Section 19: Helminthic Infections

INTRODUCTION

The word helminth is derived from the Greek helmins (“parasitic worm”). Helminthic worms are highly prevalent and, depending on the species, may exist as free-living organisms or as parasites of plant or animal hosts. The parasitic helminths have co-evolved with specific mammalian and other host species. Accordingly, most helminthic infections are restricted to nonhuman hosts, and only rarely do these zoonotic helminths accidentally cause human infections.

Helminthic parasites of humans belong to two phyla: Nemathelminthes, which includes nematodes (roundworms), and Platyhelminthes, which includes cestodes (tapeworms) and trematodes (flukes). Helminthic parasites of humans reside within the human body and hence are the cause of true infections. In contrast, parasites of other genera that reside only on mucocutaneous surfaces of humans (e.g., the parasites causing myiasis and scabies) are considered to represent infestations rather than infections.

Helminthic parasites differ substantially from protozoan parasites in several respects. First, protozoan parasites are unicellular organisms, whereas helminthic parasites are multicellular worms that possess differentiated organ systems. Second, helminthic parasites have complex life cycles that require sequential stages of development outside the human host. Thus, most helminths do not complete their replication within the human host; rather, they develop to a certain stage within the mammalian host and, as part of their obligatory life cycle, must mature further outside that host. During the “extra-human” stages of their life cycle, helminths exist either as free-living organisms or as parasites within another host species and thereafter mature into new developmental stages capable of infecting humans. Thus, with only two exceptions (Strongyloides stercoralis and Capillaria philippinensis, which are capable of internal human reinfections), increases in the number of adult helminths (i.e., the “worm burden”) within the human host require repeated exogenous reinfections. In the case of protozoan parasites, a brief, even singular exposure (e.g., a single mosquito bite transmitting malaria) may lead rapidly to intense parasite loads and overwhelming infections; in contrast, for all but the two helminths noted above, increases in worm burden require multiple and usually ongoing exposures to infectious forms, such as ingestion of eggs of intestinal helminths or waterborne exposures to infectious cercariae of Schistosoma mansoni. This requirement is germane both to the consideration of helminthic infections in individuals and to ongoing global efforts to interrupt and/or minimize the acquisition of helminthic infections by humans.

Third, helminthic infections have a predilection toward stimulation of host immune responses that elicit eosinophilia within human tissues and blood. The many protozoan infections characteristically do not elicit eosinophilia in infected humans, with only three exceptions (two intestinal protozoan parasites, Cystoisospora belli and Dientamoeba fragilis, and tissue-borne Sarcocystis species). The magnitude of helminth-elicited eosinophilia tends to correlate with the extent of tissue invasion by larvae or adult helminths. For example, in several helminthic infections, including acute schistosomiasis (Katayama syndrome), paragonimiasis, and hookworm and Ascaris infections, eosinophilia is most pronounced during the early phases of infection, when migrations of infecting larvae and progression of subsequent developmental stages through the tissues are greatest. In established infections, local eosinophilia is often present around helminths in tissues, but blood eosinophilia may be intermittent, mild, or absent. In helminthic infections in which parasites are well contained within tissues (e.g., echinococcal cysts) or confined within the lumen of the intestinal tract (e.g., adult Ascaris or tapeworms), eosinophilia is usually absent.

NEMATODES

Nematodes are nonsegmented roundworms. Species of nematodes are remarkably diverse and abundant in nature. Among the many thousands of nematode species, few are parasites of humans. Most nematodes are free-living, and these species have variably evolved to survive in diverse ecologic niches, including saltwater, freshwater, or soil. The well-studied organism Caenorhabditis elegans is a free-living nematode. Nematodes can be either beneficial or deleterious parasites of plants. Parasitic nematodes have co-evolved with specific mammalian hosts and have no capacity to live their full life cycles in other hosts. Uncommonly, humans are exposed to infectious stages of nonhuman nematode parasites, and the resultant zoonotic nematode infections can elicit inflammatory and immune responses as larval forms migrate and die in the unsuitable human host. Examples include pulmonary coin lesions due to mosquito-transmitted infections with the dog heartworm Dirofilaria immitis; eosinophilic meningoencephalitis due to ingested eggs of the raccoon ascarid Baylisascaris procyonis; and eosinophilic meningitis due to ingestion of larvae of the rat lungworm Angiostrongylus cantonensis.

Nematode parasites of humans include worms that reside in the intestinal tract or localize in extraintestinal vascular or tissue sites. Roundworms are bisexual, with separate male and female forms (except for S. stercoralis, whose adult females are hermaphroditic in the human intestinal tract). Depending on the species, fertilized females release either larvae or eggs containing larvae. Nematodes have five developmental stages: an adult stage and four sequential larval stages. These parasites characteristically are surrounded by a durable outer cuticular layer. Nematodes have a nervous system; a muscular system, including muscle cells under the cuticle; and a developed intestinal tract, including an oral cavity and an elongated gut that ends in an anal pore. Adults may range in size from minute to >1 meter in length (with Dracunculus medinensis, for example, at the long end of this spectrum).

Humans acquire infections with nematode parasites by various routes, depending on the parasitic species. Ingestion of eggs passed in human feces is a major global health problem with many of the intestinal helminths (e.g., Ascaris lumbricoides). In other species, infecting larvae penetrate skin exposed to fecally contaminated soil (e.g., S. stercoralis, hookworms) or traverse the skin after the bite of infected insect vectors (e.g., filariae). Some nematode infections are acquired by consumption of specific animal-derived foods (e.g., trichinellosis from raw or undercooked pork or wild carnivorous mammals). As noted above, only two nematodes, S. stercoralis and C. philippinensis, can internally reinfect humans; thus, for all other nematodes, any increases in worm burden must be due to continued exogenous reinfections.

CESTODES

Tapeworms are the cestode parasites of humans. Adult tapeworms are elongated, segmented, hermaphroditic flatworms that reside in the intestinal lumen or, in their larval forms, may live in extraintestinal tissues. Tapeworms include a head (scolex) and a number of attached segments (proglottids). The worms attach to the intestinal tract via their scolices, which may possess suckers, hooks, or grooves. The scolex is the site of formation of new proglottids. Tapeworms do not have a functional gut tract; rather, each tapeworm segment passively and actively obtains nutrients through its specialized surface tegument. Mature proglottids possess both male and female sex organs, but insemination usually occurs between adjacent proglottids. Fertilized proglottids release eggs that are passed in the feces. When ingested by an intermediate host, an egg releases an oncosphere that penetrates the gut and develops further in tissues as a cysticercus. Humans acquire infection by ingesting animal tissues that contain cysticerci, and the resultant tapeworms develop and reside in the proximal small bowel (e.g., Taenia solium, T. saginata). Alternatively, if humans ingest eggs of these cestodes that have been passed in human or animal feces, oncospheres develop and can cause space-occupying extraintestinal cystic lesions in tissues; examples include cysticercosis due to T. solium and hydatid disease due to species of Echinococcus.

TREMATODES

Trematodes of medical importance include blood flukes, intestinal flukes, and tissue flukes. Adult flukes are often leaf-shaped flatworms. Oral and/or ventral suckers help adult flukes maintain their positions in situ. Flukes have an oral cavity but no distal anal pore. Nutrients are obtained both through their integument and by ingestion into the blind intestinal tract. Flukes are hermaphroditic except for blood flukes (schistosomes), which are bisexual. Eggs are passed in human feces (Fasciola, Fasciolopsis, Clonorchis, Schistosoma japonicum, S. mansoni), urine (Schistosoma haematobium), or sputum and feces (Paragonimus). Expelled eggs release miracidia—usually in water—that infect specific snail species. Within snails, parasites multiply and cercariae are released. Depending on the species, cercariae can penetrate the skin (schistosomes) or can develop into metacercariae that can be ingested with plants (e.g., watercress for Fasciola) or with fish (Clonorchis) or crabs (Paragonimus).

CONCLUSION

Many of the so-called neglected tropical diseases are due to helminthic infections. The health impacts of many helminthic infections are varied and are based on the frequent need for repeated exposures to increase the worm burdens in infected humans. In global regions where exposures to specific helminths occur even in childhood (e.g., fecally derived intestinal nematodes, mosquito-transmitted filariae, or waterborne snail-transmitted schistosomes), the morbidities in infected individuals can include nutritional, developmental, cognitive, and functional impairments. Ongoing global mass-treatment programs are currently aimed at diminishing the local prevalences of specific helminths and their consequent impacts on the health of local populations.

INTRODUCTION

Nematodes are elongated, symmetric roundworms. Parasitic nematodes of medical significance may be broadly classified as either predominantly intestinal or tissue nematodes. The intestinal nematodes are covered in Chap. 227. This chapter covers the tissue nematodes that cause trichinellosis, visceral and ocular larva migrans, cutaneous larva migrans, cerebral angiostrongyliasis, and gnathostomiasis. All of these zoonotic infections result from incidental exposure to infectious nematodes. The clinical symptoms of these infections are due largely to invasive larval stages that (except in the case of Trichinella) do not reach maturity in humans.

TRICHINELLOSIS

Trichinellosis develops after the ingestion of meat containing cysts of Trichinella (e.g., pork or other meat from a carnivore). Although most infections are mild and asymptomatic, heavy infections can cause severe enteritis, periorbital edema, myositis, and (infrequently) death.

Life Cycle and Epidemiology

Eight species of Trichinella are recognized as causes of infection in humans. Two species are distributed worldwide: T. spiralis, which is found in a great variety of carnivorous and omnivorous animals, and T. pseudospiralis, which is found in mammals and birds. T. nativa is present in Arctic regions and infects bears; T. nelsoni is found in equatorial eastern Africa, where it is common among felid predators and scavengers such as hyenas and bush pigs; and T. britovi is found in Europe, western Africa, and western Asia among carnivores but not among domestic swine. T. murrelli is present in North American game animals.

After human consumption of trichinous meat, encysted larvae are liberated by digestive acid and proteases (Fig. 226-1). The larvae invade the small-bowel mucosa and mature into adult worms. After ~1 week, female worms release newborn larvae that migrate via the circulation to striated muscle. The larvae of all species except T. pseudospiralis, T. papuae, and T. zimbabwensis then encyst by inducing a radical transformation in the muscle cell architecture. Although host immune responses may help to expel intestinal adult worms, they have few deleterious effects on muscle-dwelling larvae.

Human trichinellosis is often caused by the ingestion of infected pork products and thus can occur in almost any location where the meat of domestic or wild swine is eaten. Human trichinellosis may also be acquired from the meat of other animals, including dogs (in parts of Asia and Africa), horses (in Italy and France), and bears and walruses (in northern regions). Although cattle (being herbivores) are not natural hosts of Trichinella, beef has been implicated in outbreaks when contaminated or adulterated with trichinous pork. Laws that prohibit the feeding of uncooked garbage to pigs have greatly reduced the transmission of trichinellosis in the United States. About 12 cases of trichinellosis are reported annually in this country, but most mild cases probably remain undiagnosed. Recent U.S. and Canadian outbreaks have been attributable to consumption of wild game (especially bear meat) and, less frequently, of pork.

Pathogenesis and Clinical Features

Clinical symptoms of trichinellosis arise from the successive phases of parasite enteric invasion, larval migration, and muscle encystment (Fig. 226-1). Most light infections (those with <10 larvae per gram of muscle) are asymptomatic, whereas heavy infections (which can involve >50 larvae per gram of muscle) can be life-threatening. Invasion of the gut by large numbers of parasites occasionally provokes diarrhea during the first week after infection. Abdominal pain, constipation, nausea, or vomiting also may be prominent.

Symptoms due to larval migration and muscle invasion begin to appear in the second week after infection. The migrating Trichinella larvae provoke a marked local and systemic hypersensitivity reaction, with fever and hypereosinophilia. Periorbital and facial edema is common, as are hemorrhages in the subconjunctivae, retina, and nail beds (“splinter” hemorrhages). A maculopapular rash, headache, cough, dyspnea, or dysphagia sometimes develops. Myocarditis with tachyarrhythmias or heart failure—and, less commonly, encephalitis or pneumonitis—may develop and accounts for most deaths of patients with trichinellosis.

Upon onset of larval encystment in muscle 2–3 weeks after infection, symptoms of myositis with myalgias, muscle edema, and weakness develop, usually overlapping with the inflammatory reactions to migrating larvae. The most commonly involved muscle groups include the extraocular muscles; the biceps; and the muscles of the jaw, neck, lower back, and diaphragm. Peaking ~3 weeks after infection, symptoms subside only gradually during a prolonged convalescence. Uncommon infections with T. pseudospiralis, whose larvae do not encapsulate in muscles, elicit prolonged polymyositis-like illness.

Laboratory Findings and Diagnosis

Blood eosinophilia develops in >90% of patients with symptomatic trichinellosis and may peak at a level of >50% 2–4 weeks after infection. Serum levels of muscle enzymes, including creatine phosphokinase, are elevated in most symptomatic patients. Patients should be questioned thoroughly about their consumption of pork or wild animal meat and about illness in other individuals who ate the same meat. A presumptive clinical diagnosis can be based on fevers, eosinophilia, periorbital edema, and myalgias after a suspect meal. A rise in the titer of parasite-specific antibody, which usually does not occur until after the third week of infection, confirms the diagnosis. Alternatively, a definitive diagnosis requires surgical biopsy of at least 1 g of involved muscle; the yields are highest near tendon insertions. The fresh muscle tissue should be compressed between glass slides and examined microscopically (Fig. 226-2) because larvae may be missed by examination of routine histopathologic sections alone.

TREATMENT

Prevention

Larvae are usually killed by cooking pork until it is no longer pink or by freezing it at −15°C for 3 weeks. However, Arctic T. nativa larvae in walrus or bear meat are relatively resistant and may remain viable despite freezing.

VISCERAL AND OCULAR LARVA MIGRANS

Visceral larva migrans is a syndrome caused by nematodes that are normally parasitic for nonhuman host species. In humans, these nematode larvae do not develop into adult worms but instead migrate through host tissues and elicit eosinophilic inflammation. The most common form of visceral larva migrans is toxocariasis due to larvae of the canine ascarid Toxocara canis; the syndrome is due less commonly to the feline ascarid T. cati and even less commonly to the pig ascarid Ascaris suum. Rare cases with eosinophilic meningoencephalitis have been caused by the raccoon ascarid Baylisascaris procyonis.

Life Cycle and Epidemiology

The canine roundworm T. canis is distributed among dogs worldwide. Ingestion of infective eggs by dogs is followed by liberation of Toxocara larvae, which penetrate the gut wall and migrate intravascularly into canine tissues, where most remain in a developmentally arrested state. During pregnancy, some larvae resume migration in bitches and infect puppies prenatally (through transplacental transmission) or after birth (through suckling). Thus, in lactating bitches and puppies, larvae return to the intestinal tract and develop into adult worms, which produce eggs that are released in the feces. Eggs must undergo embryonation over several weeks to become infectious. Humans acquire toxocariasis mainly by eating soil contaminated by puppy feces that contains infective T. canis eggs. Visceral larva migrans is most common among children who habitually eat dirt.

Pathogenesis and Clinical Features

Clinical disease most commonly afflicts preschool children. After humans ingest Toxocara eggs, the larvae hatch and penetrate the intestinal mucosa, from which they are carried by the circulation to a wide variety of organs and tissues. The larvae invade the liver, lungs, central nervous system (CNS), and other sites, provoking intense local eosinophilic granulomatous responses. The degree of clinical illness depends on larval number and tissue distribution, reinfection, and host immune responses. Most light infections are asymptomatic and may be evidenced only by blood eosinophilia. Characteristic symptoms of visceral larva migrans include fever, malaise, anorexia and weight loss, cough, wheezing, and rashes. Hepatosplenomegaly is common. These features may be accompanied by extraordinary peripheral eosinophilia at levels that may approach 90%. Uncommonly, seizures or behavioral disorders develop. Rare deaths are due to severe neurologic, pneumonic, or myocardial involvement.

The ocular form of the larva migrans syndrome occurs when Toxocara larvae invade the eye. An eosinophilic granulomatous mass, most commonly in the posterior pole of the retina, develops around the entrapped larva. The retinal lesion can mimic retinoblastoma in appearance, and mistaken diagnosis of the latter condition can lead to unnecessary enucleation. The spectrum of eye involvement also includes endophthalmitis, uveitis, and chorioretinitis. Unilateral visual disturbances, strabismus, and eye pain are the most common presenting symptoms. In contrast to visceral larva migrans, ocular toxocariasis usually develops in older children or young adults with no history of pica; these patients seldom have eosinophilia or visceral manifestations.

Diagnosis

In addition to eosinophilia, leukocytosis and hypergammaglobulinemia may be evident. Transient pulmonary infiltrates are apparent on chest x-rays of about one-half of patients with symptoms of pneumonitis. The clinical diagnosis can be confirmed by an enzyme-linked immunosorbent assay for toxocaral antibodies. Stool examination for parasite eggs is worthless in toxocariasis, since the larvae do not develop into egg-producing adults in humans.

TREATMENT

CUTANEOUS LARVA MIGRANS

Cutaneous larva migrans (“creeping eruption”) is a serpiginous skin eruption caused by burrowing larvae of animal hookworms, usually the dog and cat hookworm Ancylostoma braziliense. The larvae hatch from eggs passed in dog and cat feces and mature in the soil. Humans become infected after skin contact with soil in areas frequented by dogs and cats, such as areas underneath house porches. Cutaneous larva migrans is prevalent among children and travelers in regions with warm humid climates, including the southeastern United States.

After larvae penetrate the skin, erythematous lesions form along the tortuous tracks of their migration through the dermal-epidermal junction; the larvae advance several centimeters in a day. The intensely pruritic lesions may occur anywhere on the body and can be numerous if the patient has lain on the ground. Vesicles and bullae may form later. The animal hookworm larvae do not mature in humans and, without treatment, will die after an interval ranging from weeks to a couple of months, with resolution of skin lesions. The diagnosis is made on clinical grounds. Skin biopsies only rarely detect diagnostic larvae. Symptoms can be alleviated by ivermectin or albendazole (Table 226-1).

ANGIOSTRONGYLIASIS

Angiostrongylus cantonensis, the rat lungworm, is the most common cause of human eosinophilic meningitis (Fig. 226-3).

Life Cycle and Epidemiology

This infection occurs principally in Southeast Asia and the Pacific Basin but has spread to other areas of the world, including the Caribbean islands, countries in Central and South America, and the southern United States. A. cantonensis larvae produced by adult worms in the rat lung migrate to the gastrointestinal tract and are expelled with the feces. They develop into infective larvae in land snails and slugs. Humans acquire the infection by ingesting raw infected mollusks; vegetables contaminated by mollusk slime; or crabs, freshwater shrimp, and certain marine fish that have themselves eaten infected mollusks. The larvae then migrate to the brain.

Pathogenesis and Clinical Features

The parasites eventually die in the CNS, but not before initiating pathologic consequences that, in heavy infections, can result in permanent neurologic sequelae or death. Migrating larvae cause marked local eosinophilic inflammation and hemorrhage, with subsequent necrosis and granuloma formation around dying worms. Clinical symptoms develop 2–35 days after the ingestion of larvae. Patients usually present with an insidious or abrupt excruciating frontal, occipital, or bitemporal headache. Neck stiffness, nausea and vomiting, and paresthesias are also common. Fever, cranial and extraocular nerve palsies, seizures, paralysis, and lethargy are uncommon.

Laboratory Findings

Examination of cerebrospinal fluid (CSF) is mandatory in suspected cases and usually reveals an elevated opening pressure, a white blood cell count of 150–2000/μL, and an eosinophilic pleocytosis of >20%. The protein concentration is usually elevated and the glucose level normal. The larvae of A. cantonensis are only rarely seen in CSF. Peripheral-blood eosinophilia may be mild. The diagnosis is generally based on the clinical presentation of eosinophilic meningitis together with a compatible epidemiologic history.

TREATMENT

GNATHOSTOMIASIS

Infection of human tissues with larvae of Gnathostoma spinigerum can cause eosinophilic meningoencephalitis, migratory cutaneous swellings, or invasive masses of the eye and visceral organs.

Life Cycle and Epidemiology

Human gnathostomiasis occurs in many countries and is notably endemic in Southeast Asia and parts of China and Japan. In nature, the mature adult worms parasitize the gastrointestinal tract of dogs and cats. First-stage larvae hatch from eggs passed into water and are ingested by Cyclops species (water fleas). Infective third-stage larvae develop in the flesh of many animal species (including fish, frogs, eels, snakes, chickens, and ducks) that have eaten either infected Cyclops or another infected second intermediate host. Humans typically acquire the infection by eating raw or undercooked fish or poultry. Raw fish dishes, such as som fak in Thailand and sashimi in Japan, account for many cases of human gnathostomiasis. Some cases in Thailand result from the local practice of applying frog or snake flesh as a poultice.

Pathogenesis and Clinical Features

Clinical symptoms are due to the aberrant migration of a single larva into cutaneous, visceral, neural, or ocular tissues. After invasion, larval migration may cause local inflammation, with pain, cough, or hematuria accompanied by fever and eosinophilia. Painful, itchy, migratory swellings may develop in the skin, particularly in the distal extremities or periorbital area. Cutaneous swellings usually last ~1 week, but often recur intermittently over many years. Larval invasion of the eye can provoke a sight-threatening inflammatory response. Invasion of the CNS results in eosinophilic meningitis with myeloencephalitis, a serious complication due to ascending larval migration along a large nerve tract. Patients characteristically present with agonizing radicular pain and paresthesias in the trunk or a limb, which are followed shortly by paraplegia. Cerebral involvement, with focal hemorrhages and tissue destruction, is often fatal.

Diagnosis and Treatment

Cutaneous migratory swellings with marked peripheral eosinophilia, supported by an appropriate geographic and dietary history, generally constitute an adequate basis for a clinical diagnosis of gnathostomiasis. However, patients may present with ocular or cerebrospinal involvement without antecedent cutaneous swellings. In the latter case, eosinophilic pleocytosis is demonstrable (usually along with hemorrhagic or xanthochromic CSF), but worms are almost never recovered from CSF. Surgical removal of the parasite from subcutaneous or ocular tissue, though rarely feasible, is both diagnostic and therapeutic. Albendazole or ivermectin may be helpful (Table 226-1). At present, cerebrospinal involvement is managed with supportive measures and generally with a course of glucocorticoids. Gnathostomiasis can be prevented by adequate cooking of fish and poultry in endemic areas.

FURTHER READING

INTRODUCTION

More than a billion persons worldwide are infected with one or more species of intestinal nematodes. Table 227-1 summarizes biologic and clinical features of infections due to the major intestinal parasitic nematodes. These parasites are most common in regions with poor fecal sanitation, particularly in resource-poor countries in the tropics and subtropics, but they have also been seen with increasing frequency among immigrants and refugees to resource-rich countries. Although nematode infections are not usually fatal, they contribute to malnutrition and diminished work capacity. It is interesting that these helminth infections may protect some individuals from allergic disease. Humans may on occasion be infected with nematode parasites that ordinarily infect animals; these zoonotic infections produce diseases such as trichostrongyliasis, anisakiasis, capillariasis, and abdominal angiostrongyliasis.

Intestinal nematodes are roundworms; they range in length from 1 mm to many centimeters when mature (Table 227-1). Their life cycles are complex and highly varied; some species, including Strongyloides stercoralis and Enterobius vermicularis, can be transmitted directly from person to person, while others, such as Ascaris lumbricoides, Necator americanus, and Ancylostoma duodenale, require a soil phase for development. Because most helminth parasites do not self-replicate, the acquisition of a heavy burden of adult worms requires repeated exposure to the parasite in its infectious stage, whether larva or egg. Hence, clinical disease, as opposed to asymptomatic (or subclinical) infection, generally develops only with prolonged exposure in an endemic area and is typically related to infection intensity. In persons with marginal nutrition, intestinal helminth infections may impair growth and development. Eosinophilia and elevated serum IgE levels are features of many helminth infections and, when unexplained, should always prompt a search for intestinal helminths. Significant protective immunity to intestinal nematodes appears not to develop in humans, although the host immune response to these infections has not been elucidated in detail.

ASCARIASIS

A. lumbricoides is the largest intestinal nematode parasite of humans, reaching up to 40 cm in length. Most infected individuals have low worm burdens and are asymptomatic. Clinical disease arises from larval migration in the lungs or effects of the adult worms in the intestines.

Life Cycle

Adult worms live in the lumen of the small intestine. Mature female Ascaris worms are extraordinarily fecund, each producing up to 240,000 eggs a day that pass with the feces. Ascarid eggs, which are remarkably resistant to environmental stresses, become infective after several weeks of maturation in the soil and can remain infective for years. After infective eggs are swallowed, larvae hatched in the intestine invade the mucosa, migrate through the circulation to the lungs, break into the alveoli, ascend the bronchial tree, and return—through swallowing—to the small intestine, where they develop into adult worms. Between 2 and 3 months elapse between initial infection and egg production. Adult worms live for 1–2 years.

Epidemiology

Ascaris is widely distributed in tropical and subtropical regions as well as in other humid areas in more temperate regions of the world. Transmission typically occurs through fecally contaminated soil and is due either to a lack of sanitary facilities or to the use of human feces as fertilizer. With their propensity for hand-to-mouth fecal carriage, younger children are most often affected. Infection outside endemic areas, though uncommon, can occur when eggs on transported vegetables are ingested.

Clinical Features

During the lung phase of larval migration, ~9–12 days after egg ingestion, patients may develop an irritating nonproductive cough and burning substernal discomfort that is aggravated by coughing or deep inspiration. Dyspnea and blood-tinged sputum are less common. Fever can occur. Eosinophilia develops during this symptomatic phase and subsides slowly over weeks. Chest x-rays may reveal evidence of eosinophilic pneumonitis (Löffler’s syndrome), with rounded infiltrates a few millimeters to several centimeters in size. These infiltrates may be transient and intermittent, clearing after several weeks. Where there is seasonal transmission of the parasite, seasonal pneumonitis with eosinophilia may develop in previously infected and sensitized hosts.

In established infections, adult worms in the small intestine usually cause no symptoms. In heavy infections, particularly in children, a large bolus of entangled worms can cause pain and small-bowel obstruction, sometimes complicated by perforation, intussusception, or volvulus. Single worms may cause disease when they migrate into aberrant sites. A large worm can enter and occlude the biliary tree, causing biliary colic, cholecystitis, cholangitis, pancreatitis, or (rarely) intrahepatic abscesses. Migration of an adult worm up the esophagus can provoke coughing and oral expulsion of the worm. In highly endemic areas, intestinal and biliary ascariasis can rival acute appendicitis and gallstones as causes of surgical acute abdomen.

Laboratory Findings

Most cases of ascariasis can be diagnosed by microscopic detection of characteristic Ascaris eggs (65 by 45 μm) in fecal samples, although increasingly polymerase chain reaction (PCR) of DNA extracted from stool is being used in research and some clinical settings. Occasionally, patients present after passing an adult worm—identifiable by its large size and smooth cream-colored surface—in the stool or, much less commonly, through the mouth or nose. During the early transpulmonary migratory phase, when eosinophilic pneumonitis occurs, larvae can be found in sputum or gastric aspirates before diagnostic eggs appear in the stool. The eosinophilia that is prominent during this early stage usually decreases to minimal levels in established infection. Adult worms may be visualized, occasionally serendipitously, on contrast studies of the gastrointestinal tract. A plain abdominal film may reveal masses of worms in gas-filled loops of bowel in patients with intestinal obstruction. Pancreaticobiliary worms can be detected by ultrasound and endoscopic retrograde cholangiopancreatography; the latter method also has been used to extract biliary Ascaris worms.

TREATMENT

HOOKWORM

Two species (A. duodenale and N. americanus) are responsible for most human hookworm infections, although A. ceylanicum is being recognized as a major hookworm pathogen in parts of Asia. Most infected individuals are asymptomatic. Hookworm disease develops from a combination of factors—a heavy worm burden, a prolonged duration of infection, and an inadequate iron intake—and results in iron-deficiency anemia and, on occasion, hypoproteinemia.

Life Cycle

Adult hookworms, which are ~1 cm long, use buccal teeth (Ancylostoma) or cutting plates (Necator) to attach to the small-bowel mucosa and suck blood (0.2 mL/d per Ancylostoma adult) and interstitial fluid. The adult hookworms produce thousands of eggs daily. The eggs are deposited with feces in soil, where rhabditiform larvae hatch and develop over a 1-week period into infectious filariform larvae. Infective larvae penetrate the skin and reach the lungs by way of the bloodstream. There they invade alveoli and ascend the airways before being swallowed and reaching the small intestine. The prepatent period from skin invasion to appearance of eggs in the feces is ~6–8 weeks, but it may be longer with A. duodenale. Larvae of A. duodenale, if swallowed, can survive and develop directly in the intestinal mucosa. Adult hookworms may survive over a decade but usually live ~6–8 years for A. duodenale and 2–5 years for N. americanus.

Epidemiology

A. duodenale is prevalent in southern Europe, North Africa, and northern Asia, and N. americanus is the predominant species in the Western Hemisphere and equatorial Africa. A. ceylanicum is most prevalent in Southeast Asia. The species can overlap geographically, particularly in Southeast Asia. Age prevalence studies have shown a constant increase in hookworm prevalence over time; older children have the greatest intensity of hookworm infection; however, in rural areas where fields are fertilized with human feces, older working adults also may be heavily infected.

Clinical Features

Most hookworm infections are clinically asymptomatic. Infective larvae may provoke pruritic maculopapular dermatitis (“ground itch”) at the site of skin penetration as well as serpiginous tracks of subcutaneous migration (similar to those of cutaneous larva migrans; Chap. 226) in previously sensitized hosts. Larvae migrating through the lungs occasionally cause mild transient pneumonitis, but this condition develops less frequently in hookworm infection than in ascariasis. In the early intestinal phase, infected persons may develop epigastric pain (often with postprandial accentuation), inflammatory diarrhea, or other abdominal symptoms accompanied by eosinophilia. The major consequence of chronic hookworm infection is iron deficiency. Symptoms are minimal if iron intake is adequate, but marginally nourished individuals develop symptoms of progressive iron-deficiency anemia and hypoproteinemia, including weakness and shortness of breath.

Laboratory Findings

The diagnosis is established by the finding of characteristic 40- by 60-μm oval hookworm eggs in the feces. Stool-concentration procedures may be required to detect light infections. Eggs of the three species are indistinguishable by light microscopy, whereas PCR has provided a significant improvement in species-specific diagnosis. In a stool sample that is not fresh, the eggs may have hatched to release rhabditiform larvae, which need to be differentiated from those of S. stercoralis. Hypochromic microcytic anemia, occasionally with eosinophilia or hypoalbuminemia, is characteristic of hookworm disease.

TREATMENT

Ancylostoma caninum and Ancylostoma braziliense

A. caninum, the canine hookworm, has been identified as a cause of human eosinophilic enteritis, especially in northeastern Australia. In this zoonotic infection, adult hookworms attach to the small intestine (where they may be visualized by endoscopy) and elicit abdominal pain and intense local eosinophilia. Treatment with mebendazole (100 mg twice daily for 3 days) or albendazole (400 mg once) or endoscopic removal is effective. Both of these animal hookworm species can cause cutaneous larva migrans (“creeping eruption”; Chap. 226).

STRONGYLOIDIASIS

S. stercoralis is distinguished by its ability—unique among helminths (except for Capillaria; see below)—to replicate in the human host. This capacity permits ongoing cycles of autoinfection as infective larvae are internally produced. Infection with S. stercoralis can thus persist for decades without further exposure of the host to exogenous infective larvae. In immunocompromised hosts, large numbers of invasive Strongyloides larvae can disseminate widely and can be fatal.

Life Cycle

In addition to a parasitic cycle of development, Strongyloides can undergo a free-living cycle of development in the soil (Fig. 227-1). This adaptability facilitates the parasite’s survival in the absence of mammalian hosts. Rhabditiform larvae passed in feces can transform into infectious filariform larvae either directly or after a free-living phase of development. Humans acquire S. stercoralis when filariform larvae in fecally contaminated soil penetrate the skin or mucous membranes. The larvae then travel through the bloodstream to the lungs, where they break into the alveolar spaces, ascend the bronchial tree, are swallowed, and thereby reach the small intestine. There the larvae mature into adult worms that penetrate the mucosa of the proximal small bowel. The minute (2-mm-long) parasitic adult female worms reproduce by parthenogenesis; adult males do not exist. Eggs hatch in the intestinal mucosa, releasing rhabditiform larvae that migrate to the lumen and pass with the feces into soil. Alternatively, rhabditiform larvae in the bowel can develop directly into filariform larvae that penetrate the colonic wall or perianal skin and enter the circulation to repeat the migration that establishes ongoing internal reinfection. This autoinfection cycle allows strongyloidiasis to persist for decades.

Epidemiology

S. stercoralis is spottily distributed in tropical areas and other hot, humid regions and is particularly common in Southeast Asia, sub-Saharan Africa, and Brazil. In the United States, the parasite is endemic in parts of the Southeast and is found in immigrants, refugees, travelers, and military personnel who have lived in endemic areas.

Clinical Features

In uncomplicated strongyloidiasis, many patients are asymptomatic or have mild cutaneous and/or abdominal symptoms. Recurrent urticaria, often involving the buttocks and wrists, is the most common cutaneous manifestation. Migrating larvae can elicit a pathognomonic serpiginous eruption, larva currens (“running larva”). This pruritic, raised, erythematous lesion advances as rapidly as 10 cm/h along the course of larval migration. Adult parasites burrow into the duodenojejunal mucosa and can cause abdominal (usually midepigastric) pain, which resembles peptic ulcer pain except that it is aggravated by food ingestion. Nausea, diarrhea, gastrointestinal bleeding, mild chronic colitis, and weight loss can occur. Small-bowel obstruction may develop with early, heavy infection. Pulmonary symptoms are rare in uncomplicated strongyloidiasis. Eosinophilia is common, with levels fluctuating over time.

The ongoing autoinfection cycle of S. stercoralis is normally constrained by unknown factors of the host’s immune system. Abrogation of host immunity, especially with glucocorticoid therapy and much less commonly with other immunosuppressive medications, leads to hyperinfection, with the generation of large numbers of filariform larvae. Colitis, enteritis, or malabsorption may develop. In disseminated strongyloidiasis, larvae may invade not only gastrointestinal tissues and the lungs but also the central nervous system, peritoneum, liver, and kidneys. Moreover, bacteremia may develop because of the passage of enteric flora through disrupted mucosal barriers. Gram-negative sepsis, pneumonia, or meningitis may complicate or dominate the clinical course. Eosinophilia is often absent in severely infected patients. Disseminated strongyloidiasis, particularly in patients with unsuspected infection who are given glucocorticoids, can be fatal. Strongyloidiasis is a frequent complication of infection with human T cell lymphotropic virus type 1 (HTLV-1), but disseminated strongyloidiasis is not common among patients infected with HIV-1.

Diagnosis

In uncomplicated strongyloidiasis, the finding of rhabditiform larvae in feces is diagnostic. Rhabditiform larvae are ~250 μm long, with a short buccal cavity that distinguishes them from hookworm larvae. In uncomplicated infections, few larvae are passed and single stool examinations detect only about one-third of cases. Serial examinations and the use of the agar plate detection method improve the sensitivity of stool diagnosis. Again, PCR has begun to be used more widely and provides increased diagnostic specificity. In uncomplicated strongyloidiasis (but not in hyperinfection), microscopy-based stool examinations may be repeatedly negative. Strongyloides larvae may also be found by sampling of the duodenojejunal contents by aspiration or biopsy. An enzyme-linked immunosorbent assay for serum antibodies to antigens of Strongyloides is a sensitive method for diagnosing uncomplicated infections. Such serologic testing should be performed for patients whose geographic histories indicate potential exposure, especially those who exhibit eosinophilia and/or are candidates for glucocorticoid treatment of other conditions. In disseminated strongyloidiasis, filariform larvae should be sought in stool as well as in samples obtained from sites of potential larval migration, including sputum, bronchoalveolar lavage fluid, or surgical drainage fluid.

TREATMENT

TRICHURIASIS

Most infections with Trichuris trichiura are asymptomatic, but heavy infections may cause gastrointestinal symptoms. Like the other soil-transmitted helminths, whipworm is distributed globally in the tropics and subtropics and is most common among poor children from resource-poor regions of the world.

Life Cycle

Adult Trichuris worms reside in the colon and cecum, the anterior portions threaded into the superficial mucosa. Thousands of eggs laid daily by adult female worms pass with the feces and mature in the soil. After ingestion, infective eggs hatch in the duodenum, releasing larvae that mature before migrating to the large bowel. The entire cycle takes ~3 months, and adult worms may live for several years.

Clinical Features

Tissue reactions to Trichuris are mild. Most infected individuals have no symptoms or eosinophilia. Heavy infections may result in anemia, abdominal pain, anorexia, and bloody or mucoid diarrhea resembling inflammatory bowel disease. Rectal prolapse can result from massive infections in children, who often suffer from malnourishment and other diarrheal illnesses. Moderately heavy Trichuris burdens also contribute to growth retardation.

Diagnosis and Treatment

The characteristic 50- by 20-μm lemon-shaped Trichuris eggs are readily detected on stool examination. Adult worms, which are 3–5 cm long, are occasionally seen on proctoscopy. Mebendazole (500 mg once) or albendazole (400 mg daily for 3 doses) is safe and moderately effective for treatment, with cure rates of 70–90%. Ivermectin (200 μg/kg daily for 3 doses) is also safe but is not quite as efficacious as the benzimidazoles.

ENTEROBIASIS (PINWORM)

E. vermicularis is more common in temperate countries than in the tropics. In the United States, ~40 million persons are infected with pinworms, with a disproportionate number of cases among children.

Life Cycle and Epidemiology

Enterobius adult worms are ~1 cm long and dwell in the cecum. Gravid female worms migrate nocturnally into the perianal region and release up to 2000 immature eggs each. The eggs become infective within hours and are transmitted by hand-to-mouth passage. From ingested eggs, larvae hatch and mature into adults. This life cycle takes ~1 month, and adult worms survive for ~2 months. Self-infection results from perianal scratching and transport of infective eggs on the hands or under the nails to the mouth. Because of the ease of person-to-person spread, pinworm infections are common among family members.

Clinical Features

Most pinworm infections are asymptomatic. Perianal pruritus is the cardinal symptom. The itching, which is often worse at night as a result of the nocturnal migration of the female worms, may lead to excoriation and bacterial superinfection. Heavy infections have been alleged to cause abdominal pain and weight loss. On rare occasions, pinworms invade the female genital tract, causing vulvovaginitis and pelvic or peritoneal granulomas. Eosinophilia is uncommon.

Diagnosis

Since pinworm eggs are not released in feces, the diagnosis cannot be made by conventional fecal ova and parasite tests. Instead, eggs are detected by the application of clear cellulose acetate tape to the perianal region in the morning. After the tape is transferred to a slide, microscopic examination will detect pinworm eggs, which are oval, measure 55 by 25 μm, and are flattened along one side.

TREATMENT

TRICHOSTRONGYLIASIS

Trichostrongylus species, which are normally parasites of herbivorous animals, occasionally infect humans, particularly in Asia and Africa. Humans acquire the infection by accidentally ingesting Trichostrongylus larvae on contaminated leafy vegetables. The larvae do not migrate in humans but mature directly into adult worms in the small bowel. These worms ingest far less blood than hookworms; most infected persons are asymptomatic, but heavy infections may give rise to mild anemia and eosinophilia. In stool examinations, Trichostrongylus eggs resemble hookworm eggs but are larger (85 by 115 μm). Treatment consists of mebendazole or albendazole (Chap. 217).

ANISAKIASIS

Anisakiasis is a gastrointestinal infection caused by the accidental ingestion in uncooked saltwater fish of nematode larvae belonging to the family Anisakidae. The incidence of anisakiasis in the United States has increased as a result of the growing popularity of raw fish dishes. Most cases occur in Japan, the Netherlands, and Chile, where raw fish—sashimi, pickled green herring, and ceviche, respectively—are national culinary staples. Anisakid nematodes parasitize large sea mammals such as whales, dolphins, and seals. As part of a complex parasitic life cycle involving marine food chains, infectious larvae migrate to the musculature of a variety of fish. Both Anisakis simplex and Pseudoterranova decipiens have been implicated in human anisakiasis, but an identical gastric syndrome may be caused by the red larvae of eustrongylid parasites of fish-eating birds.

When humans consume infected raw fish, live larvae may be coughed up within 48 h. Alternatively, larvae may immediately penetrate the mucosa of the stomach. Within hours, violent upper abdominal pain accompanied by nausea and occasionally vomiting ensues, mimicking an acute abdomen. The diagnosis can be established by direct visualization on upper endoscopy, outlining of the worm by contrast radiographic studies, or histopathologic examination of extracted tissue. Extraction of the burrowing larvae during endoscopy is curative. In addition, larvae may pass to the small bowel, where they penetrate the mucosa and provoke a vigorous eosinophilic granulomatous response. Symptoms may appear 1–2 weeks after the infective meal, with intermittent abdominal pain, diarrhea, nausea, and fever resembling the manifestations of Crohn’s disease. Ingestion of Anisakis-derived proteins through consumption of fish meat containing Anisakis parasites can elicit allergic gastrointestinal and even anaphylactic responses.

The diagnosis may be suggested by barium studies and confirmed by curative surgical resection of a granuloma in which the worm is embedded. Anisakid eggs are not found in the stool, since the larvae do not mature in humans. Serologic tests have been developed but are not widely available.

Anisakid larvae in saltwater fish are killed by cooking to 60°C, freezing at 20°C for 3 days, or commercial blast freezing, but usually not by salting, marinating, or cold smoking. No medical treatment is available; surgical or endoscopic removal should be undertaken.

CAPILLARIASIS

Intestinal capillariasis is caused by ingestion of raw fish infected with Capillaria philippinensis. Subsequent autoinfection can lead to a severe wasting syndrome. The disease occurs in the Philippines and Thailand and, on occasion, elsewhere in Asia. The natural cycle of C. philippinensis involves fish from fresh and brackish water. When humans eat infected raw fish, the larvae mature in the intestine into adult worms, which produce invasive larvae that cause intestinal inflammation and villus loss. Capillariasis has an insidious onset with nonspecific abdominal pain and watery diarrhea. If untreated, progressive autoinfection can lead to protein-losing enteropathy, severe malabsorption, and ultimately death from cachexia, cardiac failure, or superinfection. The diagnosis is established by identification of the characteristic peanut-shaped (20- by 40-μm) eggs on stool examination. Severely ill patients require hospitalization and supportive therapy in addition to prolonged anthelmintic treatment with albendazole (200 mg twice daily for 10 days; Chap. 217).

ABDOMINAL ANGIOSTRONGYLIASIS

Abdominal angiostrongyliasis is found in Latin America and Africa. The zoonotic parasite Angiostrongylus costaricensis causes eosinophilic ileocolitis after the ingestion of contaminated vegetation. A. costaricensis normally parasitizes the cotton rat and other rodents, with slugs and snails serving as intermediate hosts. Humans become infected by accidentally ingesting infective larvae in mollusk slime deposited on fruits and vegetables; children are at highest risk. The larvae penetrate the gut wall and migrate to the mesenteric artery, where they develop into adult worms. Eggs deposited in the gut wall provoke an intense eosinophilic granulomatous reaction, and adult worms may cause mesenteric arteritis, thrombosis, or frank bowel infarction. Symptoms may mimic those of appendicitis, including abdominal pain and tenderness, fever, vomiting, and a palpable mass in the right iliac fossa. Leukocytosis and eosinophilia are prominent. CT with contrast medium typically shows inflamed bowel, often with concomitant obstruction, but a definitive diagnosis is usually made surgically with partial bowel resection. Pathologic study reveals a thickened bowel wall with eosinophilic granulomas surrounding the Angiostrongylus eggs. In nonsurgical cases, the diagnosis rests solely on clinical grounds because larvae and eggs cannot be detected in the stool. Medical therapy for abdominal angiostrongyliasis is of uncertain efficacy. Careful observation and surgical resection for severe symptoms are the mainstays of treatment.

FURTHER READING

INTRODUCTION

Filarial worms are nematodes that dwell in the subcutaneous tissues and the lymphatics. Eight filarial species infect humans (Table 228-1); of these, four—Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa—are responsible for most serious filarial infections. Filarial parasites, which infect an estimated 170 million persons worldwide, are transmitted by specific species of mosquitoes or other arthropods and have a complex life cycle, including infective larval stages carried by insects and adult worms that reside in either lymphatic or subcutaneous tissues of humans. The offspring of adults are microfilariae, which, depending on their species, are 200–250 μm long and 5–7 μm wide, may or may not be enveloped in a loose sheath, and either circulate in the blood or migrate through the skin (Table 228-1). To complete the life cycle, microfilariae are ingested by the arthropod vector and develop over 1–2 weeks into new infective larvae. Adult worms live for many years, whereas microfilariae survive for 3–36 months. The bacterial endosymbiont Wolbachia has been found intracellularly in all stages of Brugia, Wuchereria, Mansonella, and Onchocerca species and has become a target for antifilarial chemotherapy.

Usually, infection is established only with repeated, prolonged exposures to infective larvae. Since the clinical manifestations of filarial diseases develop relatively slowly, these infections should be considered to induce chronic infections with possible long-term debilitating effects. In terms of the nature, severity, and timing of clinical manifestations, patients with filarial infections who are native to endemic areas and have lifelong exposure may differ significantly from those who are travelers or who have recently moved to these areas. Characteristically, filarial disease is more acute and intense in newly exposed individuals than in natives of endemic areas.

LYMPHATIC FILARIASIS

Lymphatic filariasis is caused by W. bancrofti, B. malayi, or Brugia timori. The threadlike adult parasites reside in afferent lymphatics or lymph nodes, where they may remain viable for more than two decades.

EPIDEMIOLOGY

W. bancrofti, the most widely distributed filarial parasite of humans, affects an estimated 110 million people and is found throughout the tropics and subtropics, including Asia and the Pacific Islands, Africa, areas of South America, and the Caribbean basin. Humans are the only definitive host for the parasite. Generally, the subperiodic form is found only in the Pacific Islands; elsewhere, W. bancrofti is nocturnally periodic. Nocturnally periodic forms of microfilariae are scarce in peripheral blood by day and increase at night, whereas subperiodic forms are present in peripheral blood at all times and reach maximal levels in the afternoon. Natural vectors for W. bancrofti are Culex mosquitoes in urban settings and Anopheles or Aedes mosquitoes in rural areas.

Brugian filariasis due to B. malayi occurs primarily in eastern India, Indonesia, Malaysia, and the Philippines. B. malayi also has two forms distinguished by the periodicity of microfilaremia. The more common nocturnal form is transmitted in areas of coastal rice fields, while the subperiodic form is found in forests. B. malayi naturally infects cats as well as humans. The distribution of B. timori is limited to the islands of southeastern Indonesia.

PATHOLOGY

The principal pathologic changes result from inflammatory damage to the lymphatics, which is typically caused by adult worms and not by microfilariae. Adult worms live in afferent lymphatics or sinuses of lymph nodes and cause lymphatic dilation and thickening of the vessel walls. The infiltration of plasma cells, eosinophils, and macrophages in and around the infected vessels, along with endothelial and connective tissue proliferation, leads to tortuosity of the lymphatics and damaged or incompetent lymph valves. Lymphedema and chronic stasis changes with hard or brawny edema develop in the overlying skin. These consequences of filarial infection are due both to the direct effects of the worms and to the host’s inflammatory response to the parasite. Inflammatory responses are believed to cause the granulomatous and proliferative processes that precede total lymphatic obstruction. It is thought that the lymphatic vessel remains patent as long as the worm remains viable and that the death of the worm leads to enhanced granulomatous reactions and fibrosis. Lymphatic obstruction results, and, despite collateralization, lymphatic function is compromised.

CLINICAL FEATURES

The most common presentations of the lymphatic filariases are asymptomatic (or subclinical) microfilaremia, hydrocele (Fig. 228-1), acute adenolymphangitis (ADL), and chronic lymphatic disease. In areas where W. bancrofti or B. malayi is endemic, the overwhelming majority of infected individuals have few overt clinical manifestations of filarial infection despite the presence of circulating microfilariae in the peripheral blood. Although they may be clinically asymptomatic, virtually all persons with W. bancrofti or B. malayi microfilaremia have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria, dilated (and tortuous) lymphatics (visualized by imaging), and—in men with W. bancrofti infection—scrotal lymphangiectasia (detectable by ultrasound). Despite these findings, the majority of individuals appear to remain clinically asymptomatic for years; in relatively few does the infection progress to either acute or chronic disease.

ADL is characterized by high fever, lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside. Regional lymph nodes are often enlarged, and the entire lymphatic channel can become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis can involve both the upper and lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection. This genital involvement can be manifested by funiculitis, epididymitis, and scrotal pain and tenderness. In endemic areas, another type of acute disease—dermatolymphangioadenitis (DLA)—is recognized as a syndrome that includes high fever, chills, myalgias, and headache. Edematous inflammatory plaques clearly demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation also may be noted. There is often a history of trauma, burns, irradiation, insect bites, punctiform lesions, or chemical injury. Entry lesions, especially in the interdigital area, are common. DLA is often diagnosed as cellulitis.

If lymphatic damage progresses, transient lymphedema can develop into lymphatic obstruction and the permanent changes associated with elephantiasis (Fig. 228-2). Brawny edema follows early pitting edema, the subcutaneous tissues thicken, and hyperkeratosis occurs. Fissuring of the skin develops, as do hyperplastic changes. Superinfection of these poorly vascularized tissues becomes a problem. In bancroftian filariasis, in which genital involvement is common, hydroceles may develop (Fig. 228-1); in advanced stages, this condition may evolve into scrotal lymphedema and scrotal elephantiasis. Furthermore, if there is obstruction of the retroperitoneal lymphatics, increased renal lymphatic pressure leads to rupture of the renal lymphatics and the development of chyluria, which is usually intermittent and most prominent in the morning.

The clinical manifestations of filarial infections in travelers or transmigrants who have recently entered an endemic region are distinctive. Given a sufficient number of bites by infected vectors, usually over a 3- to 6-month period, recently exposed patients can develop acute lymphatic or scrotal inflammation with or without urticaria and localized angioedema. Lymphadenitis of epitrochlear, axillary, femoral, or inguinal lymph nodes is often followed by evolving retrograde lymphangitis. Acute attacks are short-lived and are not usually accompanied by fever. With prolonged exposure to infected mosquitoes, these attacks, if untreated, become more severe and lead to permanent lymphatic inflammation and obstruction.

DIAGNOSIS

A definitive diagnosis can be made only by detection of the parasites and hence can be difficult. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Microfilariae can be found in blood, in hydrocele fluid, or (occasionally) in other body fluids. Such fluids can be examined microscopically, either directly or—for greater sensitivity—after concentration of the parasites by the passage of fluid through a polycarbonate cylindrical-pore filter (pore size, 3 μm) or by the centrifugation of fluid fixed in 2% formalin (Knott’s concentration technique). The timing of blood collection is critical and should be based on the periodicity of the microfilariae in the endemic region involved. Many infected individuals do not have microfilaremia, and definitive diagnosis in such cases can be difficult. Assays for circulating antigens of W. bancrofti permit the diagnosis of microfilaremic and cryptic (amicrofilaremic) infection. Two tests are commercially available: an enzyme-linked immunosorbent assay and a rapid-format immunochromatographic card test. Both assays have sensitivities of 93–100% and specificities approaching 100%. There are currently no tests for circulating antigens in brugian filariasis.

Polymerase chain reaction (PCR)–based assays for DNA of W. bancrofti and B. malayi in blood have been developed. A number of studies indicate that the sensitivity of this diagnostic method is equivalent to or greater than that of parasitologic methods.

In cases of suspected lymphatic filariasis, examination of the scrotum, the lymph nodes, or (in female patients) the breast by means of high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics. Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of men infected with W. bancrofti. Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the filarial dance sign). Radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaremic persons and those with clinical manifestations of lymphatic pathology. Although of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection; it is principally a research tool, although it has been used more widely for assessment of lymphedema of any cause. Eosinophilia and elevated serum concentrations of IgE and antifilarial antibody support the diagnosis of lymphatic filariasis. There is, however, extensive cross-reactivity between filarial antigens and antigens of other helminths. Of note, W. bancrofti– and B. malayi–specific antigens have been identified and are now available for use in rapid diagnostic tests with specificities of >98%. However, seropositivity cannot be equated with active infection: residents of endemic areas can become sensitized to filarial antigens through exposure to infective mosquitoes without having patent filarial infections.

The ADL associated with lymphatic filariasis must be distinguished from thrombophlebitis, infection, and trauma. Retrograde evolution is a characteristic feature that helps distinguish filarial lymphangitis from ascending bacterial lymphangitis. Chronic filarial lymphedema must also be distinguished from the lymphedema of malignancy, postoperative scarring, trauma, chronic edematous states, and congenital lymphatic system abnormalities.

TREATMENT

PREVENTION AND CONTROL

To protect themselves against filarial infection, individuals must avoid contact with infected mosquitoes by using personal protective measures, including bed nets, particularly those impregnated with insecticides such as permethrin. Mass drug administration (MDA) is the current approach to elimination of lymphatic filariasis as a public health problem. The underlying tenet of this approach is that mass annual distribution of antifilarial chemotherapy—albendazole with either DEC (for all areas except those where onchocerciasis is coendemic; see section on onchocerciasis treatment, below) or ivermectin or with both ivermectin and DEC (triple-drug therapy) will profoundly suppress microfilaremia. If the suppression is sustained, then transmission can be interrupted.

Created by the World Health Organization in 1997, the Global Programme to Eliminate Lymphatic Filariasis is based on mass administration of single annual doses of DEC plus albendazole in non-African regions and of albendazole plus ivermectin in Africa. Available information from late 2013 indicated that more than 792 million persons in 53 countries had thus far participated. Not only has lymphatic filariasis been eliminated in some defined areas, but collateral benefits—avoidance of disability and treatment of intestinal helminths and other conditions (e.g., scabies and louse infestation)—also have been noted. The strategy of the global program is being refined, and attempts are being made to integrate this effort with other mass-treatment strategies (e.g., deworming programs, malaria control, and trachoma control) in an integrated control strategy.

TROPICAL PULMONARY EOSINOPHILIA

Tropical pulmonary eosinophilia (TPE) is a distinct syndrome that develops in some individuals infected with the lymphatic-dwelling filarial species. The majority of cases have been reported from India, Pakistan, Sri Lanka, Brazil, Guyana, and Southeast Asia; the decreasing incidence of TPE in last decade probably reflects global MDA efforts.

CLINICAL FEATURES

The main features include a history of residence in filaria-endemic regions, paroxysmal cough and wheezing (usually nocturnal and probably related to the nocturnal periodicity of microfilariae), weight loss, low-grade fever, lymphadenopathy, and pronounced blood eosinophilia (>3000 eosinophils/μL). Chest x-rays or CT scans may be normal, but generally show increased bronchovascular markings. Diffuse miliary lesions or mottled opacities may be present in the middle and lower lung fields. Tests of pulmonary function show restrictive abnormalities in most cases and obstructive defects in half. Characteristically, total serum IgE levels (4–40 KIU/mL) and antifilarial antibody levels are markedly elevated.

PATHOLOGY

In TPE, microfilariae and parasite antigens are rapidly cleared from the bloodstream by the lungs. The clinical symptoms result from allergic and inflammatory reactions elicited by the cleared parasites. In some patients, trapping of microfilariae in other reticuloendothelial organs can cause hepatomegaly, splenomegaly, or lymphadenopathy. A prominent, eosinophil-enriched, intra-alveolar infiltrate is common, and with it comes the release of cytotoxic proinflammatory eosinophil granule proteins that may mediate some of the pathology seen in TPE. In the absence of successful treatment, interstitial fibrosis can lead to progressive pulmonary damage.

DIFFERENTIAL DIAGNOSIS

TPE must be distinguished from asthma, Löffler syndrome, allergic bronchopulmonary aspergillosis, allergic granulomatosis with polyangiitis (EGPA or Churg-Strauss syndrome), other systemic vasculitides (most notably, periarteritis nodosa), chronic eosinophilic pneumonia, and the hypereosinophilic syndromes (HESs).

TREATMENT

ONCHOCERCIASIS

EPIDEMIOLOGY

Onchocerciasis (“river blindness”) is caused by the filarial nematode O. volvulus, which infects an estimated 37 million individuals in 31 countries worldwide. The majority of individuals infected with O. volvulus live in the equatorial region of Africa extending from the Atlantic coast to the Red Sea. In the Americas, the only remaining countries with isolated foci are Venezuela and Brazil. The infection is also found in Yemen.

ETIOLOGY

Infection in humans begins with the deposition of infective larvae on the skin by the bite of an infected blackfly. The larvae develop into adults, which are typically found in subcutaneous nodules. About 7 months to 3 years after infection, the gravid female releases microfilariae that migrate out of the nodule and throughout the tissues, concentrating in the dermis. Infection is transmitted to other persons when a female fly ingests microfilariae from the host’s skin and these microfilariae then develop into infective larvae. Adult O. volvulus females and males are ~40–60 cm and ~3–6 cm in length, respectively. The life span of adults can be as long as 18 years, with an average of ~9 years. Because the blackfly vector breeds along free-flowing rivers and streams (particularly in rapids) and generally restricts its flight to an area within several kilometers of these breeding sites, both biting and disease transmission are most intense in these locations.

PATHOLOGY

Onchocerciasis primarily affects the skin, eyes, and lymph nodes. In contrast to the pathology in lymphatic filariasis, the damage in onchocerciasis is elicited by microfilariae and not by adult parasites. In the skin, there are mild but chronic inflammatory changes that can result in loss of elastic fibers, atrophy, and fibrosis. The subcutaneous nodules (onchocercomata) consist primarily of fibrous tissues surrounding the adult worm, often with a peripheral ring of inflammatory cells surrounded by an endothelial layer (characterized as lymphatic in origin). In the eye, neovascularization and corneal scarring lead to corneal opacities and blindness. Inflammation in the anterior and posterior chambers frequently results in anterior uveitis, chorioretinitis, and optic atrophy. Although punctate opacities are due to an inflammatory reaction surrounding dead or dying microfilariae, the pathogenesis of most manifestations of onchocerciasis is still unclear.

CLINICAL FEATURES

Skin

Pruritus and rash are the most common manifestations of onchocerciasis. The pruritus can be incapacitating; the rash is typically a papular eruption (Fig. 228-3) that is generalized rather than localized to a particular region of the body. Long-term infection results in exaggerated and premature wrinkling of the skin, loss of elastic fibers, and epidermal atrophy that can lead to loose, redundant skin and hypo- or hyperpigmentation. Localized eczematoid dermatitis can cause hyperkeratosis, scaling, and pigmentary changes. In an immunologically hyperreactive form of onchodermatitis (commonly termed sowdah or localized onchodermatitis), the affected skin darkens as a consequence of the profound inflammation that occurs as microfilariae in the skin are cleared.

Onchocercomata

These subcutaneous nodules, which can be palpable and/or visible, contain the adult worm. They are most common over the coccyx and sacrum, the trochanter of the femur, the lateral anterior crest, and other bony prominences. Nodules vary in size and characteristically are firm and not tender. It has been estimated that, for every palpable nodule, there are four deeper nonpalpable ones.

Ocular Tissue

Visual impairment is the most serious complication of onchocerciasis and usually affects only those persons with moderate or heavy infections. Lesions may develop in all parts of the eye. The most common early finding is conjunctivitis with photophobia. Punctate keratitis—acute inflammatory reactions surrounding dying microfilariae and manifested as “snowflake” opacities—is common among younger patients and resolves without apparent complications. Sclerosing keratitis occurs in 1–5% of infected persons and is the leading cause of onchocercal blindness. Anterior uveitis and iridocyclitis develop in ~5% of infected persons. Characteristic chorioretinal lesions develop as a result of atrophy and hyperpigmentation of the retinal pigment epithelium. Constriction of the visual fields and overt optic atrophy may occur.

Lymph Nodes

Mild to moderate lymphadenopathy is common, particularly in the inguinal and femoral areas, where the enlarged nodes may hang down in response to gravity (“hanging groin”), sometimes predisposing to inguinal and femoral hernias.

Other Manifestations

Some heavily infected individuals develop cachexia with loss of adipose tissue and muscle mass. A form of dwarfism, Nakalanga dwarfism, has been attributed to pituitary involvement in this infection. An association between onchocerciasis and epilepsy (including an epidemic form termed nodding syndrome) has gained attention recently. Among adults who become blind, there is a three- to fourfold increase in mortality rate.

DIAGNOSIS

Definitive diagnosis depends on the detection of an adult worm in an excised nodule or, more commonly, of microfilariae in a skin snip. Skin snips are obtained with a corneal-scleral punch or by lifting of the skin with the tip of a needle and excision of a small (1- to 3-mm) piece with a sterile scalpel blade. Both methods collect a blood-free skin biopsy sample extending to just below the epidermis. The biopsy tissue can be incubated in tissue culture medium or in saline on a glass slide or flat-bottomed microtiter plate. After incubation for 2–4 h (or occasionally overnight in light infections), microfilariae emergent from the skin can be seen by low-power microscopy or can be detected by PCR.

Eosinophilia and elevated serum IgE levels are common but, because these features are seen in many parasitic infections, are not diagnostic in themselves. Immunoassays to detect antibodies to Onchocerca-specific antigens are being used both in specialized laboratories and at the point of contact in rapid-diagnostic formats.

TREATMENT

PREVENTION

Vector control has been beneficial in highly endemic areas in which breeding sites are vulnerable to insecticide spraying, but most areas endemic for onchocerciasis are not suited to this type of control. Community-based administration of ivermectin every 6–12 months is being used to interrupt transmission in endemic areas. This measure, in conjunction with vector control, has already helped eliminate the infection in most of Latin America and has reduced the prevalence of disease in many endemic foci in Africa. No drug has proved useful for prophylaxis of O. volvulus infection.

LOIASIS

ETIOLOGY AND EPIDEMIOLOGY

Loiasis is caused by L. loa (the African eye worm), which is present in the rainforests of West and Central Africa. Adult parasites (females, 50–70 mm long and 0.5 mm wide; males, 25–35 mm long and 0.25 mm wide) live in subcutaneous tissues. Microfilariae circulate in the blood with a diurnal periodicity that peaks between 10:00 A.M. and 2:00 P.M.

CLINICAL FEATURES

Manifestations of loiasis in natives of endemic areas may differ from those in temporary residents or visitors. Among the indigenous population, loiasis is often an asymptomatic infection with microfilaremia. Infection may be recognized only after subconjunctival migration of an adult worm (Fig. 228-4) or may be manifested by episodic Calabar swellings—evanescent localized areas of angioedema and erythema developing on the extremities and less frequently at other sites. Nephropathy, encephalopathy, and cardiomyopathy can occur but are rare. In patients who are not residents of endemic areas, allergic symptoms predominate, episodes of Calabar swelling tend to be more frequent, microfilaremia is less common, and eosinophilia and increased levels of antifilarial antibodies are characteristic.

PATHOLOGY

The pathogenesis of the manifestations of loiasis is poorly understood. Calabar swellings are thought to result from a hypersensitivity reaction to adult worm antigens.

DIAGNOSIS

Definitive diagnosis of loiasis requires the detection of microfilariae in the peripheral blood or the isolation of the adult worm from the eye (Fig. 228-4) or from a subcutaneous biopsy specimen collected from a site of swelling developing after treatment. PCR-based assays for the detection of L. loa DNA in blood are available in specialized laboratories and are highly sensitive and specific, as are some newer recombinant antigen–based serologic techniques. In practice, the diagnosis must often be based on a characteristic history and clinical presentation, blood eosinophilia, and elevated levels of antifilarial antibodies, particularly in travelers to an endemic region, who are often amicrofilaremic.

TREATMENT

STREPTOCERCIASIS

Mansonella streptocerca, found mainly in the tropical forest belt of Africa from Ghana to the Democratic Republic of the Congo, is transmitted by biting midges. The major clinical manifestations involve the skin and include pruritus, papular rashes, and pigmentation changes. Many infected individuals have inguinal adenopathy, although most are asymptomatic. The diagnosis is made by detection of the characteristic microfilariae in skin snips. Ivermectin at a single dose of 150 μg/kg leads to sustained suppression of microfilariae in the skin and is probably the treatment of choice for streptocerciasis.

MANSONELLA PERSTANS INFECTION

M. perstans, distributed across the center of Africa and in northeastern South America, is transmitted by midges. Adult worms reside in serous cavities—pericardial, pleural, and peritoneal—as well as in the mesentery and the perirenal and retroperitoneal tissues. Microfilariae circulate in the blood without periodicity. The clinical and pathologic features of the infection are poorly defined. Most patients appear to be asymptomatic, but manifestations may include transient angioedema and pruritus of the arms, face, or other parts of the body (analogous to the Calabar swellings of loiasis); fever; headache; arthralgias; and right-upper-quadrant pain. Occasionally, pericarditis and hepatitis occur. The diagnosis is based on the demonstration of microfilariae in blood or serosal effusions. Perstans filariasis is often associated with peripheral-blood eosinophilia and antifilarial antibody elevations.

With the identification of a Wolbachia endosymbiont in M. perstans, doxycycline (200 mg twice a day) for 6 weeks has been established as the first effective treatment for this infection.

MANSONELLA OZZARDI INFECTION

The distribution of M. ozzardi is restricted to Central and South America and certain Caribbean islands. Adult worms are rarely recovered from humans. Microfilariae circulate in the blood without periodicity. Although this organism has often been considered nonpathogenic, headache, articular pain, fever, pulmonary symptoms, adenopathy, hepatomegaly, pruritus, and eosinophilia have been ascribed to M. ozzardi infection. The diagnosis is made by detection of microfilariae in peripheral blood. Ivermectin is effective in treating this infection.

ZOONOTIC FILARIAL INFECTIONS

Dirofilariae that affect primarily dogs, cats, and raccoons occasionally infect humans incidentally, as do Brugia and Onchocerca parasites that affect small mammals. Because humans are an abnormal host, the parasites never develop fully. Pulmonary dirofilarial infection caused by the canine heartworm Dirofilaria immitis generally presents in humans as a solitary pulmonary nodule. Chest pain, hemoptysis, and cough are uncommon. Infections with D. repens (from dogs) or D. tenuis (from raccoons) can cause local subcutaneous nodules in humans. Zoonotic Brugia infection can produce isolated lymph node enlargement, whereas zoonotic Onchocerca species (particularly O. lupi) can cause subconjunctival masses. Eosinophilia levels and antifilarial antibody titers are not commonly elevated. Excisional biopsy is both diagnostic and curative. These infections usually do not respond to antifilarial chemotherapy.

DRACUNCULIASIS (GUINEA WORM INFECTION)

ETIOLOGY AND EPIDEMIOLOGY

The incidence of dracunculiasis, caused by Dracunculus medinensis, has declined dramatically because of global eradication efforts. In 2017, only 30 cases worldwide were identified. The infection appears to be endemic only in Chad and Ethiopia.

Humans acquire D. medinensis when they ingest water containing infective larvae derived from Cyclops, a crustacean that is the intermediate host. Larvae penetrate the stomach or intestinal wall, mate, and mature. The adult male probably dies; the female worm develops over a year and migrates to subcutaneous tissues, usually in the lower extremity. As the thin female worm, ranging in length from 30 cm to 1 m, approaches the skin, a blister forms that, over days, breaks down and forms an ulcer. When the blister opens, large numbers of motile, rhabditiform larvae can be released into stagnant water; ingestion by Cyclops completes the life cycle.

CLINICAL FEATURES

Few or no clinical manifestations of dracunculiasis are evident until just before the blister forms, when there is an onset of fever and generalized allergic symptoms, including periorbital edema, wheezing, and urticaria. The emergence of the worm is associated with local pain and swelling. When the blister ruptures (usually as a result of immersion in water) and the adult worm releases larva-rich fluid, symptoms are relieved. The shallow ulcer surrounding the emerging adult worm heals over weeks to months. Such ulcers, however, can become secondarily infected, the result being cellulitis, local inflammation, abscess formation, or (uncommonly) tetanus. Occasionally, the adult worm does not emerge but becomes encapsulated and calcified.

DIAGNOSIS

The diagnosis is based on the findings developing with the emergence of the adult worm, as described above.

TREATMENT

PREVENTION

Prevention, which remains the only real control measure, depends on the provision of safe drinking water.

FURTHER READING

INTRODUCTION

Trematodes, or flatworms, are a group of helminths that belong to the phylum Platyhelminthes. The adult flatworms share some common characteristics, such as macroscopic size (from one to several centimeters); dorsoventrally flattened, bilaterally symmetric bodies; and two suckers—oral and ventral. Except for schistosomes, which have separate sexes, all human parasitic trematodes are hermaphroditic. Their life cycles involve a mammalian/human definitive host, in which sexual reproduction by adult worms takes place, and an intermediate host (snails), in which asexual multiplication occurs. Some species of trematodes have more than one intermediate host.

Humans are infected either by direct penetration of intact skin (schistosomiasis) or by ingestion of raw freshwater fish, crustaceans, or aquatic plants with metacercariae—the infective larval stage.

Significant trematode infections of humans may be divided according to the location of the adult worms: blood, liver (biliary tree), intestines, or lungs (Table 229-1). Adult worms do not multiply within the mammalian host but can live for up to 30 years. Infections are often chronic.

Although it is relatively rare to encounter patients with trematode infections in the United States, many millions of people are infected worldwide. Both schistosomiasis and food-borne trematode infections are poverty-related chronic diseases with high morbidity and a significant public health impact. Various factors may increase the spread of the infections globally. Increasing temperatures may render new areas suitable for the intermediate host snails, and an increase in travel and migration may increase the number of patients with trematode infections—for example, in the United States.

APPROACH TO THE PATIENT

SCHISTOSOMIASIS

Human schistosomiasis is caused by five species of the parasitic genus Schistosoma: S. mansoni, S. japonicum, S. mekongi, and S. intercalatum cause intestinal disease, and S. haematobium causes urogenital disease (Table 229-1). The infection may cause considerable intestinal, hepatic, and genitourinary morbidity. Avian schistosomes may penetrate human skin, but they die in subcutaneous tissue, producing only cutaneous manifestations.

ETIOLOGY

Schistosoma infection is contracted through contact with freshwater bodies harboring infected intermediate-host snails. Cercariae, the infective larval stage released from the snail, penetrate intact human skin within a few minutes after attaching to the skin. After penetration, the cercariae transform to schistosomula, which then enter a small vein or lymphatic vessel, circulate in the bloodstream through the lung capillaries, and are pumped via the heart to all parts of the body to reach the portal vein. There, the worms mature into adult males or females, pair, and migrate to their final location in the mesenteric or pelvic venous plexus.

The interval from cercarial penetration to sexual maturation and egg production, termed the prepatent period, lasts 5–7 weeks (up to 12 weeks for S. haematobium). The female worm then begins to produce eggs, which are excreted via feces or, for S. haematobium, urine. Approximately 50% of eggs are retained in tissue, where they are responsible for organ-specific morbidity (see “Pathogenesis,” below). When excreted eggs reach water, they hatch and release a free-swimming larval stage (miracidium), which, after penetrating a host snail, undergoes several rounds of asexual multiplication. After ~4–6 weeks, infective cercariae are shed from the infected snails into the water. One snail, infected by one miracidium, can shed thousands of cercariae per day for several months; thus the transmission potential of schistosomes is enormous.

The schistosome egg (Fig. 229-1) is the only stage of the parasites’ life cycle that can be detected in humans, either in excreta or in tissue biopsies. The eggs are large and can easily be distinguished morphologically from other helminth eggs. S. haematobium eggs are ~140 mm long, with a terminal spine; S. mansoni eggs are ~150 mm long, with a lateral spine; and S. japonicum eggs are smaller, rounder, and ~90 mm long, with a small lateral spine or knob.

Adult schistosomes are ~1–2 cm long. The male worm is flat, and the body forms a groove or gynecophoric canal in which the mature adult female is held like a sausage in a hotdog roll. Females are longer, thinner, and rounded. The females produce hundreds (African species) to thousands (Asian species) of eggs per day. Each ovum contains a ciliated miracidium larva, which secretes proteolytic enzymes that help the eggs to migrate into the lumen of the bladder (S. haematobium) or the intestine (other species). The lifespan of an adult schistosome averages 3–5 years but can be as long as 30 years. Schistosome worms feed on red blood cells; the debris is regurgitated in the host’s blood, where it can be detected as circulating antigens (see “Diagnosis,” below).

Adult schistosomes persist in the bloodstream for years and have evolved strategies of evading attack using immune effector mechanisms. This immune evasion is a result of several processes, such as binding of host proteins to the schistosome surface, which renders the parasite invisible to the host immune system.

The genome of schistosomes is relatively large (~270 Mb). Whole-genome sequences are available for S. mansoni, S. japonicum, and S. haematobium.

EPIDEMIOLOGY

Because of the complex life cycle of schistosomes, with snails as an intermediate host and humans as the final host, transmission is dependent on freshwater habitats that are suitable for the snails, are areas of human activity, and have climatic conditions favoring the survival of the snails and the development of the parasites inside the snail host. These requirements are reflected in the global distribution of schistosomiasis as well as in its microgeographic distribution within an endemic area. For S. mansoni, S. haematobium, and S. intercalatum, humans are the most important definitive host. S. japonicum and S. mekongi are zoonotic parasites, with a wide range of definitive hosts such as pigs, water buffaloes, and various rodents.

It is estimated that 230 million people are infected globally, with ~800 million people living in areas where there is a risk of infection (Fig. 229-2). More than 70% of infected people live in sub-Saharan Africa. Schistosomiasis is the most important of the neglected tropical diseases and is second only to malaria in public health impact. It is a poverty-related disease, and infection is prevalent in areas where adequate water supplies and sanitary facilities are lacking. In these areas, people come into contact with infested water through a variety of activities, including bathing, washing clothes, and collecting water for drinking or cooking. In some areas, adults have a high occupational risk of exposure; fishermen, canal cleaners, and workers in rice fields fall into this category. Among children, playing in water and swimming pose a risk. Large-scale irrigation and hydroelectric power operations can create suitable habitats for host snails and thus increase the risk of schistosomiasis transmission.

In general, children living in endemic areas initially acquire infection at ~3–4 years of age—i.e., when they are old enough to walk and come into contact with infested water. However, infection does occur in much younger children. As children grow older, the prevalence and intensity of infection increase, peaking around puberty. A characteristic feature of schistosomiasis infection in human populations is a convex age–prevalence curve, with low prevalence in very young children, higher prevalence in older children with a peak at 10–15 years of age, and declining prevalence in adults. The same pattern is observed between age and intensity of infection and is attributable to various factors. Generally, children have more frequent, prolonged, and extensive water contact than adults through activities like playing and swimming. Furthermore, several studies have indicated that acquired immunity to schistosomiasis develops slowly over several years, so that adults are reinfected to a much lesser extent than children. These factors, combined with progressive spontaneous death of adult worms from infections acquired during childhood, lead to lower levels of infection in the adult population.

PATHOGENESIS

Cercarial invasion may be associated with dermatitis arising from dermal and subdermal inflammatory reactions in response to dying cercariae that trigger innate immune responses. However, most manifestations of schistosomiasis—in the acute, established, and chronic phases of infection—are due to immunologic reactions to eggs retained in host tissues.

Around the time when oviposition commences, acute schistosomiasis (Katayama fever) may occur (see “Clinical Features,” below). Antigen excess from eggs results in the formation of soluble immune complexes, which may be deposited in several tissues and initiate a serum sickness–like illness. All evidence suggests that schistosome eggs, and not adult worms, induce the organ-specific morbidity caused by schistosome infections. Approximately half of the eggs are not excreted via feces or urine but are trapped in intestinal or hepatic tissue (S. mansoni, S. japonicum, and S. mekongi) or in the bladder and urogenital system (S. haematobium). The eggs induce a granulomatous host immune response composed primarily of lymphocytes, eosinophils, and alternatively activated macrophages. The lymphocytes produce various T_H2 cytokines such as interleukins 4, 5, and 13. Later, in the chronic phase of infection, regulatory cytokines are responsible for immunomodulation or downregulation of host responses to schistosome eggs and play an important role in reducing the size of granulomas.

When S. mansoni or S. japonicum eggs are swept into the small portal branches of the liver via the portal vein, they lodge in the presinusoidal periportal tissues. The formation of granulomas around the eggs can cause significant enlargement of the spleen and liver. High-intensity infections in children are often accompanied by hepatosplenomegaly that generally decreases over time, partly because the number of eggs being deposited in the tissue gradually declines after the early teenage years as partial immunity to new infections develops and partly because of immunologic downregulation of the granulomatous response. However, in some infected individuals, egg-induced granulomatous responses lead to severe periportal fibrosis (Symmers clay pipestem fibrosis), with deposition of collagen around the portal vein, occlusion of the smaller portal branches, and severe, often irreversible, pathology. Occlusion of the portal branches may result in marked portal hypertension.

The signs and symptoms of S. haematobium infection relate to the worms’ predilection for the veins of the urogenital plexus and result from deposition of eggs in the bladder, ureters, and genital organs. During established active infection, clusters of living eggs in the urogenital tissues can be found surrounded by intense inflammatory reactions and intense tissue eosinophilia. Movement of egg clusters into the lumen of the bladder is often followed by sloughing off of the epithelial surface, ulceration, and bleeding. Intense egg-induced tissue inflammation can result in bladder wall thickening and development of masses and pseudopolyps. Inflammation and granuloma formation around the ureteral ostia can lead to hydronephrosis.

Generally, late chronic-stage infections are characterized by accumulation of dead calcified eggs in tissue. Characteristic cervical lesions are found in S. haematobium infections, including active-stage lesions with intense tissue inflammation around live eggs and chronic-stage sandy patches with clusters of calcified eggs.

CLINICAL FEATURES

In general, disease manifestations of schistosomiasis occur in three stages—acute, active, and chronic—according to the duration and intensity of infection.

Cercarial Dermatitis (“Swimmer’s Itch”)

Cercarial penetration of the skin may result in a maculopapular rash called cercarial dermatitis or “swimmer’s itch.” Cercarial dermatitis can develop in people who have not previously been exposed to schistosomiasis (e.g., travelers), whereas it is rare among people living in endemic areas. A particularly severe form of cercarial dermatitis is commonly seen after exposure to cercariae from avian schistosomes. These cercariae cannot complete their development in humans and die in the skin, causing an inflammatory allergic reaction. This form of cercarial dermatitis can occur in people who have been in contact with water from lakes (e.g., in Europe or the United States) where various species of water birds, such as ducks, geese, and swans, are found. The rash may last for 1–2 weeks. This condition normally requires no treatment, but systemic antihistamines or topical antihistamines or glucocorticoids can be used to reduce symptoms.

Acute Schistosomiasis (Katayama Fever)

Symptomatic acute schistosomiasis, also known as Katayama fever or Katayama syndrome, is usually seen in travelers who have contracted the infection for the first time. The onset occurs between 2 weeks and 3 months after exposure to the parasite. The symptoms may appear suddenly and include fever, myalgia, general malaise and fatigue, headache, nonproductive cough, and intestinal symptoms such as abdominal tenderness or pain. Various combinations of these symptoms are often accompanied by eosinophilia and transient pulmonary infiltrates. Many patients recover spontaneously from acute schistosomiasis after 2–10 weeks, but the illness follows a more severe clinical course in some individuals, with weight loss, dyspnea, diarrhea, and hepatomegaly. Severe cerebral or spinal cord manifestations may occur, and even light infections may cause severe illness. The syndrome can, in rare cases, be fatal.

Differential diagnosis includes many other febrile infectious diseases with acute onset, including malaria, salmonellosis, and acute hepatitis. Fever and eosinophilia occur in trichinosis, tropical eosinophilia, invasive ankylostomiasis, strongyloidiasis, visceral larva migrans, and infections with Opisthorchis and Clonorchis species. Katayama fever is rare in people chronically exposed to infection in areas endemic for S. mansoni or S. haematobium.

Intestinal Schistosomiasis (S. mansoni, S. japonicum, S. mekongi)

In intestinal schistosomiasis, adult worms are located in the mesenteric veins, and disease manifestations are associated with parasite eggs passing through or becoming trapped in intestinal tissue. This event induces mucosal granulomatous inflammation with microulcerations, superficial bleeding, and sometimes pseudopolyposis. The symptoms tend to be more pronounced with a high intensity of infection and include intermittent abdominal pain, loss of appetite, and sometimes bloody diarrhea. The clinical manifestations of S. intercalatum and S. mekongi infection are generally milder.

Hepatosplenic Schistosomiasis

Hepatosplenic schistosomiasis is caused by schistosome eggs trapped in liver tissue and occurs in S. mansoni and S. japonicum infections. There are two distinct clinical entities: early inflammatory hepatosplenomegaly and late hepatosplenic disease with periportal fibrosis.

Early inflammatory hepatosplenic schistosomiasis is the main entity seen in children and adolescents. The liver is enlarged, especially the left lobe, and is smooth and firm. The spleen is enlarged, often extending below the umbilicus, and is firm or hard. Generally, ultrasonography shows no hepatic fibrosis. This form of hepatosplenic schistosomiasis may be found in up to 80% of infected children. Its severity is closely associated with the intensity of infection and may also be associated with concomitant chronic exposure to malaria.

Late hepatosplenic schistosomiasis with periportal or Symmers fibrosis may develop in young and middle-aged adults with long-standing, high-level exposure to infection. Patients with periportal fibrosis may excrete very few or no eggs in feces. During the early stage, the liver is enlarged, especially the left lobe; it is smooth and firm or hard. The spleen is enlarged, often massively, and is firm or hard. The patient may report a left hypochondrial mass with discomfort and anorexia. Ultrasonography reveals typical periportal fibrosis and dilation of the portal vein. Other complications include delayed growth and puberty, especially in S. japonicum infections, and severe anemia. Severe hepatosplenic schistosomiasis may lead to portal hypertension, but hepatic function usually remains normal, even in cases with marked periportal fibrosis and portal hypertension.

Ascites, attributable both to portal hypertension and to hypoalbuminemia, may be seen, especially in S. japonicum infection. Patients with severe hepatosplenic disease and portal hypertension may develop esophageal varices detectable by endoscopy or ultrasound. These patients may experience repeated bouts of hematemesis, melena, or both. Hematemesis is the most severe complication of hepatosplenic schistosomiasis, and death may result from massive loss of blood.

Urogenital Schistosomiasis (S. haematobium)

The signs and symptoms of S. haematobium infection relate to the worms’ predilection for the veins of the urogenital tract. Two stages of infection are recognized. An active stage occurring mainly in children, adolescents, and younger adults is characterized by egg excretion in the urine, with proteinuria and macroscopic or microscopic hematuria and deposition of eggs in the urinary tract. A chronic stage in older individuals is characterized by sparse or no urinary egg excretion despite urogenital tract pathology.

A characteristic sign in the active stage is painless, terminal hematuria. Dysuria and suprapubic discomfort or pain are associated with active urogenital schistosomiasis and may persist throughout the course of active infection. Eggs deposited in the bladder mucosa may give rise to an intense inflammatory response of the bladder wall, which may cause ureteric obstruction and lead to hydroureter and hydronephrosis. These early inflammatory lesions, including obstructive uropathy, can be visualized by ultrasonography.

As the infection progresses, the inflammatory component decreases and fibrosis becomes more prominent. The symptoms at this stage are nocturia, urine retention, dribbling, and incontinence. Cystoscopy reveals “sandy patches” composed of large numbers of calcified eggs surrounded by fibrous tissue and an atrophic mucosal surface. The ureters are less commonly involved, but ureteral fibrosis can cause irreversible obstructive uropathy that can progress to uremia.

Egg deposition may cause granulomas and lesions in the genital organs, most commonly in the cervix and vagina in women and the seminal vessels in men. The results may include dyspareunia, abnormal vaginal discharge, contact bleeding, and lower back pain in women and perineal pain, painful ejaculation, and hematospermia in men. Genital symptoms like bloody discharge and genital itch are associated with S. haematobium infection in school-aged girls living in schistosomiasis-endemic areas. Symptoms such as hematospermia and perineal discomfort have been described in travelers, and eggs have been demonstrated in seminal fluid. An association between female genital schistosomiasis and HIV infection has been demonstrated, but the impact of genital schistosomiasis on HIV transmission needs further elucidation.

S. haematobium has been classified by the International Agency for Research on Cancer (IARC) as definitely carcinogenic to humans (i.e., a group 1 carcinogen). Chronic S. haematobium infection is associated with squamous cell carcinoma of the urinary bladder.

Other Manifestations

Worms and eggs can sometimes be located in ectopic sites, causing site-specific manifestations and symptoms. Neuroschistosomiasis is one of the most severe clinical forms of schistosomiasis and is caused by the inflammatory response around eggs in the cerebral or spinal venous plexus. S. mansoni and S. haematobium worms can end up in the spinal venous plexus, where they may cause transverse myelitis—an acute complication sometimes seen in travelers returning home with schistosomiasis. S. japonicum is mainly associated with granulomatous lesions in the brain, causing epileptic seizures, encephalopathy with headache, visual impairment, motor deficit, and ataxia. Pulmonary schistosomiasis is caused by portacaval shunting of eggs into the lung capillaries, where they induce granulomas in the perialveolar area. The consequences may be fibrosis, pulmonary hypertension, and cor pulmonale.

DIAGNOSIS

Anamnestic information on recent travels to endemic areas and exposure to freshwater bodies through recreational or other activities is important in the diagnosis of schistosomiasis in travelers. Information about exact geographic locations can facilitate identification of the relevant species of Schistosoma. Eosinophilia is a common finding and is often associated with helminthic infections such as schistosomiasis.

Detection of schistosome eggs in stool or urine is indicative of active infection and is the standard diagnostic method. The diagnosis is often based on the detection of eggs in a fixed small amount of excreta—e.g., 50 mg of stool or filtration of 10 mL of urine. This method is widely used among populations in endemic areas and allows quantitation of the level of infection (eggs per gram of feces or per 10 mL of urine). However, levels of egg excretion in people from nonendemic areas may be very low, in which case a larger sample and concentration methods (e.g., formol-ether concentration) may be needed.

Eggs can also be detected in rectal biopsies (both S. mansoni and S. haematobium) and occasionally in Pap smears and semen samples (S. haematobium). Polymerase chain reaction (PCR)–based detection of parasite DNA in stool or urine is more sensitive than parasitologic methods and is increasingly used. Schistosoma DNA can be detected in cerebrospinal fluid samples for diagnosis of neuroschistosomiasis.

Serology, with detection of specific antibodies to schistosomes, is useful in travelers but less so in people from endemic areas where transmission is ongoing. The serologic assays employed at the CDC are a Falcon assay screening test/enzyme-linked immunosorbent assay (FAST-ELISA) using S. mansoni adult microsomal antigen and a confirmatory species-specific immunoblot assay performed in light of the patient’s travel history.

Schistosome proteoglycans—circulating anodic and cathodic antigens (CAAs and CCAs)—regurgitated into the bloodstream by the feeding worms can be detected in serum and urine by ELISA or monoclonal antibody–based lateral flow assays. The presence of CAA or CCA is an indication of active infection, and levels of these antigens correlate well with the intensity of infection. However, detection of CAAs and CCAs is not currently suitable for diagnosis in travelers, who are likely to have low levels of infection and very few worms. A commercially available point-of-care assay (Rapid Medical Diagnostics, Pretoria, South Africa) that detects CCA in urine is now widely used for screening of infected communities in relation to mass drug administration programs.

TREATMENT

PREVENTION AND CONTROL

Schistosomiasis is contracted through direct contact with infested freshwater. Travelers should be made aware of the risk of infection if they come into contact with freshwater sources in schistosomiasis-endemic areas. For people living in rural areas where schistosomiasis is endemic, it may be very difficult, if not impossible, to avoid water contact—for example, during occupational activities such as fishing and working in rice fields. Schistosomiasis is a poverty-related disease, and access to safe water and good sanitary facilities may rarely be available. Because S. japonicum is a zoonotic parasite, preventive measures should target not only the human population but also animals such as water buffalo, which act as reservoirs for infection.

Praziquantel treatment of infected people, often during mass drug-administration programs, is a cornerstone of the management and control of schistosomiasis. Regular treatment will reduce the level of schistosomiasis morbidity in affected populations. However, treatment should be combined with other relevant strategies, such as control of the intermediate host snails, improved water-quality and sanitation facilities, and health education. Schistosomiasis control measures should be integrated into local health programs.

There have been intensive efforts to develop vaccines, but none is yet available. One vaccine candidate, S. haematobium 28GST, has been tested in a clinical phase 3 trial in populations living in an endemic area.

FOOD-BORNE TREMATODE INFECTIONS

Food-borne trematode infections are a group of zoonotic diseases caused by hepatic, intestinal, and pulmonary parasitic flukes. These infections are contracted by ingestion of infective parasites in undercooked aquatic food or water plants. In 2005, an estimated 56.2 million people were infected with food-borne trematodes and 7.9 million had severe sequelae of these infections.

LIVER FLUKES

The most important liver flukes causing human infections are the related species Opisthorchis viverrini and Opisthorchis felineus, which cause opisthorchiasis; Clonorchis sinensis, which causes clonorchiasis; and Fasciola hepatica and Fasciola gigantica, which cause fascioliasis (Table 229-1).

Opisthorchiasis and Clonorchiasis

O. viverrini is found mainly in northeastern Thailand, Laos, and Cambodia; O. felineus mainly in Europe and Asia, including the former Soviet Union; and C. sinensis in Asia, including Korea, China, Taiwan, Vietnam, Japan, and Asian regions of Russia. Parasite eggs excreted from infected humans or animals are ingested by a host snail (the first intermediate host), where they undergo several developmental stages. Cercariae are then released from the snail and penetrate freshwater fish (the second intermediate host), encysting as metacercariae in the muscles or under the scales. Humans become infected by eating raw or undercooked fish from endemic countries. After ingestion, the metacercariae excyst in gastric juices and migrate via the duodenum, the ampulla of Vater, and the extrahepatic biliary system to the intrahepatic bile ducts.

The clinical manifestations of infection with Opisthorchis species and C. sinensis are similar. Pathologic changes are typically seen in the bile ducts, liver, and gallbladder (Table 229-3). Tissue damage and intense inflammation is caused by mechanical and chemical irritation and immune responses to worms or worm products, and chronic inflammation may result in the development of cholangiocarcinoma. Both O. viverrini and C. sinensis are classified by the IARC as definitely carcinogenic (class 1). Acute and light infections are mostly asymptomatic, but hepatitis-like signs and symptoms, with high fever and chills, have been reported, especially in O. felineus infections. In general, only heavily infected people have symptoms and severe complications (Table 229-3).

The diagnosis of these infections is based on microscopic identification of parasite eggs in stool specimens. The eggs of Opisthorchis are indistinguishable from those of Clonorchis.

Fascioliasis

Fascioliasis occurs in many areas of the world and usually is caused by Fasciola hepatica, a common liver fluke of sheep and cattle. F. hepatica is found in more than 50 countries on all continents except Antarctica; F. gigantica is less widespread. The areas with the highest known rates of human Fasciola infection are in the Andean highlands of Bolivia and Peru. In other areas where fascioliasis is found, human cases are sporadic.

Unlike the other liver flukes, Fasciola species have no second intermediate host, as their infectious metacercariae adhere directly to aquatic plants. Humans usually acquire infection by ingesting aquatic plants, such as watercress, that contain viable metacercariae or by drinking water with free metacercariae.

After metacercariae have excysted in the duodenum, Fasciola species migrate through the intestinal wall into the body cavity, penetrate the liver capsule, and move through the liver into the bile ducts. This migration route is different from that of other liver flukes and gives rise to symptoms during the acute migratory phase; the parasites may cause tissue destruction, focal bleeding, and inflammation. Some migrating flukes may deviate from their usual route to cause ectopic infections. In the established latent stage of infection, the parasites may cause bile duct inflammation, resulting in thickening and expansion of the ducts, fibrosis, and ultimately biliary obstruction (Table 229-3). Although some infected people are asymptomatic in the latent phase, others may experience repeated relapses of acute manifestations.

The most widely used diagnostic approach is direct detection of Fasciola eggs by microscopic examination of stool or of duodenal or biliary aspirates. Eggs generally cannot be detected until 3–4 months after exposure, whereas antibodies to the parasite may become detectable 2–4 weeks after exposure. More than one stool specimen may be needed for diagnosis, especially in light infections.

INTESTINAL FLUKES

More than 70 species of intestinal flukes can cause human infection. These parasites are found in different geographic areas, with a relatively high prevalence in Southeast Asia. Humans are infected by ingestion of infective metacercariae attached to aquatic plants (Fasciolopsis buski) or encysted in freshwater fish. Flukes mature in the human intestines, and eggs are passed with feces. Mechanical irritation of the intestinal wall and inflammation may lead to nonspecific gastrointestinal symptoms such as diarrhea, constipation, and abdominal pain. Most individuals infected with intestinal flukes are asymptomatic, but heavy infections can be severe, with intestinal mucosal ulcerations and malabsorption (Table 229-3). The diagnosis is established by detection of eggs in stool samples. However, eggs from various intestinal trematodes are often morphologically similar, and it is very difficult to distinguish among species. A cautionary note: Fasciola eggs can be difficult to distinguish on the basis of morphologic criteria from the eggs of the intestinal fluke F. buski. The distinction has implications for therapy: infection with F. buski is treated with praziquantel, which is not effective against fascioliasis (Table 229-2).

LUNG FLUKES

Paragonimiasis is a parasitic lung infection caused by lung flukes of the genus Paragonimus. It is a food-borne parasitic zoonosis, with most cases reported from Asia and attributable to consumption of raw or undercooked freshwater crustaceans. Paragonimus westermani and related species (e.g., Paragonimus africanus) are endemic in West Africa, Central and South America, and Asia. The United States has one indigenous species of lung fluke, Paragonimus kellicotti.

Paragonimus species require two intermediate hosts: first, a freshwater snail; and second, a freshwater crustacean, such as a freshwater crab. Humans are infected by consuming raw or undercooked infected crustaceans containing Paragonimus metacercariae. Paragonimus infects other carnivores such as cats, dogs, foxes, rodents, and pigs in addition to humans. After ingestion, metacercariae quickly penetrate the duodenum and traverse the peritoneal cavity, diaphragm, and parietal pleura to mature into hermaphroditic worm pairs in the pleural spaces or lungs within 6–10 weeks. Adults cross-fertilize in cystic cavities in the pleural spaces or lungs within another 4–16 weeks and release unembryonated eggs into bronchioles. The eggs are then coughed up in bloody (“rusty”) sputum and either discharged in sputum or swallowed and later excreted in feces. Unembryonated eggs are passed from the mammalian host into freshwater ecosystems, where they infect intermediate host snails.

The symptoms and signs of paragonimiasis are fever, cough, hemoptysis, and peripheral eosinophilia. Some patients with paragonimiasis and low parasite burdens may remain relatively asymptomatic for prolonged periods or may have recurrent attacks of cough, sputum production, fever, and night sweats that mimic tuberculosis. Infective metacercariae may migrate to extrapulmonary sites such as the brain (cerebral paragonimiasis).

Pulmonary paragonimiasis is diagnosed by detection of parasite ova in sputum and/or feces. Serology can be helpful in egg-negative cases and in cerebral paragonimiasis. Anamnestic information about the consumption of raw or undercooked freshwater crabs by immigrants, expatriates, and returning travelers—and, in the United States, the consumption of raw or undercooked crayfish from freshwater river systems where P. kellicotti is endemic—is important in patients presenting with fever, cough, hemoptysis, pleural effusions, and peripheral eosinophilia.

TREATMENT

CONTROL AND PREVENTION

Drugs are currently the main method of controlling the morbidity associated with food-borne trematode infections, but integrated programs (including improved sanitation; food inspections; and information, education, and communication campaigns) are important for sustainable disease control. Collaboration with other sectors (e.g., agricultural, environmental, and educational) is necessary to tackle highly complex situations in which human behavior, biological factors, and agricultural practices all play a role.

FURTHER READING

Additional Online References

INTRODUCTION

Cestodes, or tapeworms, are segmented worms. The adults reside in the gastrointestinal tract, but the larvae can be found in almost any organ. Human tapeworm infections can be divided into two major clinical groups. In one group, humans are the definitive hosts, with the adult tapeworms living in the gastrointestinal tract (Taenia saginata, Diphyllobothrium, and Dipylidium caninum). In the other, humans are intermediate hosts, with larval-stage parasites present in the tissues; diseases in this category include echinococcosis, sparganosis, and coenurosis. Humans may be the definitive and/or intermediate hosts for Taenia solium; both stages of Hymenolepis nana are found simultaneously in the human intestines.

The ribbon-shaped tapeworm attaches to the intestinal mucosa by means of sucking cups or hooks located on the scolex. Behind the scolex is a short, narrow neck from which proglottids (segments) form. As each proglottid matures, it is displaced further back from the neck by the formation of new, less mature segments. The progressively elongating chain of attached proglottids, called the strobila, constitutes the bulk of the tapeworm. The length varies among species. In some, the tapeworm may consist of more than 1000 proglottids and may be several meters long. The mature proglottids are hermaphroditic and produce eggs, which are subsequently released. Because eggs of the different Taenia species are morphologically identical, differences in the morphology of the scolex or proglottids provide the basis for diagnostic identification to the species level.

Most human tapeworms require at least one intermediate host for complete larval development. After ingestion of the eggs or proglottids by an intermediate host, the larval oncospheres are activated, escape the egg, and penetrate the intestinal mucosa. The oncosphere migrates to tissues and develops into an encysted form known as a cysticercus (single scolex), a coenurus (multiple scolices), or a hydatid (cyst with daughter cysts, each containing several protoscolices). The definitive host’s ingestion of tissues containing a cyst enables a scolex to develop into a tapeworm.

TAENIASIS SAGINATA AND TAENIASIS ASIATICA

The beef tapeworm T. saginata occurs in all countries where raw or undercooked beef is eaten. It is most prevalent in sub-Saharan African and Middle Eastern countries. Taenia asiatica is closely related to T. saginata and is found in Asia, with pigs as intermediate hosts. The clinical manifestations and morphology of these two species are very similar and are therefore discussed together.

Etiology and Pathogenesis

Humans are the only definitive host for the adult stage of T. saginata and T. asiatica. The tapeworms, which can reach 8 m in length with 1000–2000 proglottids, inhabit the upper jejunum. The scolex of T. saginata has four prominent suckers, whereas T. asiatica has an unarmed rostellum. Each gravid segment has 15–30 uterine branches (in contrast to 8–12 for T. solium). The eggs are indistinguishable from those of T. solium; they measure 30–40 μm, contain the oncosphere, and have a thick brown striated shell. Eggs deposited on vegetation can live for months or years until they are ingested by cattle or other herbivores (T. saginata) or pigs (T. asiatica). The embryo released after ingestion invades the intestinal wall and is carried to striated muscle or viscera, where it transforms into the cysticercus. When ingested in raw or undercooked meat, the cysticercus evaginates and forms a tapeworm in the human intestines. Over ~2 months, the adult worm matures and begins to produce eggs.

Clinical Manifestations

Patients become aware of the infection most commonly by noting passage of proglottids in their feces. The proglottids of T. saginata are motile, and patients may experience perianal discomfort when proglottids are discharged. Mild abdominal pain or discomfort, nausea, change in appetite, weakness, and weight loss can occur.

Diagnosis

The diagnosis is made by the detection of eggs or proglottids in the stool. Eggs may also be present in the perianal area; thus, if proglottids or eggs are not found in the stool, the perianal region should be examined with use of a cellophane-tape swab (as in pinworm infection; Chap. 227). Distinguishing T. saginata or T. asiatica from T. solium requires examination of mature proglottids. All three species can be distinguished by examining the scolex. Available serologic tests are not helpful diagnostically. Eosinophilia and elevated levels of serum IgE are usually absent.

TREATMENT

Prevention

The major method of preventing infection is the adequate cooking of beef or pork viscera; exposure to temperatures as low as 56°C for 5 min will destroy cysticerci. Refrigeration or salting for long periods or freezing at –10°C for 9 days also kills cysticerci in beef. General preventive measures include inspection of beef and proper disposal of human feces.

TAENIASIS SOLIUM AND CYSTICERCOSIS

The pork tapeworm T. solium can cause two distinct forms of infection in humans: adult tapeworms in the intestine or larval forms in the tissues (cysticercosis). Humans are the only definitive hosts for T. solium; pigs are the usual intermediate hosts, although other animals may harbor the larval forms.

T. solium is found worldwide in areas where pigs are raised and have access to human feces. However, it is most prevalent in Latin America, sub-Saharan Africa, China, India, and Southeast Asia. Cysticercosis occurs in industrialized nations largely as a result of the immigration of infected persons from endemic areas.

Etiology and Pathogenesis

The adult tapeworm generally resides in the upper jejunum. The scolex attaches by both sucking disks and two rows of hooklets. The adult worm usually lives for a few years. The mature tapeworm, usually ~3 m in length, may have as many as 1000 proglottids, each of which produces up to 50,000 eggs. Proglottids are released and excreted into the feces, and the eggs in these proglottids are infective for both humans and animals. After ingestion of eggs by the pig intermediate host, the larvae are activated, escape the egg, penetrate the intestinal wall, and are carried to many tissues; they are most frequently identified in striated muscle of the neck, tongue, and trunk. Within 60–90 days, the encysted larval stage develops. These cysticerci can survive for months to years. By ingesting undercooked pork containing cysticerci, humans acquire infections that lead to intestinal tapeworms. Infections that cause human cysticercosis follow the ingestion of T. solium eggs. The eggs are sticky and may be found under the fingernails of tapeworm carriers. Transmission is usually associated with close contact with a tapeworm carrier. Autoinfection may occur if an individual with an egg-producing tapeworm ingests eggs derived from his or her own feces.

Clinical Manifestations

Intestinal infections with T. solium may be asymptomatic. Fecal passage of proglottids may be noted by patients. Other symptoms are infrequent.

In cysticercosis, the clinical manifestations are variable. Cysticerci can be found anywhere in the body but are most commonly detected in the brain, cerebrospinal fluid (CSF), skeletal muscle, subcutaneous tissue, or eye. The clinical presentation of cysticercosis depends on the number and location of cysticerci as well as on the extent of associated inflammatory responses or scarring. Neurologic manifestations are the most common (Fig. 230-1). Seizures are associated with inflammation surrounding cysticerci in the brain parenchyma. These seizures may be generalized, focal, or Jacksonian. Hydrocephalus results from CSF flow obstruction by cysticerci and accompanying inflammation or by CSF outflow obstruction from arachnoiditis. Symptoms of increased intracranial pressure, including headache, nausea, vomiting, changes in vision, dizziness, ataxia, or confusion, are often evident. Patients with hydrocephalus may develop papilledema or display altered mental status. When cysticerci develop at the base of the brain or in the subarachnoid space, they may cause chronic meningitis or arachnoiditis, communicating hydrocephalus, hemorrhages, or strokes.

Diagnosis

The diagnosis of intestinal T. solium infection is made by the detection of eggs or proglottids, as described for T. saginata. More sensitive methods, including antigen-capture enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and serology for tapeworm stage-specific antigens, are currently available only as research techniques. In cysticercosis, diagnosis can be difficult. A panel of international experts recently proposed revised diagnostic criteria (Table 230-1). Diagnostic certainty is possible only with definite demonstration of the parasite (absolute criteria). This task can be accomplished by histologic observation of the parasite in excised tissue, by funduscopic visualization of the parasite in the subretinal space of the eye, or by neuroimaging studies with definite evidence of a cystic lesion containing a characteristic scolex (Fig. 230-1). With improving resolution of neuroimaging studies, the scolex can now be identified in a large proportion of cases. In other instances, a clinical diagnosis is based on a combination of clinical presentation, radiographic studies, and exposure history (including serodiagnosis).

Neuroimaging findings constitute the primary major diagnostic criteria (Fig. 230-1). Major findings include cystic lesions with or without enhancement (e.g., ring enhancement), one or more nodular calcifications (which may also have associated enhancement), focal enhancing lesions, or multilobulated cystic lesions in the subarachnoid space. Cysticerci in the brain parenchyma are usually 5–20 mm in diameter and rounded. Cystic lesions in the subarachnoid space or fissures may enlarge up to 6 cm in diameter and may be lobulated. For cysticerci within the subarachnoid space or ventricles, the walls may be very thin and the cyst fluid is often isodense with CSF. Thus, obstructive hydrocephalus or enhancement of the basilar meninges may be the only finding on CT in extraparenchymal neurocysticercosis. However, since these findings are less specific, they are considered only minor criteria. Cysticerci in the ventricles or subarachnoid space are more readily identified by MRI, especially with three-dimensional views (e.g., fast imaging employing steady-state acquisition [FIESTA] or three-dimensional constructive interference in steady state [3D CISS]). CT is more sensitive than MRI in identifying calcified lesions, whereas MRI is better for identifying cystic lesions, scolices, and enhancement. Spontaneous resolution, resolution after therapy with albendazole, or mobile cystic lesions within the ventricles are findings that can confirm the diagnosis of neurocysticercosis.

Prior exposure significantly modifies the interpretation of neuroimaging studies. Detection of specific antibodies to or antigens of T. solium are major exposure criteria. Antibody tests using unfractionated antigens (e.g., ELISAs using crude parasite antigen) have high rates of false-positive and false-negative results and should be avoided. An immunoblot assay using lentil lectin–purified glycoproteins is >99% specific and highly sensitive. However, patients with single intracranial lesions or with calcifications may be seronegative. With this assay, serum samples provide greater diagnostic sensitivity than CSF. All of the diagnostic antigens have been cloned, and assays using recombinant antigens are being developed. Antigen detection assays using monoclonal antibodies to detect parasite antigen in the blood or CSF may also facilitate diagnosis and patient follow-up. These assays are currently available commercially in Europe but not in the United States.

Other major clinical/exposure criteria for neurocysticercosis include the presence of cysticerci outside the central nervous system (CNS) (e.g., typical cigar-shaped calcifications in muscle) or exposure to a tapeworm carrier or a household member infected with T. solium. Minor clinical/exposure criteria include residence in an endemic area or clinical symptoms suggestive of neurocysticercosis (e.g., seizures or obstructive hydrocephalus).

Studies have demonstrated that clinical criteria may aid in diagnosis in selected cases. In patients from endemic areas who had single enhancing lesions presenting with seizures, a normal physical examination, and no evidence of systemic disease (e.g., no fever, adenopathy, or chest radiographic abnormalities), the constellation of rounded CT lesions 5–20 mm in diameter with no midline shift was almost always caused by neurocysticercosis.

A definite or probable diagnosis is made in accordance with the criteria and combinations of criteria listed in the footnote of Table 230-1. Patients may have CSF pleocytosis with a predominance of lymphocytes, neutrophils, or eosinophils. The protein level in CSF may be elevated; the glucose concentration is usually normal but may be depressed.

TREATMENT

Prevention

Measures for the prevention of intestinal T. solium infection consist of the application to pork of precautions similar to those described above for beef with regard to T. saginata infection. The prevention of cysticercosis involves minimizing the opportunities for ingestion of fecally derived eggs by means of good personal hygiene, effective fecal disposal, and treatment and prevention of human intestinal infections. Mass chemotherapy has been administered to human and porcine populations in efforts at disease eradication. Finally, vaccines to prevent porcine cysticercosis have shown promise in studies and are under development.

ECHINOCOCCOSIS

Echinococcosis is an infection caused in humans by the larval stage of Echinococcus granulosus sensu lato, E. multilocularis, or E. vogeli. E. granulosus sensu lato parasites produce cystic hydatid disease, with unilocular cystic lesions. These infections are prevalent in most areas where livestock is raised in association with dogs. Molecular evidence has demonstrated that E. granulosus strains belong to a range of genotypes and more than one species. Currently, human cystic hydatid disease is caused by organisms formerly termed E. granulosus that are now classified as E. granulosus sensu stricto (genotypes 1–3), E. canadensis (genotypes 6–8 and 10), and E. ortleppi (genotype 5). Other species—E. equinus (genotype 4) and E. felidis (lion strain)—have not been identified in human infections. E. granulosus sensu lato parasites are found on all continents, with areas of high prevalence in China, central Asia, the Middle East, the Mediterranean region, eastern Africa, and parts of South America. E. multilocularis, which causes multilocular alveolar lesions that are locally invasive, is found in Alpine, sub-Arctic, or Arctic regions, including central and northern Europe; western China and central Asia; and isolated areas in North America. E. vogeli causes polycystic hydatid disease and is found only in Central and South America.

Like other cestodes, echinococcal species have both intermediate and definitive hosts. The definitive hosts are canines that pass eggs in their feces. After the ingestion of eggs, cysts develop in the intermediate hosts—sheep, cattle, humans, goats, camels, and horses for the E. granulosus complex and mice and other rodents for E. multilocularis. When a dog (E. granulosus) or fox (E. multilocularis) ingests infected meat containing cysts, the life cycle is completed.

Etiology

The small (5-mm-long) adult E. granulosus sensu lato worms live for 5–20 months in the jejunum of dogs. They have three proglottids: one immature, one mature, and one gravid. The gravid segment splits to release eggs that are morphologically similar to Taenia eggs and are extremely hardy. After humans ingest the eggs, embryos escape from the eggs, penetrate the intestinal mucosa, enter the portal circulation, and are carried to various organs, most commonly the liver and lungs. Larvae of E. granulosus sensu lato develop into fluid-filled unilocular hydatid cysts that consist of an external membrane and an inner germinal layer. Daughter cysts develop from the inner aspect of the germinal layer, as do germinating cystic structures called brood capsules. New larvae, called protoscolices, develop in large numbers within the brood capsule. The cysts expand slowly over a period of years.

The life cycle of E. multilocularis is similar except that wild canines, such as foxes, serve as the definitive hosts, and small rodents serve as the intermediate hosts. The larval form of E. multilocularis, however, is quite different in that it remains in the proliferative phase, the parasite is always multilocular, and vesicles without brood capsules or protoscolices progressively invade the host tissue by peripheral extension of processes from the germinal layer.

Clinical Manifestations

Slowly enlarging echinococcal cysts generally remain asymptomatic until their expanding size or their space-occupying effect in an involved organ elicits symptoms. The liver and the lungs are the most common sites of these cysts. The liver is involved in about two-thirds of E. granulosus infections and in nearly all E. multilocularis infections. Because a period of years elapses before cysts enlarge sufficiently to cause symptoms, they may be discovered incidentally on a routine x-ray or ultrasound study.

Patients with hepatic echinococcosis who are symptomatic most often present with abdominal pain or a palpable mass in the right upper quadrant. Compression of a bile duct or leakage of cyst fluid into the biliary tree may mimic recurrent cholelithiasis, and biliary obstruction can result in jaundice. Rupture of or episodic leakage from a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or anaphylaxis. Pulmonary hydatid cysts may rupture into the bronchial tree or pleural cavity and produce cough, salty phlegm, dyspnea, chest pain, or hemoptysis. Rupture of hydatid cysts, which can occur spontaneously or at surgery, may lead to multifocal dissemination of protoscolices, which can form additional cysts. Other presentations are due to the involvement of bone (invasion of the medullary cavity with slow bone erosion producing pathologic fractures), the CNS (space-occupying lesions), the heart (conduction defects, pericarditis), and the pelvis (pelvic mass).

The larval forms of E. multilocularis characteristically present as a slowly growing hepatic tumor, with progressive destruction of the liver and extension into vital structures. Patients commonly report upper-quadrant and epigastric pain. Liver enlargement and obstructive jaundice may be apparent. The lesions may infiltrate adjoining organs (e.g., diaphragm, kidneys, or lungs) or may metastasize to the spleen, lungs, or brain.

Diagnosis

Radiographic and related imaging studies are important in detecting and evaluating echinococcal cysts. Plain x-rays will define pulmonary cysts of E. granulosus sensu lato—usually as rounded masses of uniform density—but may miss cysts in other organs unless there is cyst wall calcification (as occurs in the liver). MRI, CT, and ultrasound reveal well-defined cysts with thick or thin walls. Imaging methods may reveal a fluid layer of different density, termed hydatid sand, that contains protoscolices. However, the most pathognomonic finding, if demonstrable, is that of daughter cysts within the larger cyst. This finding, like eggshell or mural calcification on CT, is indicative of E. granulosus infection and helps to distinguish the cyst from carcinomas, bacterial or amebic liver abscesses, or hemangiomas. In contrast, ultrasound or CT of alveolar hydatid cysts reveals indistinct solid masses with central necrosis and plaquelike calcifications.

A specific diagnosis of cystic hydatid disease can be made by the examination of aspirated fluids for protoscolices or hooklets, but diagnostic aspiration is not usually recommended because of the potential risk of fluid leakage resulting in either dissemination of infection or anaphylactic reactions. Serodiagnostic assays can be useful, although a negative test does not exclude the diagnosis of echinococcosis. Cysts in the liver elicit positive antibody responses in ~90% of cases, whereas up to 50% of individuals with cysts in the lungs are seronegative. Detection of antibody to specific echinococcal antigens by immunoblotting has the highest degree of specificity.

TREATMENT

Prevention

In endemic areas, echinococcosis can be prevented by administering praziquantel to infected dogs, by denying dogs access to viscera from infected animals, or by vaccinating sheep. Limiting the number of stray dogs is helpful in reducing the prevalence of infection among humans. In Europe, E. multilocularis infection has been associated with gardening; gloves should be used when working with soil.

HYMENOLEPIASIS NANA

Infection with H. nana, the dwarf tapeworm, is the most common of all the cestode infections. H. nana is endemic in both temperate and tropical regions of the world. Infection is spread by fecal/oral contamination.

Etiology and Pathogenesis

H. nana is the only cestode of humans that does not require an intermediate host. Both the larval and adult phases of the life cycle take place in the human. The adult—the smallest tapeworm parasitizing humans—is ~2 cm long and dwells in the proximal ileum. Proglottids, which are small and rarely seen in the stool, release spherical eggs 30–44 μm in diameter, each of which contains an oncosphere with six hooklets. The eggs are immediately infective and are unable to survive for >10 days in the external environment. When the egg is ingested by a new host, the oncosphere is freed and penetrates the intestinal villi, becoming a cysticercoid larva. Larvae migrate back into the intestinal lumen, attach to the mucosa, and mature into adult worms over 10–12 days. Eggs may also hatch before passing into the stool, causing internal autoinfection with increasing numbers of intestinal worms. Although the life span of adult H. nana worms is only ~4–10 weeks, the autoinfection cycle perpetuates the infection.

Clinical Manifestations

H. nana infection, even with many intestinal worms, is usually asymptomatic. Heavy infection may be associated with diarrhea, abdominal pain, and weight loss.

Diagnosis

Infection is diagnosed by the finding of eggs in the stool.

TREATMENT

Prevention

Good personal hygiene and improved sanitation can eradicate the disease. Epidemics have been controlled by mass chemotherapy coupled with improved hygiene.

HYMENOLEPIASIS DIMINUTA

Hymenolepis diminuta, a cestode of rodents, occasionally infects small children, who ingest the larvae in uncooked cereal foods contaminated by fleas and other insects in which larvae develop. Infection is usually asymptomatic and is diagnosed by the detection of eggs in the stool. Treatment with praziquantel results in cure in most cases.

DIPHYLLOBOTHRIASIS

Diphyllobothrium latum and other diphyllobothriid parasites (including Adenocephlus pacificus and Diplogonoporus species) are found in the lakes, rivers, and deltas of the Northern Hemisphere, central Africa, and South America.

Etiology and Pathogenesis

The adult worm—the longest tapeworm (up to 25 m)—attaches to the ileal and occasionally to the jejunal mucosa by its suckers, which are located on its elongated scolex. The adult worm has 3000–4000 proglottids, which release ~1 million eggs daily into the feces. If an egg reaches water, it hatches and releases a free-swimming embryo that can be eaten by small freshwater crustaceans (Cyclops or Diaptomus species). After an infected crustacean containing a developed procercoid is swallowed by a fish, the larva migrates into the fish’s flesh and grows into a sparganum, or plerocercoid larva. Humans acquire the infection by ingesting infected raw or smoked fish. Within 3–5 weeks, the tapeworm matures into an adult in the human intestine.

Clinical Manifestations

Most D. latum infections are asymptomatic, although manifestations may include transient abdominal discomfort, diarrhea, vomiting, weakness, and weight loss. Occasionally, infection can cause acute abdominal pain and intestinal obstruction; in rare cases, cholangitis or cholecystitis may be produced by migrating proglottids.

Because the tapeworm absorbs large quantities of vitamin B₁₂ and interferes with ileal B₁₂ absorption, vitamin B₁₂ deficiency can develop, but this effect has been noted only in Scandinavia, where up to 2% of infected patients, especially the elderly, have megaloblastic anemia resembling pernicious anemia and may exhibit neurologic sequelae of B₁₂ deficiency.

Diagnosis

The diagnosis is made readily by the detection of the characteristic eggs in the stool. The eggs possess a single shell with an operculum at one end and a knob at the other. Mild to moderate eosinophilia may be detected.

TREATMENT

Prevention

Infection can be prevented by heating fish to 54°C for 5 min or by freezing it at −18°C for 24 h. Placing fish in brine with a high salt concentration for long periods kills the eggs.

DIPYLIDIASIS

Dipylidium caninum, a common tapeworm of dogs and cats, may accidentally infect humans. Dogs, cats, and occasionally humans become infected by ingesting fleas harboring cysticercoids. Children are more likely to become infected than adults. Most infections are asymptomatic, but passage of segments in the stool or vague abdominal symptoms may occur. The diagnosis is made by the detection of proglottids or ova in the stool. As in D. latum infection, therapy consists of praziquantel. Prevention requires anthelmintic treatment and flea control for pet dogs or cats.

SPARGANOSIS

Humans can be infected by the sparganum, or plerocercoid larva, of a diphyllobothriid tapeworm of the genus Spirometra. Infection can be acquired by the consumption of water containing infected Cyclops; by the ingestion of infected snakes, birds, or mammals; or by the application of infected flesh as poultices. The worm migrates slowly in tissues, and infection commonly presents as a subcutaneous swelling. Periorbital tissues can be involved, and ocular sparganosis may destroy the eye. Surgical excision is used to treat localized sparganosis.

COENUROSIS

This rare infection of humans by the larval stage (coenurus) of the dog tapeworm Taenia multiceps or T. serialis results in a space-occupying cystic lesion. As in cysticercosis, involvement of the CNS and subcutaneous tissue is most common. Both definitive diagnosis and treatment require surgical excision of the lesion. Chemotherapeutic agents generally are not effective.

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