Epidemiology

A. lumbricoides has a worldwide distribution, although these parasites are most numerous in less-developed countries and in areas with poor sanitation. About 25% of the world’s population (1.2 billion people) harbor A. lumbricoides.^17,18 Children acquire the parasite by playing in dirt contaminated with eggs, whereas adults most often are infected by farming or eating raw vegetables from plants fertilized with untreated sewage. Pigs harbor Ascaris suum, which is closely related to A. lumbricoides, but cross-infection is rare.¹⁹

Life Cycle

Humans acquire the parasite by ingesting embryonated eggs that contain third-stage larvae. Freshly deposited fertilized eggs incubate in the soil for 10 to 15 days while the embryo develops and molts twice. The eggs become infective after this incubation period. The eggs are remarkably stable, can survive freezing, and can remain viable for seven to 10 years. The eggs are resistant to most chemical treatments including pickling, but they rapidly die in boiling water.

Once ingested, eggs hatch in the duodenum and release their larvae, which penetrate the intestinal wall and enter the mesenteric venules and lymphatics. Larvae migrating with portal blood pass to the liver, through the sinusoids to the hepatic veins, and then through the right side of the heart to enter the lungs. Larvae migrating via the lymphatics pass through mesenteric lymph nodes to the thoracic duct and enter the superior vena cava to arrive in the lungs. The larvae then lodge in the pulmonary capillaries and break into the alveoli, where they molt twice while growing to 1.5 mm in length. Larvae then ascend the tracheobronchial tree, and arrive in the hypopharynx, they are again swallowed, and pass into the small intestine, where they molt again and finally mature.

Mature male A. lumbricoides are smaller (10 to 30 cm) than females (20 to 49 cm). Worms mate in the small intestine and females deposit about 200,000 eggs a day. Adult worms live for about one year (six to 18 months). Because their eggs require incubation in the soil to become infective, Ascaris does not multiply in the host. Continued infestation requires repeat ingestion of embryonated eggs.

Clinical Features and Pathophysiology

A. lumbricoides produces no symptoms in most infected persons. Often, worms are found unexpectedly on endoscopy^20,21 (Video 110-1) or are seen on radiologic imaging,²² or eggs are identified in stool specimens of patients with symptoms not directly attributable to the worms. Disease usually develops only in those with heavy worm burdens: pulmonary, intestinal, and hepatobiliary ascariasis are well described.

Pulmonary ascariasis (Ascaris pneumonia) develops four to 16 days after ingesting infective eggs. The larvae migrate into the alveoli and elicit an inflammatory response that can cause consolidation. The pneumonia usually is self-limited but can be life-threatening.

Large numbers of mature worms can cause severe intestinal symptoms including abdominal pain, distention, nausea, and vomiting. The most common complication of intestinal ascariasis is partial or complete small bowel obstruction; such patients often have a history of passing mature worms in their stool or vomitus. Patients with intestinal obstruction generally have more than 60 worms,²³ and the rare patients with fatal cases often have more than 600 worms. Fatality results from intestinal necrosis caused by obstruction, intussusception, or volvulus (Fig. 110-1).²⁴ Most cases of obstruction, absent signs of peritonitis or perforation, can be managed conservatively.

Figure 110-1. Small intestinal obstruction caused by Ascaris lumbricoides.

(From Wasadikar PP, Kulkarni AB. Intestinal obstruction due to ascariasis. Br J Surg 1997; 84:410.)

A. lumbricoides are highly motile. Mature worms can enter the ampulla of Vater (Fig. 110-2) and migrate into the bile or pancreatic ducts, causing biliary colic, obstructive jaundice, ascending cholangitis, acalculous cholecystitis, or acute pancreatitis.¹⁶ Pregnancy can promote biliary trespass.²⁵ The worms can move in and out of the papilla, producing intermittent symptoms and fluctuating laboratory tests. Recurrent ascending cholangitis or acute pancreatitis from ascariasis is rare in highly developed Western countries but can be fatal if the diagnosis is not entertained.²⁶

Figure 110-2. A, Endoscopic view of Ascaris lumbricoides partially within the ampulla of Vater. B, Ascaris lumbricoides removed.

(From Esser-Kochling BG, Hirsch FW. Images in clinical medicine. Ascaris lumbricoides blocking the common bile duct. N Engl J Med 2005; 352:e4.)

Diagnosis

Often it is an alarmed patient who discovers Ascaris after passing a motile adult worm with a bowel movement. The worms, however, usually do not cause diarrhea. Most patients do not have specific symptoms or eosinophilia.

Ascaris eggs are visible in direct smears of stool (Fig. 110-3). The eggs begin to appear in the stool about two months after initial exposure. Fertilized eggs are 35 by 55 µm and have a thick shell and outer layer; females also lay unfertilized eggs that are larger (90 by 44 µm) and have a thin shell and outer layer. Ascaris eggs that lose their outer layer resemble the eggs of hookworms.

Figure 110-3. Stool specimen containing helminth eggs. A, Ascaris lumbricoides. B, Hookworm. C, Trichuris trichiura. D, Fasciolopsis buski.

(A to D, Courtesy of Mae Melvin, MD, Atlanta, Ga.)

Adults worms may be seen at endoscopy,²¹ or identified on upper gastrointestinal series as long, linear, filling defects within the small intestine.²² The worms retain barium after it has cleared from the patient’s gastrointestinal tract, producing linear opacities. Similar findings are seen on endoscopic retrograde cholangiopancreatography (ERCP) if a worm is in the bile or pancreatic duct (Fig. 110-4). Ascaris also has a characteristic appearance on ultrasound examination of the biliary tree or pancreas: They appear as long, linear echogenic strips that do not cast acoustic shadows.²²

Figure 110-4. Endoscopic retrograde cholangiogram showing several Ascaris lumbricoides in the bile duct.

(From van den Bogaerde JB, Jordaan M. Intraductal administration of albendazole for biliary ascariasis. Am J Gastroenterol 1997; 92:1531.)

Treatment

Asymptomatic colonization with A. lumbricoides is treated easily with a single 400-mg oral dose of albendazole. Albendazole inhibits glucose uptake and microtubule formation, effectively paralyzing the worms. Albendazole is poorly absorbed but is teratogenic, and therefore it should not be used in pregnant women. When possible, treatment with this agent should be delayed until after delivery. Single-dose mebendazole also is efficacious for Ascaris.²⁷ A study of 1042 pregnant women in Peru found no adverse effect of a single 500-mg oral dose of mebendazole on birth outcomes.²⁸

Patients with pulmonary ascariasis should be treated with glucocorticoids to reduce the pneumonitis and be given two 400-mg doses of albendazole one month apart. Because albendazole is poorly absorbed, ascaricidal tissue concentrations are not achieved. The first dose kills mature worms that finished migrating to the intestine, and the second dose kills worms that were in transit when the first dose was given. Albendazole can cause nausea, vomiting, and abdominal pain.

Intestinal ascariasis with obstruction often can be treated conservatively with fluid resuscitation, nasogastric decompression, antibiotics, and one dose of albendazole. Surgery is not required unless the patient develops signs of volvulus, intussusception, or peritonitis. If the bowel is viable, an enterotomy allows intraoperative removal of worms. Albendazole may be held until after the obstruction resolves and then used to eradicate any remaining organisms.

Hepatobiliary ascariasis also can be treated conservatively with fluid resuscitation, bowel rest, and antibiotics.²⁹ Worms in the bile duct are not effectively treated with albendazole because it is poorly absorbed and not concentrated in the bile. This feature of albendazole is advantageous because were paralyzed worms unable to pass through the sphincter of Oddi, they could become trapped in the bile duct. Patients with hepatobiliary ascariasis should be treated with albendazole each day for several days because the worms only become susceptible when they migrate out of the bile duct.

Worms also can invade the pancreatic duct and can be treated conservatively, as for hepatobiliary ascariasis.³⁰ Ascending cholangitis, acute obstructive jaundice, or acute pancreatitis requires emergent ERCP with worm extraction from the ducts by balloon, basket, or forceps—preferably without sphincterotomy. Ampullary sphincterotomy permits worms easier access to the ducts and can increase the risk of recurrent pancreaticobiliary ascariasis.³¹

Epidemiology

S. stercoralis is endemic in tropical and semitropical regions, but it can also be acquired in rural southeastern United States and northern Italy. Strongyloides exists as a free-living organism that does not require a host to replicate. Improved sanitation does not remove the risk of acquiring the parasite from soil. Patients from endemic areas, military veterans who served in Asia, and prisoners of war are at high risk for subclinical strongyloidiasis.

Life Cycle

Adult male and female S. stercoralis live in the soil and lay eggs that hatch rhabditiform larvae. Rhabditiform larvae develop in the soil into mature adults to complete the life cycle of this worm. Rhabditiform larvae (250 µm) also can develop into longer (500 µm) infective filariform larvae that can penetrate any area of skin contacting soil, after which they migrate through the dermis to enter the vasculature. The larvae circulate with the venous blood until they reach the lungs, where they break into the alveoli and ascend the bronchial tree. The worms then are swallowed with bronchial secretions and pass into the small intestine, where they embed in the jejunal mucosa and mature. Female S. stercoralis can lay fertile eggs by parthenogenesis and therefore do not require males to reproduce. The eggs hatch within the small intestine, and rhabditiform larvae migrate into the lumen. Rhabditiform larvae, not eggs, are passed in the stool.

A critical feature of S. stercoralis infestation is that some rhabditiform larvae sporadically develop into infective filariform larvae within the intestine. Filariform larvae are able to reinfest (autoinfect) the patient, thereby increasing the parasite burden and permitting prolonged colonization so that subclinical strongyloidiasis can exist for many decades after the host has left an endemic area.

Clinical Features and Pathophysiology

Most patients with S. stercoralis have no abdominal symptoms. Patients might have a serpiginous urticarial rash (larva currens) caused by the rapid (5 to 10 cm/hour) dermal migration of filariform larvae. This rash often occurs on the buttocks from larvae entering the perianal skin after they exit the anus during autoinfection. A study of prisoners of war found this creeping eruption to be a far more common symptom of chronic strongyloidiasis than were gastrointestinal complaints.³² Occasionally, patients have nausea, abdominal pain, or unexplained occult gastrointestinal blood loss from S. stercoralis. The parasite also can cause colonic inflammation that resembles ulcerative colitis but is more right-sided and strongly eosinophilic.^33–35

While the parasite burden remains balanced, symptoms are minimal or absent. Immunosuppression or glucocorticoid administration upsets this balance. Previously asymptomatic, but chronically infested, patients develop fulminant, potentially fatal strongyloidiasis due to massive autoinfection.^36,37 The mechanisms that permit massive autoinfection are unknown, but events that inhibit Th2-directed immune responses can release eosinophil-mediated control of the parasites. In addition, glucocorticoids can act directly on the parasites to increase the development of infective filariform larvae.³⁸ Fulminant disseminated strongyloidiasis rarely complicates HIV and AIDS.³⁹

Massive autoinfection produces disseminated fulminant strongyloidiasis. Migrating filariform larvae injure the intestinal mucosa and carry luminal bacteria into the bloodstream, resulting in polymicrobial sepsis with enteric organisms. Streptococcus bovis endocarditis or meningitis⁴⁰ also can result. Numerous larvae migrating through the lungs cause pneumonitis, and worms can arrive in unusual locations such as the brain. Fulminant strongyloidiasis often is fatal.

Diagnosis

A recent survey of United States physicians-in-training demonstrated very poor ability to identify or even consider strongyloidiasis.⁴¹ Patients with chronic strongyloidiasis often are asymptomatic. Peripheral blood eosinophils may be elevated, but a normal eosinophil count does not argue against infestation with the parasite. Currently, the best method for detecting exposure is enzyme-linked immunosorbent assay (ELISA) for immunoglobulin (Ig) G antibodies against S. stercoralis. This assay is performed by the Centers for Disease Control and Prevention (CDC) in the United States and is 95% sensitive,⁴² sensitivity being highest for immigrants with prolonged exposure and lowest for returning visitors with lower-level recently acquired infestation.⁴³

False-positive reactions can occur in patients exposed to other helminthic parasites,⁴⁴ and serologic positivity can indicate prior exposure to S. stercoralis, not necessarily active infestation. Because chronic strongyloidiasis can remain subclinical and difficult to detect for decades, however, treatment of seropositive patients is warranted. Indeed, some argue that patients with only suspected strongyloidiasis, such as immigrants from endemic countries who have elevated eosinophil counts, should be treated empirically before glucocorticoid therapy.⁴⁵

Active infestation can be diagnosed by finding rhabditiform larvae in direct smears of the stool, though this is an insensitive method. A 10-fold more sensitive technique is to spread stool on an agar plate and look for serpentine tracks left by migrating larvae.⁴⁶ Intestinal biopsy is also an insensitive means of diagnosis.

Treatment

Chronic strongyloidiasis is best treated with one dose of ivermectin (200 µg/kg) given orally; this dose is used in both adult and pediatric patients. Ivermectin is better tolerated than thiabendazole. Ivermectin paralyzes the intestinal adult worms but not the larvae migrating through tissue, and therefore patients can develop recurrent infestation from migrating larvae; a repeat dose after two weeks helps to prevent this outcome. Successful treatment causes a fall in antibody titer by six months in most (about 90%) patients.⁴² Immunocompromised patients require repeat doses given 2, 15, and 16 days after the first dose.³⁷

Epidemiology

The first known human case of capillariasis was reported in 1964. It remains a rare but deadly parasitic infestation. From 1965 through 1968, an epidemic in the rural Philippines involved 229 cases, with an overall mortality rate of 30%.⁴⁹ As the name implies, Paracapillaria phillippinensis is endemic to the Philippines, but it also is endemic in Thailand and cases occur in Japan, Taiwan, Egypt, and Iran. Modern travel transports cases worldwide.⁵⁰

Life Cycle

Birds, not humans, are the natural hosts for P. philippinensis. In the avian small intestine, the larvae mature into adults. The adults are very small, measuring up to 3.9 mm for males and 5.3 mm for females. Adult worms mate and produce eggs. Eggs are deposited in bird droppings into ponds and rivers and are swallowed by fish to complete the life cycle.

People become infested with the worm by eating raw or undercooked freshwater or brackish-water fish that contain the parasitic larvae. Some female adult P. philippinensis are larviparous, producing infective larvae instead of eggs. These larvae then mature in the small intestine and increase the parasite burden. This pathway of autoinfection permits a massive increase in parasite numbers. A rhesus monkey originally fed 27 larvae had more than 30,000 worms by 162 days of infection.⁵¹

Clinical Features and Pathophysiology

Capillariasis produces a progressive sprue-like illness. Symptoms begin with vague abdominal pain and borborygmi. Two or three weeks after infection, patients begin to have diarrhea. Initially intermittent, diarrhea becomes persistent and increasingly voluminous. Patients rapidly waste from escalating steatorrhea and protein-losing enteropathy. Eventually they manifest emaciation, anasarca, and hypotension; diarrhea produces severe hypokalemia. If untreated, patients die from cardiac failure or secondary bacterial sepsis usually about two months after the initial onset of symptoms.

The progressive disease is believed to result from an ever-increasing number of poorly adapted intestinal parasites. In autopsy studies, the jejunal intestinal mucosa showed flattened, denuded villi with numerous plasma cells, lymphocytes, macrophages, and neutrophils infiltrating the lamina propria.⁴⁷

Diagnosis

Diagnosis is made by finding eggs and larvae in stool specimens. No serologic tests for capillariasis are available. Symptomatic patients have detectable eggs in their stool. The eggs are easily confused with those of Trichuris trichiura, but T. trichiura eggs have prominent bipolar plugs that appear cut off in P. phillipinensis.⁴⁷

Treatment

Capillariasis requires extended anthelminthic treatment with albendazole 200 mg orally twice daily for 10 days or mebendazole 200 mg orally twice daily for 20 days to prevent recurrence. Albendazole is better tolerated than mebendazole, which can cause headache, diarrhea, and abdominal pain. Extended treatment is necessary because larvae are resistant to these agents.

Necator americanus and Ancylostoma duodenale

Life Cycle

Infective third-stage hookworm larvae penetrate intact skin, such as between the toes of bare feet while walking on contaminated ground. Larvae migrate through the dermis to reach blood vessels. This migration can cause a pruritic, serpiginous rash, cutaneous larva migrans (Fig. 110-5). Ancylostoma braziliense normally infests dogs and cats, but it produces a similar rash during infective dermal wandering in humans and is the usual cause of cutaneous larva migrans. Larvae of N. americanus and A. duodenale enter blood vessels in the skin and migrate with venous flow through the right side of the heart to the lungs. A. duodenale larvae can arrest their migration and become dormant for many months before proceeding to the lungs.⁵² In the lungs, larvae penetrate the alveoli and enter the air spaces, after which they migrate up the pulmonary tree, are swallowed with saliva, and pass into the small intestine, where they mature. Patients also can acquire A. duodenale by directly ingesting larvae crawling on contaminated fresh vegetables. Adult worms develop large buccal cavities and graze on the intestinal mucosa, ingesting epithelial cells and blood (Figs. 110-6 and 110-7). Adults are about one centimeter long and can live for up to 14 years. Mature worms mate and lay eggs. Each female N. americanus lays about 10,000 eggs a day, and each female A. duodenale lays about 20,000 eggs a day. Eggs are deposited with feces in moist, shady soil, where they hatch to release larvae. The larvae molt twice after which they move to the soil surface and seek a suitable host.

Figure 110-5. Serpiginous rash caused by hookworm larvae migrating through the dermis.

(Courtesy of the University of Iowa Department of Dermatology, Iowa City, Ia.)

Figure 110-6. Scanning electron micrographic view of the buccal cavities of Ancylostoma duodenale (left) and Necator americanus (right).

(From Hotez PJ, Pritchard DI. Hookworm infection. Sci Am 1995; 272:70.)

Figure 110-7. Longitudinal section of a hookworm grazing on intestinal mucosa.

(Courtesy of Wayne M. Meyers, Washington, DC.)

Diagnosis

Hookworms can be visible endoscopically (Fig. 110-8),⁶⁰ but diagnosis is made by identifying eggs on direct smears of formalin-fixed stool (see Fig. 110-3). Evaluation of three stool specimens obtained on separate days should permit diagnosis of hookworm,⁶¹ but light infestations can require concentration techniques. Eggs mature rapidly at room temperature and can hatch to release larvae. It is difficult to distinguish N. americanus eggs from those of A. duodenale simply by morphology.

Figure 110-8. Endoscopic view of Necator americanus in the duodenum (arrow).

(From Reddy SC, Vega KJ. Endoscopic diagnosis of chronic severe upper GI bleeding due to helminthic infection. Gastrointest Endosc 2008; 67:990.)

Ancylostoma caninum

Epidemiology

An estimated 800 million people harbor T. trichiura. It occurs in temperate and tropical countries and remains prevalent in areas with suboptimal sanitation. In one equatorial Cameroon province, 97% of the school-age children had T. trichiura.⁶⁵ Whipworm eggs are sensitive to desiccation, so prevalence is low in desert climates.

Life Cycle

T. trichiura has a simple life cycle. Colonization occurs by ingesting the parasite egg, each of which contains one developed larva. The eggs hatch in the intestine, and larvae migrate to the cecum, where they mature, mate, and lay eggs. This process takes about eight to 12 weeks. Adult worms are approximately three centimeters long and have a thin tapered anterior region so that the worm resembles a whip (Fig. 110-9, Video 110-2).⁶⁶ A mature female worm lays about 20,000 eggs a day and can live for three years. Eggs are deposited with feces into the soil. Over the next two to six weeks, one larva develops within each egg, but the egg is not infective until it has fully embryonated. Therefore, T. trichiura does not multiply in the host and is not directly transmitted to other persons.

Figure 110-9. Trichuris species: Adult male () and female () whipworms.

Clinical Features and Pathophysiology

Most persons with T. trichiura infestation have no symptoms attributable to the parasite. Most people in an endemic area are colonized by small numbers (less than 15) of worms and for them, the parasite is a commensal organism rather than a pathogen. Some people harbor hundreds or even thousands of worms,⁶⁷ and they are the ones who develop symptoms⁶⁸; this bimodal distribution of infestation persists after patients are treated and then become reinfected naturally, suggesting that unique host factors (genetic or behavioral) contribute to determining an individual patient’s worm burden.

Rectal prolapse can occur in children with extremely high numbers of T. trichiura worms.⁶⁹ Some persons with numerous worms have mucoid diarrhea and occasional bleeding, a combination of symptoms called the Trichuris dysentery syndrome (TDS). Children with this condition have growth retardation,⁷⁰ but studies attributing these symptoms to T. trichiura are complicated, because persons with TDS often are socioeconomically deprived and may be coinfected with other pathogens. Colonic biopsy specimens from children with TDS show few or no abnormalities compared with healthy local children,⁷¹ other than an increase in mast cells⁷² and in the number of cells that express TNF-α and calprotectin.⁷³

A different but closely related species, Trichuris muris, infests mice. Mouse strains that react to the parasite with a strong Th2 response, characterized by production of interleukin (IL)-4, IL-5, and IL-13, are able to expel the worms, whereas strains that respond with a Th1 response (interferon [IFN]-γ) have difficulty expelling the worms.⁷⁴ Blocking IL-4 makes resistant strains susceptible, and blocking IFN-γ makes susceptible strains resistant to chronic infestation with T. muris.⁷⁵ The type of immune response developed by inbred mice to T. muris is an important factor in determining length and intensity of infestation. A similar response in humans might explain why some people repeatedly acquire heavy infestations whereas others carry only a few worms.

Diagnosis

Diagnosis is made by identifying T. trichiura eggs in stool specimens. Trichuris eggs are 23 µm by 50 µm and have characteristic plugs at each end (see Fig. 110-3).

Treatment

T. trichiura is treated with mebendazole 100 mg twice a day for three days; alternatively, patients can take albendazole 400 mg each day for three days. Heavily infested patients might require seven days of treatment.⁷⁶ Single-dose treatment with albendazole is ineffective²⁷ but one treatment with a combination of albendazole (400 mg) and ivermectin (200 µg/kg) appears quite effective, with cure rates of up to 80% and egg reduction rates of 94%.^77,78

Epidemiology

E. vermicularis is a quintessential intestinal parasite with no geographic constraints. It is transmissible by close contact with colonized persons. People have had pinworm for thousands of years, and before modern sanitation, colonization by pinworm probably was universal. E. vermicularis eggs were identified in a 10,000-year-old human coprolite found in Utah.⁷⁹ The pinworm Enterobius gregorii, originally thought to be a separate species of pinworm,^80,81 actually may be just a young adult form of E. vermicularis.⁸²

People of every socioeconomic group can acquire pinworm and it remains quite prevalent. School-age children are most often colonized, compelling other household members to acquire the parasite. Crowding and institutionalization promotes acquisition. Eggs can survive in the environment for approximately 15 to 20 days and are resistant to chlorinated water (e.g., swimming pools).

Pinworm remains common in many areas, but it appears to be decreasing in prevalence. A survey of positive cellophane tape tests (see later) in New York City documented a sharp decline in positivity from 57 of 248 tests in 1971 to 17 of 165 in 1978 to 0 of 38 in 1986.⁸³ Similar trends are reported from California.

Life Cycle

E. vermicularis has a simple life cycle with a “hand to mouth” existence. The worm is acquired by ingesting parasite eggs. Most often these eggs are on the hands of the host; however, the small eggs also may become airborne, inhaled, and then swallowed.

Eggs hatch in the duodenum, releasing larvae that molt twice as they mature and migrate to the cecum and ascending colon (Fig. 110-10, Video 110-3).⁸⁴ The parasites are small: adult males measure 0.2 mm by 2 to 5 mm, and adult females measure 0.5 mm by 8 to 13 mm. After mating, gravid females migrate to the rectum. During the night, egg-laden females migrate out of the anal canal and onto the perianal skin. Each female deposits up to 17,000 eggs, which mature rapidly, becoming infective within six hours. Pinworm infestation typically causes perianal itching, and scratching gathers eggs onto the hands, promoting reinfection and transmission to others.

Figure 110-10. Pinworm (Enterobius vermicularis, arrows) found on screening colonoscopy of an institutionalized man.

Clinical Features and Pathophysiology

E. vermicularis is an extremely well adapted parasite that produces no specific symptoms in the vast majority of colonized persons. Most symptoms are minor, such as pruritus ani and restless sleeping. Rarely, pinworm causes eosinophilia or eosinophilic enteritis.⁸⁵

Vulvovaginitis is more common in girls with pinworm than in girls without this infection. Vulvovaginitis may be caused by migration of the worms into the introitus and genital tract. Dead worms and eggs encased in granulomas have been found in the cervix, endometrium, fallopian tubes, and peritoneum, attesting to the migratory effort of female worms.⁸⁶ Ectopic enterobiasis is rare and causes no or very little overt pathology.

Infestation with E. vermicularis can influence mucosal immune responses. One case report described a 12-year-old girl with pinworm and apparently latent ulcerative colitis, who developed severe ulcerative colitis after treatment with pyrantel to remove the worms.⁸⁷ While she was colonized with E. vermicularis, intestinal biopsies showed increased expression of mRNA for IL-4, transforming growth factor (TGF)-β, IL-10, and FOXP3 compared with biopsy specimens taken after anthelminthic treatment; these transcripts are associated with immune regulatory pathways that suppress inflammation.

Diagnosis

E. vermicularis eggs are not plentiful in stool, an observation that might explain the low prevalence rates found in studies that only use stool specimens for diagnosis. The NIH cellophane tape test is the classic diagnostic test for pinworm. A two- to three-inch piece of clear tape is applied serially to several perianal areas in the morning before washing. The tape is then applied to a glass slide. Microscopic evaluation demonstrates parasite eggs that measure 30 by 60 µm, have a thin shell, and appear flattened on one side. Three to seven daily samples are needed to exclude pinworm infestation.

Treatment

Pinworm actually requires no treatment unless the patient is symptomatic. It is highly transmittable, however, and for that reason should be expunged. E. vermicularis is readily treated with a single 100-mg dose of mebendazole or a 400-mg dose of albendazole. Reinfestation is common, and patients should receive a second treatment after 15 days. All members of the family should be treated and clothes and bed linens should be washed. Albendazole and mebendazole are potentially teratogenic. Because E. vermicularis has very low pathogenicity, treatment of pregnant women should be postponed until after delivery.

Epidemiology

Trichinosis is acquired by eating raw or undercooked meat that contains parasite larvae of Trichinella species. Worldwide, domestic pigs are the most common carriers. Trichinella species are divided into two groups,⁸⁸ one that forms encapsulated muscle cysts and only infests mammals (Trichinella spiralis, Trichinella britovi, Trichinella nelsoni, Trichinella native, Trichinella murrelli), and one that does not form encapsulated cysts and infests mammals and birds (Trichinella pseudospiralis) or mammals and reptiles (Trichinella papuae, Trichinella zimbabwensis). To date only T. zimbabwensis has not been implicated in human disease.

These species are closely related, morphologically nearly identical, and distinguished using molecular approaches. Trichinella has worldwide distribution, with T. nativa and T. murrelli in the Arctic and subarctic regions; T. spiralis and T. pseudospiralis in the Americas, Europe, and Russia; T. britovi in Europe, north Africa, the Middle East, and Asia; T. nelsoni in equatorial Africa; T. zimbabwensis in Zimbabwe, Ethiopia, and Mozambique; and T. papuae only in Papua New Guinea. Each of the Trichinella species can infest any mammal. T. nativa is resistant to freezing for up to five years.

Trichinosis was much more common in the United States than it is now. In the late 1940s, about 400 cases per year of symptomatic trichinosis were reported to various health agencies, and this number dropped to an average of 14.4 cases per year in the time period 1997 to 2001⁸⁹; reports from Germany show a similar pattern.⁹⁰ This decrease is explained by two major factors: First is the strong admonition to thoroughly cook all pork products; second is a change in farming practice to now feed pigs only grain. Industrialized pig farms in North America have been free of trichinosis for more than 50 years, but trichinosis is a reemerging illness in eastern Europe, related to relaxed enforcement of regulations.⁹¹

Currently, most reported cases involve a discrete exposure. For example, a 1991 outbreak in Wisconsin involved 40 people who ate pork sausage from one shop. A 1995 outbreak in Idaho involved 10 people who ate cougar jerky.⁹² A 2005 outbreak in Canada involved at least 14 people who ate frozen then stewed black bear meat.⁹³ In France, several outbreaks have resulted from eating raw horse meat.⁹⁴ This emphasizes that all mammals including herbivores can transmit Trichinella.

Life Cycle

The same host harbors both the adult and larval form of Trichinella.⁹⁵ People acquire the parasite by eating raw or undercooked meat that contains encapsulated parasite larvae. Each cyst dissolves in the digestive tract, releasing one larva that invades the small intestinal mucosa and lives within the cytoplasm of about 45 villus cells (Fig. 110-11). Larvae mature rapidly and mate within 30 hours. Adults are minute: Male worms measure 60 µm by 1.2 mm and female worms measure 90 µm by 2.2 mm. Females are viviparous and begin releasing larvae about one week after their initial ingestion. Adults are short-lived, producing larvae for only four weeks, by which time they are expelled by the host.

Figure 110-11. Illustration of Trichinella spiralis coiled through enterocytes in the small intestine. Each Trichinella larva lives within the cytoplasm of approximately 45 villus cells.

The larvae live much longer than the adult worms. Larvae measure six by 100 µm and enter the intestinal blood and lymphatic vessels. They are distributed by the circulatory system through the body but develop only within striated muscle. The larva enters a striated muscle fiber but does not kill the myocyte. Instead, it induces the cell to transform into a novel nurse cell that houses and feeds the parasite. The larva grows and develops into the infective stage in about five weeks. The coiled larvae remain viable for many years awaiting ingestion by another animal.

Clinical Features and Pathophysiology

Although most infestations with Trichinella are asymptomatic, significant exposure produces illness and even death.⁹⁶ Clinical trichinosis has two phases caused by the enteral (adult) and parenteral (larval) stages of the parasite. Intestinal symptoms result from enteritis due to adult worms that have embedded themselves in the intestinal epithelium. Enteritis produces abdominal pain, nausea, vomiting, diarrhea, and low-grade fever. Intestinal symptoms begin about two days to one week and peak at two weeks after ingestion of contaminated meat. The timing and severity of symptoms vary with intensity of exposure. The intestinal phase of trichinosis often is misdiagnosed as viral gastroenteritis or food poisoning.

T. spiralis also infests mice and rats, permitting detailed study of the intestinal phase of infection.⁹⁷ Mice begin to expel adult worms about two weeks after initial infestation. Type 2 (Th2) cytokines (IL-4 and IL-5) promote worm expulsion. Expulsion of adult worms results from focal immune attack, increased secretions, and enhanced intestinal motility; T lymphocytes, eosinophils, and mast cells assist this primary response. Rats previously exposed to T. spiralis rapidly expel the parasite upon rechallenge, a protection likely resulting from an immediate-type hypersensitivity response to the parasite triggered by IgE-armed mast cells.

The parenteral phase of trichinosis begins with the birth of migratory larvae about one week after ingestion of the contaminated meat. Larvae migrate into muscle and other organs such as the brain, spinal cord, and heart, evoking inflammatory responses; high fever, myalgia, periorbital edema, dysphagia, headache, and paresthesia result. Symptoms peak about four to five weeks after initial exposure and can take months to resolve. The severity and timing of symptoms vary with the intensity of exposure. Many patients develop systemic complaints without prior intestinal symptoms.

The inflammatory response to migrating larvae produces myositis. Patients have eosinophilia and an elevated serum level of creatine phosphokinase (CPK). An intense exposure can cause fatal myocarditis, neuritis, and vasculitis or thrombosis. Patients are at highest risk of death between the third and sixth week after exposure. Because trichinosis is rare, index cases often are misdiagnosed initially. Numerous persons presenting in a narrow time frame and with similar and compatible symptoms should prompt consideration of trichinosis as the diagnosis.

Diagnosis

Trichinella cannot by diagnosed by stool examination or intestinal biopsy. Trichinella species do not lay eggs, and no larvae are present in stool specimens. Even with heavy infestations, adult worms are too uncommon to be found by random biopsy. Diagnosis is made by muscle biopsy demonstrating larvae within nurse cells. Diagnosis also can be made by serology. Acute and convalescent serum samples confirm a rise in anti-Trichinella antibody.

Treatment

Although adults are short-lived, treatment with albendazole 400 mg twice a day or mebendazole 5 mg/kg/day for 10 to 15 days⁹⁸ is warranted and abbreviates the production of larvae by adult worms. Addition of glucocorticoids reduces inflammation and systemic symptoms; however, glucocorticoids given in the absence of a benzimidazole can prolong the intestinal phase, increasing the number of larvae released.

Epidemiology and Life Cycle

A. simplex and P. decipiens infest fish and marine mammals.⁹⁹ People become accidental hosts by eating raw or pickled fish. Anisakidosis has become more common with the increased popularity of eating raw fish (e.g., sushi). Many species of saltwater fish harbor A. simplex larvae including herring, mackerel, salmon, plaice, and squid. The parasite larvae initially infest crustaceans that are consumed by fish. The larvae migrate to the fish musculature and, if a parasitized fish is eaten by another fish, the larvae again migrate to the musculature of their new host. Eventually, a parasitized fish is eaten by a marine mammal that serves as the definitive host. In the marine mammal, the parasite larvae mature into adult intestinal worms and lay eggs that are passed with feces, the eggs hatch to release larvae that infest crustaceans, and the life cycle is thus renewed.

Clinical Features and Pathophysiology

A. simplex and P. decipiens cause transient infestations in humans. They do not reach full maturity in humans and therefore produce no eggs. The most common gastrointestinal symptom is acute severe stomach pain with nausea and hematemesis shortly after eating larva-infested raw fish. Endoscopy may demonstrate a small larva partially penetrating the gastric or intestinal wall.^100,101 Rarely, A. simplex can enter the intestinal wall and cause a strong inflammatory reaction that can mimic acute appendicitis¹⁰² or Crohn’s disease. Human infestations with either A. simplex or P. decipiens is termed anisakidosis after the family name (Anisakidae) for these parasites.

A. simplex is a potent allergen, and many cases of seafood (fish) allergy actually may be reactions to A. simplex,¹⁰³ including anaphylaxis from well-cooked marine fish.^99,104 In Spain, 12% to 22% of persons are seropositive for IgE against A. simplex.^105,106

Diagnosis and Treatment

A history of recent (within three days) ingestion of raw fish suggests anisakidosis in the appropriately symptomatic patient. Diagnosis is made by finding the larvae on endoscopy or in surgically excised specimens. Gastric anisakidosis is diagnosed by endoscopy, and endoscopic removal of the anisakid alleviates symptoms. Intestinal anisakidosis can prompt surgery for patients presenting with symptoms of acute small bowel obstruction or peritonitis,¹⁰⁷ but surgery may be avoidable if a recent history of eating raw fish is elicited and conservative treatment is tolerated.¹⁰⁸

A. simplex and P. decipiens infestations are transient because the parasites do not survive in humans. Therefore, treatment with an anthelminthic is not needed.

Epidemiology

D. latum is most common but other Diphyllobothrium species (e.g., Diphyllobothrium dendriticum, Diphyllobothrium nihonkaiense) can colonize humans.^109,110 D. latum is endemic in northern Europe, Russia, and Alaska, but fish tapeworm has been reported in Africa, Japan, Taiwan, Australia, South America, North America, and Canada.¹¹¹

Life Cycle

Fish tapeworm has a complex life cycle with two intermediate hosts. Parasite eggs that reach fresh water embryonate and then release free-swimming larvae called coracidia. Coracidia are ingested by water fleas (Cyclops and Diaptomus) and develop into procercoid larvae. Freshwater fish eat these small crustaceans, and the parasite changes into the infective plerocercoid form. The plerocercoid larva embeds in fish muscle and organs, growing to two centimeters in length. If an infected fish is consumed by another fish, the plerocercoid larva simply migrates into the flesh of the second fish.

Trout, salmon, pike, perch, and whitefish all can harbor D. latum. People acquire the parasite by eating raw or undercooked fish. D. latum also can colonize many other mammals such as dogs, cats, bears, and seals. In mammals, the ingested plerocercoid larva attaches to the wall of the small intestine and matures into an adult worm. A long chain of proglottids, called the strobila, develops off of the scolex (Fig. 110-12). D. latum is the largest parasite of humans, reaching 12 meters (40 feet) in length. The proglottids release eggs into the lumen that pass with the feces.

Figure 110-12. Endoscopic view of the cecum in a middle-aged woman with watery diarrhea after a fishing trip in Northern Canada during which she also frequently ate sushi. Part of a fish tapeworm is seen, and the strobila with maturing proglottids is visible. The worm, which was several feet long, was residing in the small intestine and was retrieved by suction. She was treated successfully with praziquantel.

(Courtesy of Dr. Roy Joseph, MD, Denton, Tex.)

Clinical Features and Pathophysiology

Fish tapeworm is not invasive and causes no direct symptoms. The worm obtains nutrients by absorbing luminal contents through its surface. D. latum produces a substance that splits B₁₂ from intrinsic factor in the intestine,¹¹² interfering with host absorption of the vitamin. The tapeworm also avidly absorbs B₁₂, effectively competing with its host’s use of the vitamin. D. latum is long-lived and, over time, can cause significant B₁₂ deficiency in patients with limited dietary cobalamin. Rarely, severe B₁₂ deficiency results in megaloblastic anemia and neurologic symptoms.

Diagnosis and Treatment

Fish tapeworm is diagnosed by identifying D. latum eggs in stool specimens. Occasionally, diagnosis is made because the patient passes proglottids and brings them in for identification or the worm is seen on endoscopy.¹¹³ Praziquantel is effective in a single oral dose of 10 mg/kg. Patients should be warned that they might pass a rather long worm two to five hours after taking the medication. Albendazole 400 mg each day for three days also kills the tapeworms.

Epidemiology

Beef and pork tapeworm occur where livestock are exposed to untreated human waste and people eat raw or undercooked meat. Both parasites have a worldwide distribution, although infestations originating in the United States and Europe are rare. Beef tapeworm is endemic in Africa, the Middle East, Eastern Europe, Asia, and Latin America. Pork tapeworm is endemic in Africa, India, China, Asia, and Latin America. T. solium is rare in Muslim countries, where pork consumption is prohibited. T. solium is considered an eradicable parasite,¹¹⁶ though progress in such eradication is hindered by socioeconomic barriers.¹¹⁷

Life Cycle

Adult tapeworms release gravid proglottids each containing up to 100,000 eggs that are released when the proglottid degenerates. Proglottids and eggs are passed with the stool. Proglottids of T. saginata remain motile and can crawl out of the feces, alarming the patient. Untreated human waste used to fertilize fields allows cattle to eat infective eggs on vegetation. Free-ranging pigs are coprophagous and directly consume poorly disposed human waste.

Ingested eggs release an embryo (oncosphere) that penetrates the intestinal wall and enters the blood vessels or lymphatics. The oncospheres are carried to subcutaneous tissue, muscle, and organs, where they develop into cysticerci that can live for several years awaiting human consumption of infected meat. Once in the human intestine, the cysticercus evaginates to form a scolex that serves as the anterior attachment point of the tapeworm to the mucosa of the proximal jejunum. The worm develops over several months as proglottids form and mature in a chain behind the scolex, referred to as the strobila. Beef tapeworms can reach four to 10 meters in length, and pork tapeworms attain lengths of two to four meters. Mature gravid proglottids break away from the distal end of the worm, pass with the stool, and rupture to release eggs to complete the life cycle. Adult tapeworms can live in the small intestine for 25 years.

Clinical Features and Pathophysiology

Most people colonized with adult T. saginata or T. solium are asymptomatic; those with symptoms complain of mild abdominal discomfort, loss of appetite, or change in stool pattern. Colonization usually is limited to one worm that obtains nutrients by absorbing luminal contents through its surface. Motile proglottids can crawl out of the anus or “swim” in the toilet, eliciting immediate concern. Rarely, acute biliary or pancreatic duct obstruction can occur if proglottids migrate into these sites.

The most feared complication of T. solium infestation is cysticercosis,¹¹⁸ which occurs when people inadvertently consume T. solium eggs. Just as in pigs, the eggs release oncospheres that penetrate the intestinal wall, disseminate through the body, and form cysticerci. Cysticerci produce localized inflammation in the brain, spinal cord, eye, and heart, with dire consequences. Neurocysticercosis is a common cause of epilepsy in countries where T. solium is endemic. Worldwide, an estimated 50,000 people die of neurocysticercosis each year. In the United States, 221 people died from cysticercosis between 1990 and 2002.¹¹⁹ Because the disease occurs after ingestion of parasite eggs, neurocysticercosis in a patient who has not visited or emigrated from an endemic country should prompt an effort to identify local carriers.

Diagnosis

Beef and pork tapeworm are diagnosed by identifying eggs or proglottids in stool specimens. The eggs of the two species are indistinguishable microscopically. The proglottids of T. saginata are two centimeters long and have more than 12 uterine branches; those of T. solium measure 1.2 cm and have fewer than 10 uterine branches.¹¹² Egg and proglottid production can be sporadic, necessitating repeated stool tests. Cysticercosis usually is diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI) and confirmed by serology using a larval cyst antigen-specific immunoblot.¹²⁰

Treatment

Praziquantel is effective in a single oral dose of 10 mg/kg. Albendazole 400 mg daily for three days also kills the tapeworms. The worms usually break apart and are passed as sections of disintegrating strobila. Patients with cysticercosis should be treated with albendazole 15 mg/kg daily for eight days to kill the cysticerci. Local inflammation transiently increases as cysticerci die. The addition of glucocorticoids prevents exacerbation of neurocysticercosis during therapy.

Epidemiology

H. nana is the most common tapeworm of humans. Unlike other tapeworms, it can be transmitted from person to person without an intermediate host. Dwarf tapeworm has a worldwide distribution, with highest prevalence in warm and arid regions. A survey of Egyptian children found that 16% carried H. nana.¹²¹ In the United States, a 1987 survey of state diagnostic laboratories found that 900 of 216,000 submitted stool specimens demonstrated H. nana, with 34 states reporting positive specimens.¹²² H. nana also colonizes mice and rats; however, the strains that colonize people appear to differ from those of rodents.

Human colonization with H. diminuta is rare, but it too has worldwide distribution. Rats and mice are the parasite’s usual hosts. People acquire rodent tapeworm by ingesting fleas, grain beetles, mealworms, or cockroaches infested with larval forms of the parasite. Most cases involve young children. The incorporation of beetles in traditional oriental medications also permits transmission.¹²³

Life Cycle

H. nana does not require an intermediate insect host. Ingested eggs release oncospheres that invade the mucosa of the small intestine. They lodge within the lymphatics of the villi and develop into cysticercoid larvae. Each cysticercoid larva then ruptures into the lumen and evaginates a scolex that attaches to the mucosa of the ileum. The worms mature, growing a strobila or chain of developing proglottids. Adult worms average two centimeters in length and have about 200 proglottids, each containing about 150 eggs. The most distal proglottids disintegrate to release eggs into the lumen. About 20 to 30 days after initial ingestion, the worm begins to shed eggs in the stool. H. nana adults live for only four to six weeks, but eggs shed in the stool are immediately infective. Self-inoculation or internal autoinfection allows colonization to persist for years. Ineffective sanitation or poor hand washing permits transmission to others.

Like other Hymenolepis species, H. nana can infest insects, forming cysticercoid larvae. Ingestion of infested fleas, beetles, mealworms, or cockroaches allows transmission of H. nana; however, acquisition by this pathway is rare, and most transmission is by direct ingestion of eggs.

H. diminuta requires intermediate insect hosts. Insects ingest eggs as they consume rodent droppings. The eggs release oncospheres that penetrate into the insect’s viscera and form cysticercoid larvae. Rats and mice that eat infested insects acquire the tapeworm. People acquire rodent tapeworm the same way, by eating infested insects. Once in the intestine, the cysticercoid larva evaginates to form a scolex that attaches to the ileal mucosa. The worm matures, growing a strobila of proglottids and reaching a length of up to 90 cm. The most distal proglottids disintegrate, releasing eggs into the intestinal lumen.

Clinical Features and Pathophysiology

Most people colonized with H. nana or H. diminuta have no symptoms, but self-inoculation or internal autoinfection can cause heavy infestations with H. nana, resulting in anorexia, abdominal pain, and diarrhea.

Mice can harbor Hymenolepis, permitting investigation of the mechanisms that limit worm density. It appears that a Th1-mediated IFN-γ response provides protective immunity against cysticercoid larvae,^124,125 and a Th2 response involving IgE and mast cells assists in the expulsion of adult worms.^126,127 The mucosal immune response to the tapeworm can alter intestinal inflammation elicited by other agents; for example, mice colonized with H. dimunita are protected from dinitrobenzene sulfonic acid (DNBS)-induced colitis¹²⁸ but are more susceptible to oxazalone-induced colitis.¹²⁹

Diagnosis and Treatment

Dwarf and rodent tapeworm are diagnosed by finding parasite eggs in the stool. H. nana eggs measure 30 to 47 µm in diameter. The eggs of the much less prevalent H. diminuta are larger, measuring 56 to 86 µm in diameter. Examination of several stool specimens taken on different days is needed to identify low-level colonization. Adults of both parasites can be killed with a single oral dose of praziquantel at 25 mg/kg, although eggs escape this treatment. Therefore, patients with H. nana infestation should be retreated one week after initial treatment. Family members also should be examined and considered for treatment.

Epidemiology

D. caninum is the most common tapeworm of domesticated dogs and cats, and it has a worldwide distribution. People acquire dog tapeworm by inadvertently ingesting fleas infested with the parasite. Most cases involve infants and young children who have close contact with their pets.

Life Cycle

Parasite eggs are ingested by the larval form of fleas that inhabit dogs or cats. Each egg releases an oncosphere that penetrates the gut wall and develops into a cysticercoid larva within the flea larva’s viscera. The insect larva then develops into an adult flea that can distribute the cysticercoid larva to other animals. Dogs, cats, and occasionally children ingest infested adult fleas. Once in the mammalian intestine, the cysticercoid larva evaginates to form a scolex that attaches to the mucosa of the small intestine. The worm matures, forming a strobila or chain of developing proglottids that trails the scolex. The adult worm measures 10 to 70 cm in length. Gravid proglottids detach from the distal end of the worm and pass with the stool. The proglottids look like cucumber seeds (12 by 3 mm), are motile, and occasionally move out of the anus. They can be mistaken for maggots. As they dry, they release small packets, each of which contain five to 15 eggs.

Clinical Features and Pathophysiology

Because people don’t often eat fleas, colonization is limited. Low numbers of dog tapeworms cause no symptoms. D. caninum is discovered when children or their parents find motile proglottids crawling in a diaper, underwear, or stool.

Diagnosis and Treatment

D. caninum is identified by its characteristic proglottid that looks like a moving cucumber seed. Often the proglottids of D. caninum are mistaken for adult pinworms (E. vermicularis) because the latter is much more common than the former. Stool examination for egg packets usually is unrewarding.

D. caninum causes a self-limited colonization that spontaneously clears, and dog tapeworm requires no treatment. Most patients and their families, however, prefer that the parasite be expunged actively, and so treatment is given with a single oral dose of praziquantel 10 mg/kg, or niclosamide 500 mg (chewable tablet).

Fasciolopsis buski

F. buski is the largest intestinal trematode that colonizes humans. Adults measure 7.5 cm long and 2 cm wide. F. buski is endemic in southeast Asia and Indonesia¹³¹ and is acquired by ingesting metacercariae encysted on freshwater plants. The metacercariae excyst in the duodenum and attach to the small intestinal mucosa. Within three months, they mature to adult flatworms and begin to lay eggs. The eggs pass with feces, and if they are deposited into fresh water, they embryonate. Each egg releases a ciliated miracidium that seeks a suitable snail to infect. The miracidium enters the snail and develops into a sporocyst that asexually multiplies, releasing numerous cercariae. The cercariae swim to freshwater plants, and each encysts to form a metacercaria on the plant’s surface, awaiting ingestion by a mammal.

Adult F. buski live for about one year and cause no symptoms in most people.¹³² Histology of jejunal biopsy specimens along with carbohydrate, fat, and protein absorption were normal in one study of patients harboring F. buski¹³³; however, in 1952, a 15-year-old Thai girl, hospitalized for diarrhea and abdominal pain, died of anasarca with more than 470 adult worms in her small intestine.¹³⁴ Diagnosis is by finding parasite eggs in the stool (see Fig 110-3). Rarely the large flatworm is found on endoscopy (Video 110-6).¹³⁵ Treatment is one dose of praziquantel 15 mg/kg given orally.

Heterophyes Species

Heterophyes species and the closely related Metagonimus yokogawai are small, flat worms measuring about 1.0 to 1.7 mm long by 0.3 to 0.6 mm wide. Heterophyes heterophyes is endemic in west Africa, Egypt, Israel, Turkey, China, Japan, Taiwan, and the Philippines. Heterophyes nocens is endemic to Japan and Korea. M. yokogawai is endemic in Siberia, the Balkans, China, Korea, and Japan.

People acquire these parasites by eating raw or undercooked fish that contain metacercariae. In the United States, a case of H. heterophyes involved a Pennsylvanian woman who ate sushi flown in from Asia.¹³⁶ The metacercariae ingested in raw fish excyst in the intestine, attach to the small intestinal mucosa, and develop into adults. The adults lay eggs that are deposited with feces. If passed into fresh or brackish water, the eggs release miracidia that swim in search of a suitable snail. A miracidium enters a snail and develops into a sporocyst that asexually multiplies, releasing numerous cercariae. The cercariae swim away from the snail in search of a fish to infect. Either freshwater fish or saltwater fish feeding in brackish outlets can become infected.

These parasites produce no specific symptoms in most people. Occasional heavy infections cause mild abdominal pain and diarrhea. The worms attach at the villus crypts and produce a localized eosinophilic inflammation. Rarely, parasite eggs enter blood vessels and lymphatics, producing distant granulomatous reactions. Diagnosis is by finding eggs in the stool, which can require concentration techniques. The eggs of Heterophyes species appear similar to those of M. yokogawai. Treatment of the trematodes is a single 20-mg/kg oral dose of praziquantel.

Echinostoma Species

There are at least 16 species of Echinostoma that can colonize humans.¹³⁷ Adults are 2 to 6 mm long and 1 to 1.5 mm wide, depending on the species. Echinostoma species are endemic in Taiwan, Korea, Thailand, Japan, Indonesia, and the Philippines. One outbreak of probable echinostomiasis involved 18 of 20 American travelers returning from Kenya.¹³⁸

People acquire Echinostoma by eating raw or undercooked freshwater mollusks or fish infected with metacercariae. The ingested metacercariae excyst in the intestine, attach to the small intestinal mucosa, and develop into adults. The adults lay eggs that, if deposited into fresh water with feces, embryonate and hatch to release miracidia that swim in search of suitable snails. A miracidium enters a snail and develops into a sporocyst that asexually multiplies, releasing numerous cercariae. Depending on the species, the Echinostoma cercariae swim away from the snail in search of another mollusk or fish to infect.

Echinostoma species produce no symptoms in most people, but these parasites can cause epigastric pain, abdominal cramps, and diarrhea.¹³⁸ Diagnosis is by finding eggs in the stool or adults on endoscopy.¹³⁹ Echinostoma eggs resemble those of F. buski but are smaller. Treatment is one 25-mg/kg dose of praziquantel given orally.

Clonorchis sinensis, Opisthorchis viverrini, and Opisthorchis felineus

C. sinensis and Opisthorchis species are closely related parasites that have similar life cycles and cause similar disease. C. sinensis is endemic to China, Hong Kong, Taiwan, the Republic of Korea, and North Vietnam. O. viverrini is endemic to Thailand and Laos.¹⁴⁰ O. felineus is endemic to Russia and the Ukraine. Infection with C. sinensis and other food-borne trematodes is increasing in prevalence, possibly due to fish farming.¹⁴¹ People acquire these parasites by eating metacercariae present in raw or undercooked fish such as grass carp (Ctenopharyngodon idellus) or pond smelt (Hypomesus olidus). Studies in Korea show that at least 80 species of freshwater fish can harbor metacercariae.¹⁴²

The metacercariae excyst in the stomach and duodenum as the meat is digested. The worms migrate along the mucosa to the ampulla of Vater and into the biliary tree, where they grow into adults. Leaf-shaped adult C. sinensis measure 5 mm wide by 2.5 cm long by 1 mm thick. Opisthorchis is smaller. The adult parasites lay eggs that pass with the bile into the intestinal lumen to be excreted. The excreted eggs are ingested by freshwater snails in which they hatch, releasing miracidia that develop into sporocysts. Each sporocyst asexually reproduces within the snail, eventually producing numerous cercariae. The cercariae exit the snail and swim in search of a suitable fish to invade. The parasites encyst as metacercariae in the muscles of the fish, awaiting ingestion by a mammalian host.

Most infections with C. sinensis or Opisthorchis are asymptomatic. With heavy exposures, patients develop fever, malaise, hepatic tenderness, and eosinophilia,¹⁴³ symptoms and signs that abate as the worms mature and begin laying eggs in the bile ducts (Video 110-7).¹⁴⁴ In a minority of patients, these parasites can cause relapsing cholangitis (see Chapter 82). The worms elicit a fibrotic and adenomatous reaction in the smaller branches of the biliary ducts, which can produce a localized obstruction and hepatic abscess. The flukes also can migrate into the pancreatic duct and cause pancreatitis.

The most important complication of chronic infection with C. sinensis or O. viverrini is cholangiocarcinoma (see Chapter 69).¹⁴⁵ Infection with these parasites dramatically increases the risk of developing this otherwise rare cancer (Table 110-2)^146,147: Parasites damage the bile duct, causing cellular desquamation followed by hyperplasia, adenomatous hyperplasia, periductal fibrosis, dysplasia, and finally cholangiocarcinoma.¹⁵¹ Cancer can result from increased sensitivity to carcinogens. Hamsters infected with O. viverrini develop cholangiocarcinoma when treated with subcarcinogenic doses of dimethylnitrosamine. C. sinensis and O. viverrini can sensitize patients to dietary or endogenously produced N-nitroso compounds and thereby increase the risk for cholangiocarcinoma.¹⁵² This is an important consideration in Western countries as well. A 1977 study found that 26% of Chinese immigrants relocating to New York had C. sinensis.¹⁵³ Because of the increased cancer risk associated with these parasites, it is advisable to look for them in any patient from an endemic area.¹⁵⁴

Table 110-2 Relative Risks of Cholangiocarcinoma in Patients with Clonorchis or Opisthorchis Infestation

CI, confidence interval.

* Light, <1500 eggs/g stool; medium, 1501-6000 eggs/g stool; heavy, >6000 eggs/g stool.

Diagnosis is by finding parasite eggs in the stool or duodenal aspirate. Symptomatic patients might have curvilinear lucencies in the biliary and pancreatic ducts on ERCP.¹⁵⁵ Ultrasound findings include increased periductal echogenicity and floating echogenic foci in the gallbladder.¹⁵⁶ The recommended treatment is praziquantel 25 mg/kg every eight hours for three doses. Heavy infections may require two days of therapy.¹⁵⁷ An alternative treatment is albendazole 10 mg/kg twice a day for seven days. Albendazole is teratogenic and should not be given to pregnant women.

Fasciola hepatica and Fasciola gigantica

Fasciola hepatica has a worldwide distribution, whereas Fasciola gigantica is endemic in Hawaii, Asia, India, the Middle East, and Africa. Both species infect sheep, goats, and cattle as their normal hosts.

Humans acquire these parasites by ingesting metacercariae encysted on freshwater plants such as watercress. Ingested metacercariae excyst in the small intestine, penetrate through the bowel wall, and enter the peritoneal cavity, where they migrate to the liver, penetrate the capsule, and travel through the hepatic parenchyma in search of a bile duct. They reside within the bile ducts, reaching maturity within three or four months, after which they lay eggs. Adult F. hepatica are 1.3 cm by 4.0 cm, and F. gigantica grow up to 7.0 cm in length. Adults of both species are only one millimeter thick and resemble leaves. Fasciola are long-lived; one documented infection persisted for 16 years.¹⁵⁸ Adults lay eggs that pass with the bile into the intestinal lumen, from which they are excreted. Upon reaching fresh water, Fasciola eggs embryonate, hatch, and release miracidia that swim in search of a suitable snail. A miracidium enters a snail and develops into a sporocyst that asexually multiplies, eventually releasing numerous cercariae. The cercariae swim to a freshwater plant and encyst on the wall, awaiting ingestion by a mammal.

Fasciola infestations usually are asymptomatic. In the acute phase, patients can have abdominal pain and hepatomegaly as the parasites penetrate the intestinal wall and hepatic capsule. Abdominal CT scan may show low-density areas in the periphery of the liver. Patients also develop symptoms from migration of the parasites to other sites such as subcutaneous fat.¹⁵⁹ Acute symptoms wane as the parasites enter the bile ducts. During the chronic phase of fascioliasis, patients can have symptoms of intermittent biliary obstruction and cholangitis. Rarely, patients develop pancreatitis. ERCP may show curvilinear lucencies in the bile duct (Fig. 110-13).¹⁶⁰

Figure 110-13. Fasciola hepatica on an endoscopic retrograde cholangiogram, appearing as curvilinear lucencies (arrows) in the distal bile duct. A leaf-shaped fluke was extracted from the bile duct.

(From Veerappan A, Siegel JH, Podany J, et al. Fasciola hepatica pancreatitis: Endoscopic extraction of live parasites. Gastrointest Endosc 1991; 37:473.)

Diagnosis is by finding eggs in the stool. Fasciola release low numbers of eggs, however, making this test insensitive. Duodenal or bile aspirates also can demonstrate eggs. The most sensitive method to detect Fasciola infection is ELISA for antibodies against the worms¹⁶¹; antibody titer drops after successful drug treatment.

Unlike other trematodes, Fasciola are resistant to praziquantel. Triclabendazole is the drug of choice for fascioliasis. In one study, a single oral dose of triclabendazole (10 mg/kg) cured 79% of patients as measured by fecal egg counts and ELISA.¹⁶²

Epidemiology

Schistosomes are tropical parasites with a worldwide distribution. S. mansoni is endemic in regions of Africa, the Middle East, Puerto Rico, the Dominican Republic, Central America, and South America. S. japonicum is endemic in China, Indonesia, the Philippines, and Thailand. S. mekongi is endemic in Laos and Cambodia. S. intercalatum is endemic in Africa. In most countries in which schistosomes are endemic, some regions have a high prevalence of infection; in other areas the parasite is absent. Schistosomes live in tropical snails for part of their life cycle. It is the distribution of these snails that helps define the geographic limits of schistosomes.

Construction of water reservoirs and irrigation canals has expanded the snail habitat in many countries, a practice that has increased the risk of acquiring schistosomiasis. Mice and other mammals can harbor schistosomes and might allow spread of the parasite even were sanitation to be improved,¹⁶³ thereby making it difficult to eradicate. Nonetheless, Japan successfully eradicated S. japonicum, and S. mansoni is vanishing from areas of Puerto Rico.¹⁶⁴

Life Cycle

Schistosome worms are acquired by contacting fresh water infested with parasite cercariae. Cercariae are fork-tailed, microscopic larvae that swim through the water in search of a suitable mammalian host. Upon finding this host, they penetrate through intact skin, shed their tails, and transform into schistosomules that are covered with a double lipid-bilayer tegument; this tegument thwarts most immunologic attacks (see later). Schistosomules migrate into blood vessels, where they are swept with the venous flow through the right side of the heart into the lungs. They migrate through the pulmonary capillaries, flow through the left side of the heart into the systemic circulation, and eventually reach the liver, where they mature, mate, and migrate against venous flow in the portal system. The two-centimeter female is partly ensheathed by the shorter male, and the “couple” reside together within the mesenteric veins. S. mansoni and S. intercalatum prefer to dwell in the vessels drained by the inferior mesenteric vein, whereas S. japonicum and S. mekongi prefer the vessels drained by the superior mesenteric vein.

The worms remain in the mesenteric vessels, consuming blood and nutrients and depositing eggs. S. mansoni lays 250 eggs and S. japonicum lays 3500 eggs per worm pair each day. Many of the eggs pass through the intestinal wall and enter the lumen of the bowel. The eggs are excreted with the stool, and if deposited in fresh water, they hatch to release ciliated miracidia. Miracidia swim in search of a suitable tropical snail to infect. After penetrating into the snail’s foot process, a miracidium transforms into a primary (mother) sporocyst. Secondary sporocysts bud off of the primary sporocyst, migrate to the snail’s liver, and mature. Cercariae bud off the secondary sporocysts, exit the snail, and swim in search of a permissive mammalian host.

Clinical Features and Pathophysiology

Dermal invasion and migration by infecting cercariae usually produce no symptoms. Patients with repeated contact can develop a mild papular rash, in contrast to the intensely pruritic papular rash that develops after exposure to avian schistosomes such as Trichobilharzia ocellata. These avian trematodes infect water fowl but are unable to live in mammals, and so the cercariae and schisosomules die in a person’s skin, eliciting an immunologic response that produces swimmer’s itch. Swimmer’s itch is common in the Great Lakes region and has been found as far north as Iceland.¹⁶⁵ Swimmer’s itch is not dangerous, but repetitive scratching can cause secondary cellulitis.

Schistosomules migrate through the body without producing symptoms. Juvenile and adult worms evade immune attack elegantly: Their tegument is coated with histocompatibility and blood group antigens derived from the host.¹⁶⁶ The tegument contains immunoglobulin receptors and proteases that might help cleave any bound antibody. Moreover, schistosomes produce several proteins that prevent complement, neutrophils, macrophages, or lymphocytes from injuring them.¹⁶⁷ Such immune evasion allows adult worms to survive in the blood vessels without causing much direct damage. The average life span of worms is thought to be about five years, but there are documented cases of adult worms surviving for more than 35 years after persons had left an endemic area.¹⁶⁸

Schistosome worms release eggs each day throughout their long life, and it is the parasite’s eggs that cause disease. Whereas the adult worms evade an immune response, the schistosome eggs invite one, exuding antigens that trigger a strong cell-mediated Th2 immune response.

Katayama fever is the classic presentation of acute schistosomiasis. It results from a brisk early immune response to schistosome eggs that occurs within the first two weeks of egg deposition or from about 35 to 50 days after contacting water that is heavily infested with cercariae. Symptoms are caused by circulating immune complexes and resemble those of serum sickness. Patients have fever, malaise, arthralgia, myalgia, cough, and diarrhea, with the additional finding of marked eosinophilia. Serum aminotransferases are normal, and eggs usually are absent from the stool. S. japonicum releases the largest number of eggs and causes the most intense acute schistosomiasis reaction, with fatality rates approaching 25%. Most people don’t develop acute schistosomiasis, but in those who do and survive, symptoms resolve as the infection enters the chronic phase.

Each schistosome egg secretes antigens that provoke a focal granulomatous inflammatory reaction that helps move the egg from the inside of a capillary, through the intestinal wall, and out into the lumen.¹⁶⁹ Thus, inflammation actually benefits the parasite. Passage of eggs through the bowel wall causes intestinal schistosomiasis with guaiac-positive stools or even bloody diarrhea. Patients also can have tenesmus and tenderness over the sigmoid colon. Patients with S. mansoni can develop colitis with inflammatory pseudopolyps (Fig. 110-14) composed of numerous eosinophils and occasional eggs¹⁷⁰—a picture that can resemble Crohn’s disease or ulcerative colitis. S. japonicum prefers to dwell in veins drained by the superior mesenteric vein and lays thousands of eggs at a time. S. japonicum can produce upper abdominal pain unrelated to meals, gastric bleeding, and pyloric obstruction due to inflammation and fibrosis.

Figure 110-14. Film from a barium enema in a 20-year-old Egyptian man with bloody diarrhea and tenesmus. Multiple polypoid lesions due to Schistosoma mansoni are seen throughout the rectosigmoid colon, which is displaced out of the pelvis by a large pericolic abscess.

(From Reeder MM, Hamilton LC. Radiologic diagnosis of tropical diseases of the gastrointestinal tract. Radiol Clin North Am 1969; 7:57.)

About half of the eggs pass out of the body; the other half lodge in the host’s tissues and cause the pathology of chronic schistosomiasis. Eggs are carried by the portal flow and some lodge in the liver. Other eggs lodge in the mesenteric and portal veins or remain in the intestinal wall. In these locations, the eggs elicit granulomatous inflammation with eosinophils, macrophages, lymphocytes, fibroblasts, and mast cells (Fig. 110-15). Eosinophils account for 50% of the schistosome egg granuloma cell population. When eosinophils degranulate, they deposit major basic protein that produces an eosinophilic halo around the eggs, termed the Splendore-Hoeppli phenomenon. This phenomenon is nonspecific and can be seen with bacterial, fungal, and parasitic infections. Eosinophils likely assist in killing the miracidia protected by the tough egg shell. After one or two weeks the miracidium dies, antigen release wanes, and the granuloma involutes to leave a fibrotic scar.

Figure 110-15. Histopathology of a colonic biopsy specimen from a patient with schistosomiasis. A schistosome egg granuloma is seen.

Over the years, the daily production of eggs, granulomas, and scars accumulates enough damage to produce disease. Eggs that lodge in the hepatic and portal vessels produce a unique pattern of scarring called Symmers’ pipe stem fibrosis, in which the vessels become fibrotic and resemble clay pipe stems on cross section; this process causes the presinusoidal venous obstruction and portal hypertension characteristic of hepatosplenic schistosomiasis (see Chapter 82). Patients typically have an enlarged left hepatic lobe, splenomegaly, and thrombocytopenia due to platelet sequestration. Hepatocellular function remains normal because the blood supply to the liver is maintained by increased hepatic artery flow. Patients have normal serum aminotransferase levels and mildly elevated serum levels of alkaline phosphatase and gamma glutamyl transpeptidase. Patients with hepatosplenic schistosomiasis do not develop cirrhosis unless they are coinfected with hepatitis B or C, and so they lack stigmata of chronic liver disease. The classic presentation of decompensated hepatosplenic schistosomiasis is variceal hemorrhage.

Hepatosplenic schistosomiasis results from accumulated injury and requires prolonged, moderately intense infection. Patients with hepatosplenic schistosomiasis typically range in age from adolescence to late 20s and have had schistosomiasis for five to 15 years. Compensated disease improves, however, after schistosomes are killed by drug therapy, permitting the portal tributaries to heal and remodel.^171,172

Schistosome eggs also can lodge in other sites besides the intestine, liver, spleen, and splanchnic venous circulation. Eggs can percolate through portocaval collateral vessels, lodge in the pulmonary capillaries, and over time cause pulmonary hypertension and cor pulmonale. Eggs can enter the vertebral venous plexus and embolize the spinal cord or brain. Granulomatous inflammation in the CNS can result in conus equinus syndrome, transverse myelitis, or schistosomal cerebritis.

Patients with schistosomiasis can present with recurrent bacteremia. Adult schistosome worms can ingest enteric bacteria transiently present in the portal circulation, harbor these bacteria, and serve as reservoirs for infection. Recurrent salmonella infection is particularly common in patients with schistosomiasis.¹⁷³

Schistosomiasis can cause membranoproliferative glomerulonephritis or focal glomerulosclerosis with proteinuria, nephrotic syndrome, and end-stage renal disease. Schistosomal nephropathy results from deposition of immune complexes of parasite antigens and antibodies, and the renal disease can be progressive even if the parasites are killed with drug therapy.¹⁷⁴

Diagnosis

Schistosome eggs are present in stool, but not in high numbers. The classic method for detecting eggs is the Kato-Katz thick smear.¹⁷⁵ This technique is not performed as part of the standard ova and parasite test, and standard evaluation is not sensitive enough to find the relatively rare schistosome eggs. Even Kato-Katz thick smears are not highly sensitive and are unlikely to detect eggs at very low levels of infection.

The vast majority of patients with intestinal schistosomiasis are asymptomatic; patients come to medical attention during evaluation of mild anemia, positive fecal occult blood tests, or unexpected variceal hemorrhage. On endoscopy, a patient might have inflammatory polyps that contain eggs,¹⁷⁰ but usually, the intestinal mucosa appears normal. Subtle changes in the vascular pattern can result from egg emboli producing a terminal curling of small blood vessels.¹⁷⁶ Occasionally, histopathology of random biopsies of the colonic mucosa show schistosome eggs (Fig. 110-16), but this is an insensitive means of diagnosis. Biopsy of the rectum can demonstrate eggs, especially when the biopsy is crushed between two glass slides and the whole biopsy specimen is surveyed microscopically. Evaluation of six crush biopsies is more sensitive than two Kato-Katz smears for S. mansoni.¹⁷⁷

Figure 110-16. Histopathology of a colonic biopsy specimen showing viable Schistosoma mansoni eggs. A 20-year-old woman who emigrated five years earlier from the Democratic Republic of the Congo was evaluated for persistent iron-deficiency anemia. She had normal stool habits but occasional hematochezia. The mucosa was normal on colonoscopy except for some areas suggestive of neovascularization. Random biopsy specimens demonstrated viable Schistosoma mansoni eggs (20×; inset, 60×). She was treated with praziquantel and the anemia resolved.

(Courtesy of P. Kirby and F. Mitros, Iowa City, Ia.)

Although eggs lodge in the liver and cause portal hypertension, liver biopsy is an insensitive method for detecting schistosomiasis. Liver biopsy should not be used solely to test for schistosomiasis but rather to stage comorbid disease such as viral hepatitis B or C.

Present or past exposure to schistosomes is detectable by serology. Antischistosome antibodies are detected by ELISA using adult microsomal antigens. Sensitivity varies depending on whether the infecting schistosome is the same species as that used to prepare the antigens. The ELISA uses S. mansoni microsomal antigens, and immunoblot tests using antigens from S. japonicum and S. hematobium (the schistosome responsible for urinary schistosomiasis) also can be performed.¹⁷⁸ The antibody assay also is useful to diagnose acute schistosomiasis (Katayama fever) because there are few or no eggs in the stool during the peak of the reaction. The ELISA does not distinguish active from prior infections, and therefore it is most useful for diagnosis in recent travelers rather than in expatriates. Because schistosomes can be long-lived, one-time treatment of antibody-positive patients is reasonable.

Active infection can be demonstrated by detecting circulating schistosome gut-associated protein antigens CCA (circulating cathodic antigen) and CAA (circulating anodic antigen) in the patient’s serum.¹⁷⁹ Serologic detection of CCA and CAA has an equivalent or higher sensitivity than the Kato-Katz thick smear, but each test misses some low-level infections.¹⁸⁰ Measurement of circulating antigens also can prove useful to document response to treatment,¹⁸¹ but these tests are not yet commercially available in the United States.

Abdominal ultrasound is an important additional test in hepatosplenic schistosomiasis. Ultrasound evaluation documents periportal fibrosis, splenomegaly, portal blood flow, and collateral vessels. Periportal fibrosis has a characteristic appearance: multiple echogenic areas, each with central echolucency.^182,183 A scoring system exists that uses a liver parenchyma and image pattern (IP), a portal thickening (PT), and a portal hypertension (PH) score to stage the disease (Table 110-3).¹⁸⁴

Treatment

Praziquantel is the drug of choice to treat schistosomiasis. It is the safest schistosomicide in current use. Praziquantel given orally in three doses of 20 mg/kg, each four hours apart (total dose, 60 mg/kg), gives the best cure rates of 60% to 98%, depending on the series. Eggs continue to be shed in the stool for up to two weeks after drug treatment, because eggs that were deposited before treatment can take this long to work through the intestinal wall. Patients who are not cured with a single course of praziquantel have a dramatic decrease in egg counts and respond to a second course of treatment. Periportal fibrosis improves after the worms are killed, halting the daily deluge of eggs and permitting the portal tributaries to heal and remodel.^171,172

Video 110-1.

Ascaris lumbricoides in the colon. (From Jang MK, Lee KS. Images in clinical medicine. Ascariasis. N Engl J Med 2008; 358:e16.)

Video 110-2.

Trichuris trichiura in the colon. (From Taguchi H, Yamamoto H, Miyata T, et al. In vivo diagnosis of whipworm [Trichuris trichiura] with high-definition magnifying colonoscope [with video]. Gastrointest Endosc 2008; 68:376.)

Video 110-3.

Enterobius vermicularis in the colon. (From Brown MD. Images in clinical medicine. Enterobius vermicularis. N Engl J Med 2006; 354:e12.)

Video 110-4.

Taenia saginata seen on video capsule endoscopy. (From Martines H, Fanciulli E, Menardo G. Incidental video-capsule diagnosis of small-bowel Taenia saginata in a patient with recurrent hemorrhage due to angiodysplasias. Endoscopy 2006; 38[Suppl 2]:E35.)

Video 110-5.

Taenia solium seen on colonoscopy. (From Liao WS, Bair MJ. Images in clinical medicine. Taenia in the gastrointestinal tract. N Engl J Med 2007; 357:1028.)

Video 110-6.

Fasciolopsis buski in the duodenum. (Murugesh M, Veerendra S, Madhu S, et al. Endoscopic extraction of Fasciolopsis buski. Endoscopy 2007; 39[Suppl 1]:E129.)

Video 110-7.

Clonorchis sinensis exiting the ampulla during endoscopic retrograde cholangiopancreatography. (From Park DH, Son HY. Images in clinical medicine. Clonorchis sinensis. N Engl J Med 2008; 358:e18.)