective life cycle requires at least 2 weeks, some investigators recommend that treatment and screening should continue until fecal cultures have been negative for 2 weeks. For patients who cannot take or absorb oral medications, a veterinary parenteral formulation of ivermectin has been used. In disseminated strongyloidiasis, combination therapy with albendazole and ivermectin has been recommended, although there are no controlled clinical trials to support this. In hyperinfection, patients with co-infection with enteric bacteria, bacteremia, and bacterial meningitis should be treated with parenteral antibiotics. Patients with Strongyloides hyperinfection are infectious and may require isolation. After treatment for hyperinfection, some clinicians choose to keep patients on chronic suppressive therapy with anti-helminthic agents. REFERENCES
A
B
C
cb
D
Fig. 113.5 Figures of typical rhabditiform larval stages of (A) Strongyloides, (B) hookworm, (C) Trichostrongylus, and (D) Rhabditis (ca. ×400). Explanation of labels: a, anus; bc, buccal chamber; c, cardiac bulb of esophagus; cb, beadlike swelling of caudal tip; es, esophagus; gp, genital primordia; mb, midesophageal bulb; mg, midgut; nr, nerve ring. (Redrawn from Beaver PC, Jung RC, Cupp EW. Clinical parasitology, 9th ed. Philadelphia: Lea & Febiger, 1984.)
daily), should be screened for strongyloidiasis. There should be a high index of suspicion for Strongyloides in patients with an exposure history and characteristic skin and intestinal symptoms. It is important to diligently search fecal specimens for characteristic rhabditiform larvae (see Fig. 113.5). Amplifying the indirect life cycle in vitro is a technique to improve the likelihood of finding Strongyloides larvae. Fecal samples are placed on nutrient agar that is examined for tracks of bacteria from migrating larvae. The Baermann funnel gauze concentration method and Harada Mori cultures on vertical strips of damp filter paper (where the larvae migrate down) are also used. Although serology has lacked sensitivity and specificity, there is an improved immunofluorescence antibody assay using Strongyloides antigen. Newer enzyme-linked
1. Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med 2004;351:799–807. 2. Pullan RL, Smith JL, Jasrasaria R, Brooker SJ. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit Vectors 2014;7:37. 3. Brooker S, Hotez PJ, Bundy DAP. Hookworm-related anaemia among pregnant women: a systematic review. PLoS Negl Trop Dis 2008;2:e291. 4. Crompton DW. The public health importance of hookworm parasitology. Parasitology 2000;121(Suppl.):S39–50. 5. Hotez PJ. Mass drug administration and the integrated control of the world’s high prevalence neglected tropical diseases. Clin Pharmacol Ther 2009;85:649–64. 6. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA 2008;299:1937–48. 7. Steinmann P, Utzinger J, Du ZW, et al. Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: a randomized controlled trial. PLoS ONE 2011;6:e25003. 8. Diemert D, Bethony J, Hotez PJ. Hookworm vaccines. Clin Infect Dis 2008;46:282–8. 9. Hotez PJ, Bethony JM, Diemart DJ, et al. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol 2010;8(11):814–26. 10. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208–17. 11. Ramanathan R, Nutman T. Strongyloides stercoralis infection in the immunocompromised host. Curr Infect Dis Rep 2008;10:105–10.