considered nonpathogenic, headache, articular pain, fever, pulmonary ■■FURTHER READING 1635

symptoms, adenopathy, hepatomegaly, pruritus, and eosinophilia have Herrick JA et al: Eosinophil-associated processes underlie differences
been ascribed to M. ozzardi infection. The diagnosis is made by detec- in clinical presentation of loiasis between temporary residents and
tion of microfilariae in peripheral blood. Ivermectin is effective in those indigenous to Loa-endemic areas. Clin Infect Dis 60:55, 2015.
treating this infection. Hopkins DR et al: Progress toward global eradication of dracunculiasis—
January 2016–June 2017. Morb Mortal Wkly Rep 66:1327, 2017.
ZOONOTIC FILARIAL INFECTIONS Mand S et al: Doxycycline improves filarial lymphedema independent
Dirofilariae that affect primarily dogs, cats, and raccoons occasionally of active filarial infection: A randomized controlled trial. Clin Infect
infect humans incidentally, as do Brugia and Onchocerca parasites that Dis 55:621, 2012.
affect small mammals. Because humans are an abnormal host, the par- Ramaiah KD, Ottesen EA: Progress and impact of 13 years of the
asites never develop fully. Pulmonary dirofilarial infection caused by Global Programme to Eliminate Lymphatic Filariasis on reducing the
the canine heartworm Dirofilaria immitis generally presents in humans burden of filarial disease. PLoS Negl Trop Dis 8:e3319, 2014.
as a solitary pulmonary nodule. Chest pain, hemoptysis, and cough Steel C et al: Rapid point-of-contact tool for mapping and integrated
are uncommon. Infections with D. repens (from dogs) or D. tenuis (from surveillance of Wuchereria bancrofti and Onchocerca volvulus infection.
raccoons) can cause local subcutaneous nodules in humans. Zoonotic Clin Vaccine Immunol 22:896, 2015.
Brugia infection can produce isolated lymph node enlargement, Taylor MJ et al: Lymphatic filariasis and onchocerciasis. Lancet
whereas zoonotic Onchocerca species (particularly O. lupi) can cause 376:1175, 2010.
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)
229 Schistosomiasis and Other
Trematode Infections
■■ETIOLOGY AND EPIDEMIOLOGY Birgitte Jyding Vennervald
The incidence of dracunculiasis, caused by Dracunculus medin-
ensis, has declined dramatically because of global eradication
efforts. In 2017, only 30 cases worldwide were identified. The

CHAPTER 229 Schistosomiasis and Other Trematode Infections

Trematodes, or flatworms, are a group of helminths that belong to the
infection appears to be endemic only in Chad and Ethiopia. phylum Platyhelminthes. The adult flatworms share some common
Humans acquire D. medinensis when they ingest water containing characteristics, such as macroscopic size (from one to several centi-
infective larvae derived from Cyclops, a crustacean that is the inter- meters); dorsoventrally flattened, bilaterally symmetric bodies; and
mediate host. Larvae penetrate the stomach or intestinal wall, mate, two suckers—oral and ventral. Except for schistosomes, which have
and mature. The adult male probably dies; the female worm develops separate sexes, all human parasitic trematodes are hermaphroditic.
over a year and migrates to subcutaneous tissues, usually in the lower Their life cycles involve a mammalian/human definitive host, in which
extremity. As the thin female worm, ranging in length from 30 cm to sexual reproduction by adult worms takes place, and an intermediate
1 m, approaches the skin, a blister forms that, over days, breaks down host (snails), in which asexual multiplication occurs. Some species of
and forms an ulcer. When the blister opens, large numbers of motile, trematodes have more than one intermediate host.
rhabditiform larvae can be released into stagnant water; ingestion by Humans are infected either by direct penetration of intact skin
Cyclops completes the life cycle. (schistosomiasis) or by ingestion of raw freshwater fish, crustaceans, or
aquatic plants with metacercariae—the infective larval stage.
■■CLINICAL FEATURES Significant trematode infections of humans may be divided according
Few or no clinical manifestations of dracunculiasis are evident until
to the location of the adult worms: blood, liver (biliary tree), intestines,
just before the blister forms, when there is an onset of fever and gener-
or lungs (Table 229-1). Adult worms do not multiply within the mam-
alized allergic symptoms, including periorbital edema, wheezing, and
malian host but can live for up to 30 years. Infections are often chronic.
urticaria. The emergence of the worm is associated with local pain and
Although it is relatively rare to encounter patients with trem-
swelling. When the blister ruptures (usually as a result of immersion
atode infections in the United States, many millions of people
in water) and the adult worm releases larva-rich fluid, symptoms are
are infected worldwide. Both schistosomiasis and food-borne
relieved. The shallow ulcer surrounding the emerging adult worm
trematode infections are poverty-related chronic diseases with high
heals over weeks to months. Such ulcers, however, can become sec-
morbidity and a significant public health impact. Various factors may
ondarily infected, the result being cellulitis, local inflammation, abscess
increase the spread of the infections globally. Increasing temperatures
formation, or (uncommonly) tetanus. Occasionally, the adult worm
may render new areas suitable for the intermediate host snails, and an
does not emerge but becomes encapsulated and calcified.
increase in travel and migration may increase the number of patients
■■DIAGNOSIS with trematode infections—for example, in the United States.
The diagnosis is based on the findings developing with the emergence
of the adult worm, as described above. APPROACH TO THE PATIENT
Trematode Infection
TREATMENT
In the evaluation of a patient in whom trematode infection is
Dracunculiasis suspected, certain questions are highly relevant and can assist in
Gradual extraction of the worm by winding of a few centimeters establishing a diagnosis: Where have you been? If you have trav-
on a stick each day remains the common and effective practice. eled, when did you return? What activities have you been involved
Worms may be excised surgically. No drug is effective in treating in (trekking, swimming, whitewater rafting)? What have you been
dracunculiasis. 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
■■PREVENTION tissue samples or on serologic tests. The presence of eosinophilia
Prevention, which remains the only real control measure, depends on and a history of travel to endemic areas should raise suspicion
the provision of safe drinking water.

Harrisons_20e_Part5_p0859-p1648.indd 1635 6/1/18 12:12 PM

 1636 TABLE 229–1 Major Human Trematode Infections human skin, but they die in subcutaneous tissue, producing only cuta-
neous manifestations.
GEOGRAPHIC
TREMATODE TRANSMISSION ROUTE DISTRIBUTION
Blood Flukes ■■ETIOLOGY
Intestinal schistosomiasis Schistosoma infection is contracted through contact with freshwater
Schistosoma Skin penetration by Africa, Brazil, Venezuela, bodies harboring infected intermediate-host snails. Cercariae, the
mansoni cercariae released from Surinam, the Caribbean infective larval stage released from the snail, penetrate intact human
snails (Biomphalaria spp.) (low risk) skin within a few minutes after attaching to the skin. After penetration,
Shistosoma Skin penetration by China, Indonesia, the cercariae transform to schistosomula, which then enter a small
japonicum cercariae released from Philippines vein or lymphatic vessel, circulate in the bloodstream through the
snails (Oncomelania spp.) lung capillaries, and are pumped via the heart to all parts of the body
Schistosoma Skin penetration by Rain forest areas of to reach the portal vein. There, the worms mature into adult males or
guineensis and cercariae released from Central Africa females, pair, and migrate to their final location in the mesenteric or
Schistosoma snails (Bulinus spp.)
intercalatum
pelvic venous plexus.
The interval from cercarial penetration to sexual maturation and
Schistosoma Skin penetration by Several districts of
mekongi cercariae released from Cambodia and Lao egg production, termed the prepatent period, lasts 5–7 weeks (up to 12
snails (Neotricula aperta) People’s Democratic weeks for S. haematobium). The female worm then begins to produce
Republic (PDR) eggs, which are excreted via feces or, for S. haematobium, urine. Approxi-
Urogenital schistosomiasis mately 50% of eggs are retained in tissue, where they are responsible for
Schistosoma Skin penetration by Africa, Middle East, organ-specific morbidity (see “Pathogenesis,” below). When excreted
haematobium cercariae released from Corsica (France) eggs reach water, they hatch and release a free-swimming larval stage
snails (Bulinus spp.) (miracidium), which, after penetrating a host snail, undergoes several
Liver Flukes rounds of asexual multiplication. After ~4–6 weeks, infective cercariae
Clonorchis sinensis Ingestion of metacercariae Asia, including Republic are shed from the infected snails into the water. One snail, infected by
in freshwater fish of Korea, China, Taiwan, one miracidium, can shed thousands of cercariae per day for several
Vietnam months; thus the transmission potential of schistosomes is enormous.
Opisthorchis viverrini Ingestion of metacercariae Northeast Thailand, Lao The schistosome egg (Fig. 229-1) is the only stage of the parasites’
in freshwater fish PDR, Cambodia, Vietnam life cycle that can be detected in humans, either in excreta or in tissue
Opisthorchis felineus Ingestion of metacercariae Former Soviet Union, biopsies. The eggs are large and can easily be distinguished morpho-
PART 5

in freshwater fish Kazakhstan, Ukraine, logically from other helminth eggs. S. haematobium eggs are ~140 mm
Turkey long, with a terminal spine; S. mansoni eggs are ~150 mm long, with a
Fasciola hepatica Ingestion of metacercariae Worldwide lateral spine; and S. japonicum eggs are smaller, rounder, and ~90 mm
on aquatic plants or in long, with a small lateral spine or knob.
water
Infectious Diseases

Adult schistosomes are ~1–2 cm long. The male worm is flat, and
Fasciola gigantica Ingestion of metacercariae Africa, Asia the body forms a groove or gynecophoric canal in which the mature
on aquatic plants or in
adult female is held like a sausage in a hotdog roll. Females are longer,
water
thinner, and rounded. The females produce hundreds (African species)
Intestinal Flukes to thousands (Asian species) of eggs per day. Each ovum contains a
Fasciolopsis buski Ingestion of metacercariae Bangladesh, China, ciliated miracidium larva, which secretes proteolytic enzymes that help
on aquatic plants India, Indonesia, Lao the eggs to migrate into the lumen of the bladder (S. haematobium) or
PDR, Malaysia, Taiwan,
Thailand, Vietnam
the intestine (other species). The lifespan of an adult schistosome aver-
ages 3–5 years but can be as long as 30 years. Schistosome worms feed
Echinostoma spp. Ingestion of freshwater fish, China, India, Indonesia,
frogs, mussels, snails Japan, Malaysia, Russia, on red blood cells; the debris is regurgitated in the host’s blood, where
Republic of Korea, it can be detected as circulating antigens (see “Diagnosis,” below).
Philippines, Thailand Adult schistosomes persist in the bloodstream for years and have
Heterophyes Ingestion of metacercariae Egypt, Greece, Islamic evolved strategies of evading attack using immune effector mecha-
heterophyes, several in freshwater or brackish- Republic of Iran, Italy, nisms. This immune evasion is a result of several processes, such as
other species water fish Japan, Republic of Korea,
Sudan, Tunisia, Turkey
Lung Flukes
Paragonimus Ingestion of metacercariae Tropical and subtropical
westermani in crayfish or crabs areas of eastern and
southern Asia and sub-
Saharan Africa
Paragonimus Ingestion of metacercariae North America
kellicotti in crayfish or crabs

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 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 FIGURE 229-1 Schistosoma haematobium eggs.

Harrisons_20e_Part5_p0859-p1648.indd 1636 6/1/18 12:12 PM

 binding of host proteins to the schistosome surface, which renders the higher prevalence in older children with a peak at 10–15 years of age, 1637
parasite invisible to the host immune system. and declining prevalence in adults. The same pattern is observed
The genome of schistosomes is relatively large (~270 Mb). between age and intensity of infection and is attributable to various
Whole-genome sequences are available for S. mansoni, S. japonicum, factors. Generally, children have more frequent, prolonged, and
and S. haematobium. 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
■■EPIDEMIOLOGY that adults are reinfected to a much lesser extent than children. These
Because of the complex life cycle of schistosomes, with snails factors, combined with progressive spontaneous death of adult worms
as an intermediate host and humans as the final host, trans- from infections acquired during childhood, lead to lower levels of
mission is dependent on freshwater habitats that are suitable infection in the adult population.
for the snails, are areas of human activity, and have climatic conditions
favoring the survival of the snails and the development of the parasites ■■PATHOGENESIS
inside the snail host. These requirements are reflected in the global Cercarial invasion may be associated with dermatitis arising from
distribution of schistosomiasis as well as in its microgeographic distri- dermal and subdermal inflammatory reactions in response to dying
bution within an endemic area. For S. mansoni, S. haematobium, and S. cercariae that trigger innate immune responses. However, most man-
intercalatum, humans are the most important definitive host. S. japoni- ifestations of schistosomiasis—in the acute, established, and chronic
cum and S. mekongi are zoonotic parasites, with a wide range of defini- phases of infection—are due to immunologic reactions to eggs retained
tive hosts such as pigs, water buffaloes, and various rodents. in host tissues.
It is estimated that 230 million people are infected globally, with Around the time when oviposition commences, acute schistoso-
~800 million people living in areas where there is a risk of infection miasis (Katayama fever) may occur (see “Clinical Features,” below).
(Fig. 229-2). More than 70% of infected people live in sub-Saharan Antigen excess from eggs results in the formation of soluble immune
Africa. Schistosomiasis is the most important of the neglected tropical complexes, which may be deposited in several tissues and initiate a
diseases and is second only to malaria in public health impact. It is serum sickness–like illness. All evidence suggests that schistosome
a poverty-related disease, and infection is prevalent in areas where eggs, and not adult worms, induce the organ-specific morbidity
adequate water supplies and sanitary facilities are lacking. In these caused by schistosome infections. Approximately half of the eggs are
areas, people come into contact with infested water through a variety not excreted via feces or urine but are trapped in intestinal or hepatic
of activities, including bathing, washing clothes, and collecting water tissue (S. mansoni, S. japonicum, and S. mekongi) or in the bladder and
for drinking or cooking. In some areas, adults have a high occupational

CHAPTER 229 Schistosomiasis and Other Trematode Infections

urogenital system (S. haematobium). The eggs induce a granulomatous
risk of exposure; fishermen, canal cleaners, and workers in rice fields host immune response composed primarily of lymphocytes, eosin-
fall into this category. Among children, playing in water and swimming ophils, and alternatively activated macrophages. The lymphocytes
pose a risk. Large-scale irrigation and hydroelectric power operations produce various TH2 cytokines such as interleukins 4, 5, and 13. Later,
can create suitable habitats for host snails and thus increase the risk of in the chronic phase of infection, regulatory cytokines are responsi-
schistosomiasis transmission. ble for immunomodulation or downregulation of host responses to
In general, children living in endemic areas initially acquire infec- schistosome eggs and play an important role in reducing the size of
tion at ~3–4 years of age—i.e., when they are old enough to walk and granulomas.
come into contact with infested water. However, infection does occur When S. mansoni or S. japonicum eggs are swept into the small portal
in much younger children. As children grow older, the prevalence and branches of the liver via the portal vein, they lodge in the presinusoidal
intensity of infection increase, peaking around puberty. A characteristic periportal tissues. The formation of granulomas around the eggs can
feature of schistosomiasis infection in human populations is a convex cause significant enlargement of the spleen and liver. High-intensity
age–prevalence curve, with low prevalence in very young children, infections in children are often accompanied by hepatosplenomegaly

A B

FIGURE 229-2 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 with permission 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.)

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 1638 that generally decreases over time, partly because the number of Intestinal Schistosomiasis (S. mansoni, S. japonicum,
eggs being deposited in the tissue gradually declines after the early S. mekongi) In intestinal schistosomiasis, adult worms are located
teenage years as partial immunity to new infections develops and in the mesenteric veins, and disease manifestations are associated
partly because of immunologic downregulation of the granulomatous with parasite eggs passing through or becoming trapped in intestinal
response. However, in some infected individuals, egg-induced gran- tissue. This event induces mucosal granulomatous inflammation with
ulomatous responses lead to severe periportal fibrosis (Symmers clay microulcerations, superficial bleeding, and sometimes pseudopolypo-
pipestem fibrosis), with deposition of collagen around the portal vein, sis. The symptoms tend to be more pronounced with a high intensity
occlusion of the smaller portal branches, and severe, often irreversible, of infection and include intermittent abdominal pain, loss of appe-
pathology. Occlusion of the portal branches may result in marked por- tite, and sometimes bloody diarrhea. The clinical manifestations of
tal hypertension. S. intercalatum and S. mekongi infection are generally milder.
The signs and symptoms of S. haematobium infection relate to the
worms’ predilection for the veins of the urogenital plexus and result Hepatosplenic Schistosomiasis Hepatosplenic schistosomia-
from deposition of eggs in the bladder, ureters, and genital organs. sis is caused by schistosome eggs trapped in liver tissue and occurs in
During established active infection, clusters of living eggs in the S. mansoni and S. japonicum infections. There are two distinct clinical
urogenital tissues can be found surrounded by intense inflammatory entities: early inflammatory hepatosplenomegaly and late hepato-
reactions and intense tissue eosinophilia. Movement of egg clusters splenic disease with periportal fibrosis.
into the lumen of the bladder is often followed by sloughing off of the Early inflammatory hepatosplenic schistosomiasis is the main
epithelial surface, ulceration, and bleeding. Intense egg-induced tissue entity seen in children and adolescents. The liver is enlarged, espe-
inflammation can result in bladder wall thickening and development cially the left lobe, and is smooth and firm. The spleen is enlarged,
of masses and pseudopolyps. Inflammation and granuloma formation often extending below the umbilicus, and is firm or hard. Generally,
around the ureteral ostia can lead to hydronephrosis. ultrasonography shows no hepatic fibrosis. This form of hepatosplenic
Generally, late chronic-stage infections are characterized by accumu- schistosomiasis may be found in up to 80% of infected children. Its
lation of dead calcified eggs in tissue. Characteristic cervical lesions are severity is closely associated with the intensity of infection and may
found in S. haematobium infections, including active-stage lesions with also be associated with concomitant chronic exposure to malaria.
intense tissue inflammation around live eggs and chronic-stage sandy Late hepatosplenic schistosomiasis with periportal or Symmers
patches with clusters of calcified eggs. fibrosis may develop in young and middle-aged adults with long-
standing, high-level exposure to infection. Patients with periportal
■■CLINICAL FEATURES fibrosis may excrete very few or no eggs in feces. During the early
In general, disease manifestations of schistosomiasis occur in three stage, the liver is enlarged, especially the left lobe; it is smooth and firm
PART 5

stages—acute, active, and chronic—according to the duration and or hard. The spleen is enlarged, often massively, and is firm or hard.
intensity of infection. The patient may report a left hypochondrial mass with discomfort
and anorexia. Ultrasonography reveals typical periportal fibrosis and
Cercarial Dermatitis (“Swimmer’s Itch”) Cercarial pene- dilation of the portal vein. Other complications include delayed growth
tration of the skin may result in a maculopapular rash called cercarial and puberty, especially in S. japonicum infections, and severe anemia.
Infectious Diseases

dermatitis or “swimmer’s itch.” Cercarial dermatitis can develop in Severe hepatosplenic schistosomiasis may lead to portal hyperten-
people who have not previously been exposed to schistosomiasis (e.g., sion, but hepatic function usually remains normal, even in cases with
travelers), whereas it is rare among people living in endemic areas. A marked periportal fibrosis and portal hypertension.
particularly severe form of cercarial dermatitis is commonly seen after Ascites, attributable both to portal hypertension and to hypoalbu-
exposure to cercariae from avian schistosomes. These cercariae cannot minemia, may be seen, especially in S. japonicum infection. Patients
complete their development in humans and die in the skin, causing an with severe hepatosplenic disease and portal hypertension may
inflammatory allergic reaction. This form of cercarial dermatitis can develop esophageal varices detectable by endoscopy or ultrasound.
occur in people who have been in contact with water from lakes (e.g., These patients may experience repeated bouts of hematemesis, melena,
in Europe or the United States) where various species of water birds, or both. Hematemesis is the most severe complication of hepatosplenic
such as ducks, geese, and swans, are found. The rash may last for schistosomiasis, and death may result from massive loss of blood.
1–2 weeks. This condition normally requires no treatment, but systemic
antihistamines or topical antihistamines or glucocorticoids can be used Urogenital Schistosomiasis (S. haematobium) The signs
to reduce symptoms. and symptoms of S. haematobium infection relate to the worms’ predi-
lection for the veins of the urogenital tract. Two stages of infection are
Acute Schistosomiasis (Katayama Fever) Symptomatic recognized. An active stage occurring mainly in children, adolescents,
acute schistosomiasis, also known as Katayama fever or Katayama syn- and younger adults is characterized by egg excretion in the urine, with
drome, is usually seen in travelers who have contracted the infection proteinuria and macroscopic or microscopic hematuria and deposition
for the first time. The onset occurs between 2 weeks and 3 months after of eggs in the urinary tract. A chronic stage in older individuals is
exposure to the parasite. The symptoms may appear suddenly and characterized by sparse or no urinary egg excretion despite urogenital
include fever, myalgia, general malaise and fatigue, headache, nonpro- tract pathology.
ductive cough, and intestinal symptoms such as abdominal tenderness A characteristic sign in the active stage is painless, terminal hema-
or pain. Various combinations of these symptoms are often accompa- turia. Dysuria and suprapubic discomfort or pain are associated with
nied by eosinophilia and transient pulmonary infiltrates. Many patients active urogenital schistosomiasis and may persist throughout the
recover spontaneously from acute schistosomiasis after 2–10 weeks, but course of active infection. Eggs deposited in the bladder mucosa may
the illness follows a more severe clinical course in some individuals, give rise to an intense inflammatory response of the bladder wall,
with weight loss, dyspnea, diarrhea, and hepatomegaly. Severe cerebral which may cause ureteric obstruction and lead to hydroureter and
or spinal cord manifestations may occur, and even light infections may hydronephrosis. These early inflammatory lesions, including obstruc-
cause severe illness. The syndrome can, in rare cases, be fatal. tive uropathy, can be visualized by ultrasonography.
Differential diagnosis includes many other febrile infectious diseases As the infection progresses, the inflammatory component decreases
with acute onset, including malaria, salmonellosis, and acute hepatitis. and fibrosis becomes more prominent. The symptoms at this stage
Fever and eosinophilia occur in trichinosis, tropical eosinophilia, are nocturia, urine retention, dribbling, and incontinence. Cystoscopy
invasive ankylostomiasis, strongyloidiasis, visceral larva migrans, and reveals “sandy patches” composed of large numbers of calcified eggs
infections with Opisthorchis and Clonorchis species. Katayama fever is surrounded by fibrous tissue and an atrophic mucosal surface. The
rare in people chronically exposed to infection in areas endemic for S. ureters are less commonly involved, but ureteral fibrosis can cause
mansoni or S. haematobium. irreversible obstructive uropathy that can progress to uremia.

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 Egg deposition may cause granulomas and lesions in the genital commercially available point-of-care assay (Rapid Medical Diagnos- 1639
organs, most commonly in the cervix and vagina in women and the tics, Pretoria, South Africa) that detects CCA in urine is now widely
seminal vessels in men. The results may include dyspareunia, abnormal used for screening of infected communities in relation to mass drug
vaginal discharge, contact bleeding, and lower back pain in women and administration programs.
perineal pain, painful ejaculation, and hematospermia in men. Genital
symptoms like bloody discharge and genital itch are associated with TREATMENT
S. haematobium infection in school-aged girls living in schistosomiasis- Schistosomiasis
endemic areas. Symptoms such as hematospermia and perineal discom-
fort have been described in travelers, and eggs have been demonstrated The drug of choice for treatment of schistosomiasis is praziquantel. It
in seminal fluid. An association between female genital schistosomiasis is administered orally, is available as 600-mg tablets, and is effective
and HIV infection has been demonstrated, but the impact of genital against all schistosome species infecting humans. The drug is safe
schistosomiasis on HIV transmission needs further elucidation. and well tolerated. Standard regimens are shown in Table 229-2. In
S. haematobium has been classified by the International Agency for patients who are not cured by initial treatment, the same dose can
Research on Cancer (IARC) as definitely carcinogenic to humans (i.e., be repeated at weekly intervals for 2 weeks. Since praziquantel does
a group 1 carcinogen). Chronic S. haematobium infection is associated not affect the young migrating stages of the schistosomes, it may be
with squamous cell carcinoma of the urinary bladder. necessary to repeat the dose 6–12 weeks later, especially if eosino-
philia or symptoms persist despite treatment.
Other Manifestations Worms and eggs can sometimes be located As a general principle, all patients with acute schistosomiasis
in ectopic sites, causing site-specific manifestations and symptoms. should be treated with praziquantel. Glucocorticoids can be added
Neuroschistosomiasis is one of the most severe clinical forms of schis- in Katayama fever to suppress the hypersensitivity reaction. How-
tosomiasis and is caused by the inflammatory response around eggs ever, treatment for acute schistosomiasis or Katayama fever must be
in the cerebral or spinal venous plexus. S. mansoni and S. haematobium adjusted appropriately for each case, and in the most severe cases
worms can end up in the spinal venous plexus, where they may cause management in an acute-care setting is necessary.
transverse myelitis—an acute complication sometimes seen in travelers Praziquantel is effective in cerebral S. japonicum infections, result-
returning home with schistosomiasis. S. japonicum is mainly associated ing in rapid dissipation of cerebral edema and resolution of cerebral
with granulomatous lesions in the brain, causing epileptic seizures, masses. However, glucocorticoids and anticonvulsants are some-
encephalopathy with headache, visual impairment, motor deficit, and times needed in neuroschistosomiasis.
ataxia. Pulmonary schistosomiasis is caused by portacaval shunting The effect of antischistosomal treatment on disease manifesta-

CHAPTER 229 Schistosomiasis and Other Trematode Infections

of eggs into the lung capillaries, where they induce granulomas in the tions depends on the stage and severity of the lesions. Early hepa-
perialveolar area. The consequences may be fibrosis, pulmonary hyper- tosplenomegaly, mild or moderate fibrosis, and urinary bladder
tension, and cor pulmonale. lesions seen during active infection resolve after chemotherapy.
However, for late-stage manifestations (e.g., severe fibrosis with
■■DIAGNOSIS portal hypertension), praziquantel treatment is only one component
Anamnestic information on recent travels to endemic areas and expo- of management, since the main complications are due to obstructive
sure to freshwater bodies through recreational or other activities is pathology. Management of portal hypertension and prevention of
important in the diagnosis of schistosomiasis in travelers. Information bleeding from esophageal varices should follow clinical guidelines
about exact geographic locations can facilitate identification of the for treatment of these conditions.
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 TABLE 229–2 Treatment of Schistosomiasis and Food-Borne
infection and is the standard diagnostic method. The diagnosis is often Trematode Infections
based on the detection of eggs in a fixed small amount of excreta—e.g.,
INFECTION DRUG OF CHOICE ADULT DOSEa
50 mg of stool or filtration of 10 mL of urine. This method is widely
Schistosoma mansoni, Praziquantelb 40 mg/kg PO in 2
used among populations in endemic areas and allows quantitation of S. haematobium, divided doses for 1 day
the level of infection (eggs per gram of feces or per 10 mL of urine). S. intercalatum,
However, levels of egg excretion in people from nonendemic areas may S. guineensis
be very low, in which case a larger sample and concentration methods S. japonicum, S. mekongi Praziquantel 60 mg/kg PO in 3
(e.g., formol-ether concentration) may be needed. divided doses for 1 day
Eggs can also be detected in rectal biopsies (both S. mansoni and Clonorchis sinensis, Praziquantel 25 mg/kg PO tid for 2
S. haematobium) and occasionally in Pap smears and semen samples Opisthorchis viverrini, consecutive days
(S. haematobium). Polymerase chain reaction (PCR)–based detection Opisthorchis felineus
of parasite DNA in stool or urine is more sensitive than parasitologic Fasciola hepatica, Triclabendazolec 10 mg/kg PO as a
methods and is increasingly used. Schistosoma DNA can be detected Fasciola gigantica single dosed
in cerebrospinal fluid samples for diagnosis of neuroschistosomiasis. Fasciolopsis buski Praziquantel 75 mg/kg PO in 3
Serology, with detection of specific antibodies to schistosomes, is divided doses for 1 day
useful in travelers but less so in people from endemic areas where Echinostoma Praziquantel 25 mg/kg PO tid
transmission is ongoing. The serologic assays employed at the CDC spp., Heterophyes
heterophyes, several
are a Falcon assay screening test/enzyme-linked immunosorbent other species
assay (FAST-ELISA) using S. mansoni adult microsomal antigen and a
Paragonimus westermani, Praziquantel 25 mg/kg PO tid for 2
confirmatory species-specific immunoblot assay performed in light of Paragonimus kellicotti consecutive days
the patient’s travel history.
Triclabendazolec 10 mg/kg PO once (or
Schistosome proteoglycans—circulating anodic and cathodic anti- twice, 12–24 h apart)
gens (CAAs and CCAs)—regurgitated into the bloodstream by the a
The pediatric dose is the same as the adult dose in all instances. bThe safety
feeding worms can be detected in serum and urine by ELISA or mono- of praziquantel in children <4 years old has not been established, although many
clonal antibody–based lateral flow assays. The presence of CAA or children in this age group have been treated with praziquantel during mass drug-
CCA is an indication of active infection, and levels of these antigens administration programs. cTriclabendazole is not approved by the U.S. Food and
correlate well with the intensity of infection. However, detection of Drug Administration and is not yet commercially available in the United States.
It is available through the Centers for Disease Control and Prevention Drug
CAAs and CCAs is not currently suitable for diagnosis in travelers, Service (404-639-3670; drugservice@cdc.gov). dA second dose (10 mg/kg) can be
who are likely to have low levels of infection and very few worms. A administered 12–24 h after the first dose in severe fascioliasis.

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 1640 ■■PREVENTION AND CONTROL Soviet Union; and C. sinensis in Asia, including Korea, China, Taiwan,
Schistosomiasis is contracted through direct contact with infested Vietnam, Japan, and Asian regions of Russia. Parasite eggs excreted
freshwater. Travelers should be made aware of the risk of infection from infected humans or animals are ingested by a host snail (the first
if they come into contact with freshwater sources in schistosomiasis- intermediate host), where they undergo several developmental stages.
endemic areas. For people living in rural areas where schistosomiasis Cercariae are then released from the snail and penetrate freshwater fish
is endemic, it may be very difficult, if not impossible, to avoid water (the second intermediate host), encysting as metacercariae in the mus-
contact—for example, during occupational activities such as fishing cles or under the scales. Humans become infected by eating raw or
and working in rice fields. Schistosomiasis is a poverty-related disease, undercooked fish from endemic countries. After ingestion, the metacer-
and access to safe water and good sanitary facilities may rarely be cariae excyst in gastric juices and migrate via the duodenum, the
available. Because S. japonicum is a zoonotic parasite, preventive mea- ampulla of Vater, and the extrahepatic biliary system to the intrahepatic
sures should target not only the human population but also animals bile ducts.
such as water buffalo, which act as reservoirs for infection. The clinical manifestations of infection with Opisthorchis species
Praziquantel treatment of infected people, often during mass and C. sinensis are similar. Pathologic changes are typically seen in
drug-administration programs, is a cornerstone of the management the bile ducts, liver, and gallbladder (Table 229-3). Tissue damage and
and control of schistosomiasis. Regular treatment will reduce the intense inflammation is caused by mechanical and chemical irritation
level of schistosomiasis morbidity in affected populations. However, and immune responses to worms or worm products, and chronic
treatment should be combined with other relevant strategies, such as inflammation may result in the development of cholangiocarcinoma.
control of the intermediate host snails, improved water-quality and Both O. viverrini and C. sinensis are classified by the IARC as definitely
sanitation facilities, and health education. Schistosomiasis control mea- carcinogenic (class 1). Acute and light infections are mostly asymptom-
sures should be integrated into local health programs. atic, but hepatitis-like signs and symptoms, with high fever and chills,
There have been intensive efforts to develop vaccines, but none is yet have been reported, especially in O. felineus infections. In general, only
available. One vaccine candidate, S. haematobium 28GST, has been tested heavily infected people have symptoms and severe complications
in a clinical phase 3 trial in populations living in an endemic area. (Table 229-3).
The diagnosis of these infections is based on microscopic identifi-
cation of parasite eggs in stool specimens. The eggs of Opisthorchis are
FOOD-BORNE TREMATODE INFECTIONS indistinguishable from those of Clonorchis.
Food-borne trematode infections are a group of zoonotic diseases
caused by hepatic, intestinal, and pulmonary parasitic flukes. These Fascioliasis Fascioliasis occurs in many areas of the world and
infections are contracted by ingestion of infective parasites in under- usually is caused by Fasciola hepatica, a common liver fluke of sheep
cooked aquatic food or water plants. In 2005, an estimated 56.2 million and cattle. F. hepatica is found in more than 50 countries on all conti-
PART 5

people were infected with food-borne trematodes and 7.9 million had nents except Antarctica; F. gigantica is less widespread. The areas with
severe sequelae of these infections. the highest known rates of human Fasciola infection are in the Andean
highlands of Bolivia and Peru. In other areas where fascioliasis is
■■LIVER FLUKES found, human cases are sporadic.
Infectious Diseases

The most important liver flukes causing human infections are the Unlike the other liver flukes, Fasciola species have no second
related species Opisthorchis viverrini and Opisthorchis felineus, which intermediate host, as their infectious metacercariae adhere directly to
cause opisthorchiasis; Clonorchis sinensis, which causes clonorchiasis; aquatic plants. Humans usually acquire infection by ingesting aquatic
and Fasciola hepatica and Fasciola gigantica, which cause fascioliasis plants, such as watercress, that contain viable metacercariae or by
(Table 229-1). drinking water with free metacercariae.
After metacercariae have excysted in the duodenum, Fasciola spe-
Opisthorchiasis and Clonorchiasis O. viverrini is cies migrate through the intestinal wall into the body cavity, penetrate
found mainly in northeastern Thailand, Laos, and Cambodia; the liver capsule, and move through the liver into the bile ducts. This
O. felineus mainly in Europe and Asia, including the former migration route is different from that of other liver flukes and gives

TABLE 229–3 Clinical Features of Food-Borne Trematode Infections

SYMPTOMS OR SIGNS
INFECTION EARLY OR ACUTE STAGE ESTABLISHED OR CHRONIC STAGE COMPLICATIONS
Liver Flukes
Clonorchis sinensis, Often asymptomatic; sometimes Biliary colic, cholestatic jaundice, recurrent Pancreatitis, cholangiocarcinomaa
Opisthorchis viverrini, hepatitis-like symptoms and high fever cholangitis and cholelithiasis; hepatomegaly,
Opisthorchis felineus (especially with O. felineus) gallbladder enlargement, periductal fibrosis.
Light infections are often asymptomatic and remain
so for years.
Fasciola hepatica, Acute onset (1–4 weeks after infection) Biliary colic, cholestatic jaundice, recurrent Pancreatitis. In rare cases: ectopic
Fasciola gigantica with high fever, weight loss, sometimes cholangitis and cholelithiasis; thickening, infections in the central nervous
urticaria and liver tenderness enlargement, and fibrosis of biliary ducts; system, orbital area, gastrointestinal
sometimes repeated relapses of acute symptoms tract, lungs, and other organs. Rarely,
fascioliasis can be fatal.
Intestinal Flukes
Fasciolopsis buski, Often asymptomatic; sometimes Heavy infection may lead to ulceration of intestinal Malnutrition, anemia; rarely, ectopic
Echinostoma spp., nonspecific gastrointestinal symptoms mucosa and malabsorption. Mild infections are infection in the central nervous
Heterophyes heterophyes, often asymptomatic. system
several other species
Lung Flukes
Paragonimus westermani, Often asymptomatic; sometimes Bronchitis-, asthma-, and tuberculosis-like Pulmonary cyst formation; ectopic
Paragonimus kellicotti insidious onset with anorexia and symptoms and signs such as chronic cough, infection in the central nervous
weight loss dyspnea, bloody (“rusty”) sputum system, eyes, skin, heart, abdominal
and reproductive organs
Carcinogenesis has not yet been established for O. felineus.
a

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 rise to symptoms during the acute migratory phase; the parasites expatriates, and returning travelers—and, in the United States, the 1641
may cause tissue destruction, focal bleeding, and inflammation. Some consumption of raw or undercooked crayfish from freshwater river
migrating flukes may deviate from their usual route to cause ectopic systems where P. kellicotti is endemic—is important in patients present-
infections. In the established latent stage of infection, the parasites may ing with fever, cough, hemoptysis, pleural effusions, and peripheral
cause bile duct inflammation, resulting in thickening and expansion eosinophilia.
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. TREATMENT
The most widely used diagnostic approach is direct detection of
Fasciola eggs by microscopic examination of stool or of duodenal or Food-Borne Trematode Infections
biliary aspirates. Eggs generally cannot be detected until 3–4 months Praziquantel and triclabendazole are the two drugs of choice;
after exposure, whereas antibodies to the parasite may become detect- Table 229-2 summarizes the dosages recommended for the various
able 2–4 weeks after exposure. More than one stool specimen may be trematode infections. All confirmed cases of human paragonimiasis
needed for diagnosis, especially in light infections. should be treated with praziquantel (Table 229-2) to avoid the com-
plications of extrapulmonary disease. Surgical management may be
■■INTESTINAL FLUKES needed for pulmonary or cerebral lesions.
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 ■■CONTROL AND PREVENTION
infective metacercariae attached to aquatic plants (Fasciolopsis buski) or Drugs are currently the main method of controlling the morbidity asso-
encysted in freshwater fish. Flukes mature in the human intestines, and ciated with food-borne trematode infections, but integrated programs
eggs are passed with feces. Mechanical irritation of the intestinal wall (including improved sanitation; food inspections; and information,
and inflammation may lead to nonspecific gastrointestinal symptoms education, and communication campaigns) are important for sustain-
such as diarrhea, constipation, and abdominal pain. Most individuals able disease control. Collaboration with other sectors (e.g., agricultural,
infected with intestinal flukes are asymptomatic, but heavy infections environmental, and educational) is necessary to tackle highly complex
can be severe, with intestinal mucosal ulcerations and malabsorption situations in which human behavior, biological factors, and agricultural
(Table 229-3). The diagnosis is established by detection of eggs in stool practices all play a role.
samples. However, eggs from various intestinal trematodes are often

CHAPTER 230 Cestode Infections

morphologically similar, and it is very difficult to distinguish among
species. A cautionary note: Fasciola eggs can be difficult to distinguish ■■FURTHER READING
on the basis of morphologic criteria from the eggs of the intestinal fluke Andrade G et al: Decline in infection-related morbidities following
F. buski. The distinction has implications for therapy: infection with drug-mediated reductions in the intensity of Schistosoma infec-
F. buski is treated with praziquantel, which is not effective against fas- tion: A systematic review and meta-analysis. PLoS Negl Trop Dis
cioliasis (Table 229-2). 11:e0005372, 2017.
Clerinx J, Van Gompel A: Schistosomiasis in travellers and migrants.
■■LUNG FLUKES Travel Med Infect Dis 9:6, 2011.
Paragonimiasis is a parasitic lung infection caused by lung flukes Fried B, Abruzzi A: Food-borne trematode infections of humans in the
of the genus Paragonimus. It is a food-borne parasitic zoonosis, with United States of America. Parasitol Res 106:1263, 2010.
most cases reported from Asia and attributable to consumption of raw Fürst T et al: Global burden of human food-borne trematodiasis: A
or undercooked freshwater crustaceans. Paragonimus westermani and systematic review and meta-analysis. Lancet Infect Dis 12:210, 2012.
related species (e.g., Paragonimus africanus) are endemic in West Africa, Gryseels B et al: Human schistosomiasis. Lancet 368:1106, 2006.
Central and South America, and Asia. The United States has one indig- Jordan P et al (eds): Human Schistosomiasis. CAB International,
enous species of lung fluke, Paragonimus kellicotti. Wallingford, 1993.
Paragonimus species require two intermediate hosts: first, a fresh- Keiser J, Utzinger J: Food-borne trematodiases. Clin Microbiol Rev
water snail; and second, a freshwater crustacean, such as a freshwater 22:466, 2009.
crab. Humans are infected by consuming raw or undercooked infected Ross AG et al: Katayama syndrome. Lancet Infect Dis 7:218, 2007.
crustaceans containing Paragonimus metacercariae. Paragonimus infects Sripa B et al: Liver fluke induces cholangiocarcinoma. PLoS Med
other carnivores such as cats, dogs, foxes, rodents, and pigs in addi- 4:e201, 2007.
tion to humans. After ingestion, metacercariae quickly penetrate the World Health Organization: Female Genital Schistosomiasis: A
duodenum and traverse the peritoneal cavity, diaphragm, and parietal Pocket Atlas for Clinical Health-Care Professionals. Geneva, World
pleura to mature into hermaphroditic worm pairs in the pleural spaces Health Organization, 2015. (Available at http://brightresearch.org/wp-
or lungs within 6–10 weeks. Adults cross-fertilize in cystic cavities in content/uploads/2016/05/FGS-pocket-atlas_eng.pdf WHO/HTM/
the pleural spaces or lungs within another 4–16 weeks and release NTD/2015.4, 2015. Accessed July 18, 2017.)
unembryonated eggs into bronchioles. The eggs are then coughed up
in bloody (“rusty”) sputum and either discharged in sputum or swal-
lowed and later excreted in feces. Unembryonated eggs are passed
from the mammalian host into freshwater ecosystems, where they

230 Cestode Infections

infect intermediate host snails.
The symptoms and signs of paragonimiasis are fever, cough, hemop-
tysis, and peripheral eosinophilia. Some patients with paragonimiasis
and low parasite burdens may remain relatively asymptomatic for A. Clinton White, Jr., Peter F. Weller
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 Cestodes, or tapeworms, are segmented worms. The adults reside in
(cerebral paragonimiasis). the gastrointestinal tract, but the larvae can be found in almost any
Pulmonary paragonimiasis is diagnosed by detection of parasite ova organ. Human tapeworm infections can be divided into two major
in sputum and/or feces. Serology can be helpful in egg-negative cases clinical groups. In one group, humans are the definitive hosts, with
and in cerebral paragonimiasis. Anamnestic information about the the adult tapeworms living in the gastrointestinal tract (Taenia saginata,
consumption of raw or undercooked freshwater crabs by immigrants, Diphyllobothrium, and Dipylidium caninum). In the other, humans are

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