1785CHAPTER 234 Schistosomiasis and Other Trematode Infections

in (trekking, swimming, whitewater rafting)? What have you been

eating (local dishes while traveling; raw, poorly cooked, or pickled

freshwater fish or crustaceans)? Definitive diagnosis is based on

detection of parasite eggs in stool, urine, sputum, and sometimes

tissue samples or on serologic tests. The presence of eosinophilia

and a history of travel to endemic areas should raise suspicion of

trematode infection. The U.S. Centers for Disease Control and

Prevention (CDC) can provide guidance with respect to diagnosis

and treatment.

SCHISTOSOMIASIS

Human schistosomiasis is caused by six species of the parasitic genus

Schistosoma: S. mansoni, S. japonicum, S. mekongi, S. intercalatum, and

the recently described S. guineensis cause intestinal disease, and S. haematobium causes urogenital disease (Table 234-1). 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. 234-1) 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

FIGURE 234-1 Schistosoma haematobium eggs.

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 (~300 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, S. intercalatum and S. guineensis, 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 229 million people are infected globally and

at least 229 million people required preventive treatment in 2018.

Schistosomiasis transmission has been reported from 78 countries,

of which 52 endemic countries have moderate to high transmission

(Fig. 234-2). 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.

1786 PART 5 Infectious Diseases

■ 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 TH2 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, 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

A B

FIGURE 234-2 Global distribution of human schistosomiasis. A. Schistosoma mansoni infection (dark blue) is endemic in Africa, the Middle East, South America, and a few

Caribbean countries. S. intercalatum infection (green) is endemic in sporadic foci in West and Central Africa. B. Schistosoma haematobium infection (purple) is endemic in

Africa and the Middle East. The major endemic countries for S. japonicum infection (green) are China, the Philippines, and Indonesia. Schistosoma mekongi infection (red)

is endemic in sporadic foci in Southeast Asia. (Reprinted from CH King, AAF Mahmoud: Schistosomiasis and other trematode infections, in DL Kasper et al [eds], Harrison’s

Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015, pp 1423–1429.)

1787CHAPTER 234 Schistosomiasis and Other Trematode Infections

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) 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, S. guineensis,

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.

1788 PART 5 Infectious Diseases

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, but

promising results have been obtained using an ultrasensitive lateral

flow assay. 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

Schistosomiasis

The drug of choice for treatment of schistosomiasis is praziquantel.

It is administered orally, is available as 600-mg tablets, and is effective against all schistosome species infecting humans. The drug is

safe and well tolerated. Standard regimens are shown in Table 234-2.

In patients who are not cured by initial treatment, the same dose

can be repeated at weekly intervals for 2 weeks. Since praziquantel

does not affect the young migrating stages of the schistosomes, it

may be necessary to repeat the dose 6–12 weeks later, especially if

eosinophilia or symptoms persist despite treatment.

As a general principle, all patients with acute schistosomiasis

should be treated with praziquantel. Glucocorticoids can be added

in Katayama fever to suppress the hypersensitivity reaction. However, treatment for acute schistosomiasis or Katayama fever must be

adjusted appropriately for each case, and in the most severe cases,

management in an acute-care setting is necessary.

Praziquantel is effective in cerebral S. japonicum infections,

resulting in rapid dissipation of cerebral edema and resolution of

cerebral masses. However, glucocorticoids and anticonvulsants are

sometimes needed in neuroschistosomiasis.

The effect of antischistosomal treatment on disease manifestations depends on the stage and severity of the lesions. Early hepatosplenomegaly, mild or moderate fibrosis, and urinary bladder

lesions seen during active infection resolve after chemotherapy.

However, for late-stage manifestations (e.g., severe fibrosis with

portal hypertension), praziquantel treatment is only one component of management, since the main complications are due to

obstructive pathology. Management of portal hypertension and

prevention of bleeding from esophageal varices should follow clinical guidelines for treatment of these conditions.

■ 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 schistosomiasisendemic 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. Two vaccine candidates are in clinical phase 1 trials and

one is in phase 2 trials. Only one candidate, S. haematobium 28GST,

has been tested in a clinical phase 3 trial in populations living in an

endemic area. The vaccine candidate was immunogenic and well tolerated by infected children, but a sufficient efficacy was not reached.

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 2015, an estimated 71 million

people were infected with food-borne trematodes, and infections cause

2 million life-years lost to disability and death worldwide every year.

■ 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 234-1).

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.

TABLE 234–2 Treatment of Schistosomiasis and Food-Borne

Trematode Infections

INFECTION DRUG OF CHOICE ADULT DOSEa

Schistosoma mansoni, S.

haematobium, S. intercalatum,

S. guineensis

Praziquantelb 40 mg/kg PO in 2 divided

doses for 1 day

S. japonicum, S. mekongi Praziquantel 60 mg/kg PO in 3 divided

doses for 1 day

Clonorchis sinensis,

Opisthorchis viverrini,

Opisthorchis felineus

Praziquantel 25 mg/kg PO tid for

2 consecutive days

Fasciola hepatica, Fasciola

gigantica

Triclabendazolec 2 doses of 10 mg/kg PO

given 12 h apart

Fasciolopsis buski Praziquantel 75 mg/kg PO in 3 divided

doses for 1 day

Echinostoma spp., Heterophyes

heterophyes, several other

species

Praziquantel 25 mg/kg PO tid

Paragonimus westermani,

Paragonimus kellicotti

Praziquantel

Triclabendazolec

25 mg/kg PO tid for

2 consecutive days

10 mg/kg PO once (or

twice, 12–24 h apart)

a

The pediatric dose is the same as the adult dose in all instances. b

The safety of

praziquantel in children <4 years old has not been established, although many

children in this age group have been treated with praziquantel during mass drugadministration programs. c

In February 2019, the U.S. Food and Drug Administration

(FDA) approved triclabendazole for treatment of fascioliasis in patients at least 6

years of age.

1789CHAPTER 234 Schistosomiasis and Other Trematode Infections

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 234-3). Tissue damage and

intense inflammation are 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 234-3).

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 234-3). 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 234-3). 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 234-2).

■ 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

TABLE 234–3 Clinical Features of Food-Borne Trematode Infections

SYMPTOMS OR SIGNS

INFECTION EARLY OR ACUTE STAGE ESTABLISHED OR CHRONIC STAGE COMPLICATIONS

Liver Flukes

Clonorchis sinensis,

Opisthorchis viverrini,

Opisthorchis felineus

Often asymptomatic; sometimes

hepatitis-like symptoms and high fever

(especially with O. felineus)

Biliary colic, cholestatic jaundice, recurrent

cholangitis and cholelithiasis; hepatomegaly,

gallbladder enlargement, periductal fibrosis. Light

infections are often asymptomatic and remain so

for years.

Pancreatitis, cholangiocarcinomaa

Fasciola hepatica,

Fasciola gigantica

Acute onset (1–4 weeks after infection)

with high fever, weight loss, sometimes

urticaria and liver tenderness

Biliary colic, cholestatic jaundice, recurrent

cholangitis and cholelithiasis; thickening,

enlargement, and fibrosis of biliary ducts;

sometimes repeated relapses of acute symptoms

Pancreatitis. In rare cases: ectopic

infections in the central nervous system,

orbital area, gastrointestinal tract, lungs,

and other organs. Rarely, fascioliasis can

be fatal.

Intestinal Flukes

Fasciolopsis buski,

Echinostoma spp.,

Heterophyes heterophyes,

several other species

Often asymptomatic; sometimes

nonspecific gastrointestinal symptoms

Heavy infection may lead to ulceration of

intestinal mucosa and malabsorption. Mild

infections are often asymptomatic.

Malnutrition, anemia; rarely, ectopic

infection in the central nervous system

Lung Flukes

Paragonimus westermani,

Paragonimus kellicotti

Often asymptomatic; sometimes

insidious onset with anorexia and

weight loss

Bronchitis-, asthma-, and tuberculosis-like

symptoms and signs such as chronic cough,

dyspnea, bloody (“rusty”) sputum

Pulmonary cyst formation; ectopic infection

in the central nervous system, eyes, skin,

heart, abdominal and reproductive organs

a

Carcinogenesis has not yet been established for O. felineus.

1790 PART 5 Infectious Diseases

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

Food-Borne Trematode Infections

Praziquantel and triclabendazole are the two drugs of choice;

Table 234-2 summarizes the dosages recommended for the various

trematode infections. All confirmed cases of human paragonimiasis

should be treated with praziquantel (Table 234-2) to avoid the complications of extrapulmonary disease. Surgical management may be

needed for pulmonary or cerebral lesions.

■ 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

Andrade G et al: Decline in infection-related morbidities following

drug-mediated reductions in the intensity of Schistosoma infection: A systematic review and meta-analysis. PLoS Negl Trop Dis

11:e0005372, 2017.

Cucchetto G et al: High-dose or multi-day praziquantel for imported

schistosomiasis? A systematic review. J Travel Med 26:taz050,

2019.

Fried B, Abruzzi A: Food-borne trematode infections of humans in

the United States of America. Parasitol Res 106:1263, 2010.

Fürst T et al: Global burden of human food-borne trematodiasis:

A systematic review and meta-analysis. Lancet Infect Dis 12:210,

2012.

Jordan P et al (eds): Human Schistosomiasis. CAB International,

Wallingford, 1993.

Keiser J, Utzinger J: Food-borne trematodiases. Clin Microbiol Rev

22:466, 2009.

Mcmanus DP et al: Schistosomiasis. Nat Rev Dis Primers 4:13, 2018.

Ross AG et al: Katayama syndrome. Lancet Infect Dis 7:218, 2007.

Sripa B et al: Update on pathogenesis of opisthorchiasis and cholangiocarcinoma. Adv Parasitol 102:97, 2018.

World Health Organization: Female Genital Schistosomiasis:

A Pocket Atlas for Clinical Health-Care Professionals. Geneva, World

Health Organization, 2015. Available at http://brightresearch.org/

wp-content/uploads/2016/05/FGS-pocket-atlas_eng.pdf. WHO/HTM/

NTD/2015.4, 2015. Accessed March 16, 2020.

Cestodes, or tapeworms, are segmented flat worms. The adult worms

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 proglottids mature, they are 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, only morphologic

differences in the scolices or proglottids enable species-level diagnosis.

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 invasive larvae (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.

235 Cestode Infections

A. Clinton White, Jr., Peter F. Weller

1791CHAPTER 235 Cestode Infections

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. 232). Distinguishing T. saginata or T. asiatica from

T. solium requires examination of mature proglottids or the scolex.

Available serologic tests are not helpful diagnostically. Eosinophilia and

elevated levels of serum IgE are usually absent.

TREATMENT

Taeniasis Saginata and Taeniasis Asiatica

A single dose of praziquantel (10 mg/kg) is highly effective. Niclosamide (adult dose, 2 g; 1 g for children weighing 11−34 kg) is also

effective but is less available.

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 invasive larvae are activated, escape the egg, penetrate the intestinal wall, and are carried via the bloodstream 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. Transmission is usually associated

with close contact with a tapeworm carrier. The eggs are sticky and may

be found under the fingernails of tapeworm carriers. 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. 235-1). 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 235-1). 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. 235-1). 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,

exposure history, and serodiagnosis.

Neuroimaging findings constitute the primary major diagnostic criteria (Fig. 235-1). 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 support

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. More recently, real-time PCR has been employed for diagnosis

and follow-up of extraparenchymal disease.

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).