The n e w e ng l a n d j o u r na l
Clinical Problem-Solving
From the Department of Internal Medi-
cine, Sections of Gastroenterology, Hep-
atology, and Nutrition (D.M., M.R.C.)
and Infectious Diseases (J.-L.B.), and the
Department of Radiology (A.O.), Univer-
sity of Chicago Medicine, and the De-
partment of Internal Medicine, Univer­
sity of Chicago Medicine, and the MacLean
Center for Clinical Medical Ethics, Uni-
versity of Chicago (M.S.) — all in Chicago.
Address reprint requests to Dr. Micic at
5841 S. Maryland Ave., MC4076, Chicago,
IL 60637, or at ­dmicic@​­medicine​.­bsd​
.­uchicago​.­edu.
N Engl J Med 2020;382:1844-9.
DOI: 10.1056/NEJMcps1902741
Copyright © 2020 Massachusetts Medical Society.
1844
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of m e dic i n e
Caren G. Solomon, M.D., M.P.H., Editor
Hiding in the Water
Dejan Micic, M.D., Aytekin Oto, M.D., M.B.A., Michael R. Charlton, M.B., B.S.,
Jean‑Luc Benoit, M.D., and Mark Siegler, M.D.​​
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information by sharing relevant background and reasoning with the reader
(regular type). The authors’ commentary follows.
A 59-year-old woman presented to her primary care physician with a 3-month his-
tory of dyspepsia and loss of appetite. Her upper abdominal discomfort was sharp in
quality, radiated to the right upper quadrant, persisted for 3 to 5 hours, and occurred
roughly every 6 days. The discomfort was not associated with eating or moving her
bowels; rare episodes woke her from sleep. She reported no nausea, vomiting, weight
loss, or change in bowel habits. Two days before presentation, she had a temperature
that peaked at 39.9°C, associated with rigors and an erythematous, pruritic rash over
her arms, hips, and buttocks. She reported no cough or dysuria.
Dyspepsia may occur with gastroesophageal reflux, peptic ulcer disease, or cancer.
The fever suggests an infectious or malignant process or an unrelated coexisting
condition. Celiac disease can present with upper abdominal symptoms and a pro-
totypical rash, dermatitis herpetiformis, which is often pruritic. When dyspepsia
is associated with features that are cause for concern (e.g., weight loss, anemia,
dysphagia, or an age >55 years), endoscopic evaluation is indicated to rule out
cancer.
The patient had a history of osteoporosis. She had no history of surgery and did not
use prescription or over-the-counter medications. Screenings for breast and colon
cancer were up to date. Serum electrolyte levels, liver-function studies, and a com-
plete blood count were normal 4 months before her presentation. She lived in a metro-
politan area with her husband and dog. Recent travel included trips to Italy, Switzer-
land, and Denmark. While in Italy, 3 months before her presentation, the patient
reported an upper gastrointestinal illness, with associated emesis and several epi-
sodes of syncope, which began approximately 3 hours after she drank a fresh green
juice blend containing watercress and kale. She noted that the recurrent episodes of
upper abdominal discomfort had begun after this illness.
Acute gastroenteritis is common among travelers and can result from a number of
infectious pathogens. Unlike the present case, however, most cases of acute viral
and bacterial gastroenteritis are self-limited, and patients present with diarrhea.
Norovirus may cause chronic gastroenteritis in immunosuppressed persons, but
this patient has no history of immunocompromise. Bacterial gastroenteritis typi-
cally has an incubation period of 1 to 7 days, although pathogens releasing pre-
formed enterotoxins, including Staphylococcus aureus and Bacillus cereus, can cause
n engl j med 382;19  nejm.org  May 7, 2020
The New England Journal of Medicine
 Clinical Problem-Solving
upper gastrointestinal symptoms within hours
after intake. In these cases, symptoms are expect­
ed to subside within 24 to 48 hours. Protozoal
pathogens, including cryptosporidium, cyclospora,
and Giardia lamblia (also known as G. intestinalis),
could cause symptoms of abdominal discomfort
and bloating for 3 months, although the absence
of diarrhea would be atypical.
On physical examination, the patient’s tempera-
ture was 37.2°C, the heart rate 80 beats per min-
ute, and the blood pressure 135/80 mm Hg. She
appeared comfortable, with no signs of acute
distress. No scleral icterus was present. Her heart
rate was regular, and lung auscultation was nor-
mal. Abdominal examination showed no hepato-
megaly or splenomegaly, and there was only mild
tenderness on palpation in the epigastric region.
Skin examination showed resolving urticaria and
excoriations over the arms and trunk.
The white-cell count was 10,900 per cubic milli-
meter, with 28% neutrophils, 20% lymphocytes,
13% monocytes, and 37% eosinophils. The hemo-
globin level was 12.0 g per deciliter, and the plate-
let count was 252,000 per cubic millimeter. Se-
rum electrolyte levels and renal function were
normal. The aspartate aminotransferase level was
61 U per liter (normal range, ≤37), and the alanine
aminotransferase level was 88 U per liter (normal
range, ≤35). The alkaline phosphatase level was
141 U per liter (normal range, 30 to 120).
The prominent presenting feature in this case is
the peripheral eosinophilia, defined as more than
500 eosinophils per cubic millimeter. Hypereo-
sinophilia may reflect clonal expansion due to a
hematopoietic stem-cell mutation or, more com-
monly, may be due to another condition. The
patient was not exposed to medications com-
monly associated with eosinophilia (e.g., non-
steroidal antiinflammatory drugs, penicillins,
nitrofurantoin, or sulfonamides). Patients with
adrenal insufficiency can present with a periph-
eral eosinophilia and gastrointestinal symptoms,
including abdominal pain and nausea, and in rare
cases, aminotransferase elevations; however, this
patient did not have other suggestive findings,
such as hypotension or hyperpigmentation. She
had no history of allergic rhinitis or asthma,
which might have suggested eosinophilic granu-
lomatosis with polyangiitis.
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A chest radiograph was normal. An ultrasound
examination of the abdomen showed a normal
liver size, at 12.9 cm, and ill-defined hypoechoic
areas within the liver. No intrahepatic or extrahe-
patic ductal dilatation was present. Examination
of the gallbladder did not show wall thickening or
cholelithiasis. A morning serum cortisol level was
12.8 μg per deciliter (353 nmol per liter) (normal
range, 6.0 to 18.4 μg per deciliter [166 to 508 nmol
per liter]), and testing for antineutrophil cyto-
plasmic antibodies (ANCAs) was negative. The
tryptase level was 3.7 ng per milliliter (normal
range, <11.5), and the serum vitamin B12 level was
948 pg per milliliter (699 pmol per liter) (normal
range, 240 to 900 pg per milliliter [177 to 664 pmol
per liter]).
The normal tryptase level is inconsistent with
systemic mastocytosis, and the morning serum
cortisol level makes adrenal insufficiency unlike-
ly. Although testing for antineutrophil cytoplas-
mic antibodies was negative, only half of cases
of eosinophilic granulomatosis with polyangiitis
are positive for myeloperoxidase ANCAs. Vita-
min B12 levels may be mildly elevated in patients
with liver injury, owing to the release of stored
vitamin B12 from damaged cells. The differential
diagnosis for the findings in the liver on ultra-
sound examination ranges from benign lesions
(e.g., focal nodular hyperplasia) to infiltrative
conditions and malignant lesions.
One week after her initial presentation, the pa-
tient was admitted to the hospital with a tempera-
ture of 39.4°C and rigors. During the previous
week, she had restricted her diet and reported a
2.2-kg weight loss. Examination of her abdomen
was normal, with no tenderness on palpation
and no hepatomegaly. The white-cell count was
11,600 per cubic millimeter, with 12% neutro-
phils, 23% lymphocytes, 5% monocytes, and 59%
eosinophils. The absolute eosinophil count was
6830 per cubic millimeter. The hemoglobin level
was 11.3 g per deciliter, and the platelet count was
241,000 per cubic millimeter. The aspartate ami-
notransferase level was 41 U per liter, and the ala-
nine aminotransferase level was 49 U per liter; the
alkaline phosphatase level had normalized. Three
separate stool samples were negative for ova and
parasites. A multiplex gastrointestinal panel was
negative for common viral, bacterial, and proto-
1845
 The n e w e ng l a n d j o u r na l
zoal causes of gastroenteritis, including norovi-
rus, salmonella, cryptosporidium, and G. lamblia.
In the absence of other explanations, the persis-
tent and increasingly severe peripheral eosino-
philia, in combination with the gastrointestinal
symptoms, makes helminthic infection a pri-
mary concern. In returning travelers, infection
with Strongyloides stercoralis can be manifested as
abdominal pain, eosinophilia, and recurrent urti-
caria, and in uncomplicated disease, repeated
stool examinations for rhabditiform larvae may
be negative. However, this infection would not
be expected to cause the abnormalities seen on
liver imaging in this patient, except in rare cases
of hyperinfection and dissemination of larvae in
an immunocompromised host.
Delayed, contrast-enhanced, T1-weighted mag-
netic resonance imaging (MRI) scans of the liver
showed patchy areas of hypoenhancement rela-
tive to the hepatic parenchyma, predominantly
within the periphery of the right hepatic lobe, ex-
tending to the capsule. The portal and hepatic
veins were patent, and there was no intrahepatic
or extrahepatic ductal dilatation. Prominent peri-
portal lymph nodes were observed, measuring up
to 2.6 cm by 1.4 cm (Fig. 1).
Given the patient’s history of exposure to a pet
dog, visceral larva migrans, which results from
the migrating larvae of the nematode Toxocara
canis, should be considered. This could explain
the abdominal pain and eosinophilia, as well as
the ill-defined oval lesions within the hepatic
parenchyma that were seen on imaging. How-
ever, symptomatic infection is characteristically
seen in children with a history of consumption
of contaminated soil, and pulmonary manifesta-
tions are common.
Infection with flukes that have parasitized
the liver provides an alternative explanation for
the constellation of clinical findings in this pa-
tient. Fasciola hepatica has a worldwide distribu-
tion and is acquired through ingestion of aquatic
plants harboring the F. hepatica metacercariae. The
acute symptoms of infection generally last 2 to
3 months and can include abdominal pain and
nausea, which are related to larval migration
through the intestine and liver parenchyma.
During acute infection, immature larvae do not
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of m e dic i n e
Figure 1. Axial, Contrast-Enhanced, T1-Weighted MRI
Scan of the Liver at Presentation.
Ill-defined, hypointense lesions are present in both
lobes of the liver, extending to the liver capsule.
release eggs and are therefore not detected on
stool examination. Dermatologic manifestations
of acute infection include urticaria and migrat-
ing cutaneous nodules as a result of larval mi-
gration to the skin. Imaging of the liver shows
characteristic hypoattenuating tracks extending
from the liver capsule into the parenchyma due
to larval penetration and migration.
Since the patient had ingested watercress while
traveling in Italy, her local health department was
contacted, and serum samples were sent to the
Centers for Disease Control and Prevention (CDC)
for testing of antibodies to F. hepatica. The im-
munoblot assay was positive for an antibody to
FhSAP2, a recombinant antigen derived from
F. hepatica. The patient was treated with triclaben-
dazole, at a dose of 10 mg per kilogram of body
weight, with a second dose given after 24 hours.
The dyspepsia and the peripheral eosinophilia re-
solved over a period of 3 weeks. Repeat imaging
of the liver 6 months after therapy showed im-
provement (Fig. 2).
C om men ta r y
Although this patient initially presented with dys-
pepsia, recognition of the marked eosinophilia
quickly redirected the evaluation away from
common disorders such as peptic ulcer disease
to conditions that could explain the high eosino-
phil count; the recognition of infiltrative disease
of the liver further narrowed the differential
 Clinical Problem-Solving
Figure 2. Axial, Contrast-Enhanced, T1-Weighted MRI
Scan of the Liver, Obtained 6 Months after Treatment.
The lesions have decreased in size and number but are
still detectable.
diagnosis. Ultimately, the patient’s history of
ingestion of freshwater aquatic plants preceding
the onset of symptoms led to a unifying diagno-
sis of acute fascioliasis.
Fascioliasis is a helminthic infection resulting
from exposure to F. hepatica or F. gigantica. F. hepati-
ca infection is common in sheep and cattle, but
the pathogen can also cause disease that is spo-
radic or endemic in humans. Human fascioliasis
most often results from the consumption of
freshwater plants such as watercress and water
chestnuts, to which the infective metacercariae
attach themselves. Cattle, sheep, pigs, and other
domesticated herbivores such as donkeys and
llamas are the definitive hosts from which fas-
ciola eggs are released to form ciliated swim-
ming miracidia, which infect the intermediate
host, lymnaeid snails. The infected snails release
the cercariae that form cysts on freshwater plants
(Fig. 3).1-3
Once they are ingested by humans, the meta-
cercariae excyst (i.e., emerge from a cyst) in the
intestine, and within a period of 2 to 24 hours,
they migrate into the peritoneal cavity as imma-
ture flukes. After 48 hours, the larvae penetrate
Glisson’s capsule, and over a period of 7 weeks,
the immature flukes migrate through the liver
parenchyma, resulting in necrosis and an eosino-
philic infiltration.4 During this larval stage, the
immature larvae do not release eggs, and the
clinical symptoms and signs include right-upper-
quadrant abdominal pain, weight loss, and fever,
as well as eosinophilia resulting from the inflam-
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
matory response to the migrating larvae.5 As in
this case, urticaria, pruritus, or both, are seen in
20 to 25% of cases during acute infection and
are classically described as occurring with der-
matographia.6
In the chronic, or biliary, stage of fascioliasis,
adult hermaphrodite flukes release eggs in the
hepatic and common bile duct of the host. This
latent stage, which can last for decades, may be
characterized by biliary obstruction, ascending
cholangitis, acute pancreatitis, or mucosal ero-
sion and hemobilia.5 Stool can be examined for
the presence of eggs in the biliary stage of dis-
ease. The eggs are characteristically yellowish
brown, nonembryonated, ovoid, and large (130 to
150 μm by 60 to 90 μm). Ova are present only
in the biliary stage, which occurs 2 to 4 months
after ingestion of the infective metacercariae;
testing of stool samples for ova and parasites is
uninformative early in the course of infection.
Since the eggs are released sporadically in chron-
ic fascioliasis, examination of multiple concen-
trated stool specimens may be required for an
accurate diagnosis.5
In chronic fascioliasis, ultrasonography can
show spontaneously moving parasites or charac-
teristic crescent-shaped contents in the biliary
tract.7 In an acute F. hepatica infection, parenchy-
mal heterogeneity with hypoechoic coalescing
nodules can be seen on ultrasound examination,
but this finding is nonspecific.8 Confined, sub-
capsular, irregular coalescing nodules with peri-
portal lymph-node enlargement can be seen on
cross-sectional computed tomography or MRI,8 a
finding that was observed in this patient.
The present case is most consistent with an
acute infection, given the ingestion of water-
cress, followed within hours by an acute illness,
which occurred 3 months before the current
presentation. No features of obstructive jaundice
were present, and the abnormalities on imaging
involved the liver parenchyma — in particular,
the subcapsular region. Despite the examination
of three separately submitted stool specimens for
detection of ova and parasites, eggs consistent
with F. hepatica infection were not identified.
Because immature flukes do not produce eggs,
the diagnosis of acute infection is based on sero-
logic testing, available through the CDC, with
the use of an immunoblot assay based on a re-
combinant F. hepatica antigen; the reported sen-
1847
 The n e w e ng l a n d j o u r na l of m e dic i n e

LIVER

Immature flukes Cattle

migrate from duodenum
to liver parenchyma
and biliary ducts
Human

LIVER

LIVER

Sheep
LIVER
Fluke

Unembryonated eggs
WATERCRESS Infective metacercariae passed in feces
ingested by definitive hosts
(sheep, cattle, humans)

Metacercariae
Embryonated
egg

Unembryonated eggs
become embryonated
in water

Watercress

Miracidia
Cercariae are released
and encyst on
freshwater plants Miracidia hatch
and invade
snail host

Cercariae

Freshwater snail
(e.g., Galba truncatula)

Figure 3. Life Cycle of Fasciola hepatica.

Embryonated eggs release miracidia, which invade an intermediate snail host. Cercariae are released from the snail and encyst as meta-
cercariae on freshwater plants. Ingestion of the plants by mammals, including humans, can result in disease when metacercariae excyst
in the small bowel. Data are from the Centers for Disease Control and Prevention.3

1848 n engl j med 382;19 nejm.org May 7, 2020

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 Clinical Problem-Solving

sitivity is 94%, and the specificity is 98% or
higher.3 Since antibodies to Fasciolidae can de-
velop within 2 to 4 weeks after cyst ingestion,
serologic testing is the mainstay of diagnosis in
patients with an acute infection.
Given the availability of serologic testing,
histologic examination to confirm the diagnosis
is usually not required. When histologic exami-
nation is performed, typical findings include
necrotic debris, tracklike destruction of the liver
parenchyma, and polymorphonuclear infiltration
with eosinophils.9 Eggs or flukes are often not
identified.5
F. hepatica is found throughout the world, with
an estimated 2.4 million to 17 million persons
infected.10 Since fascioliasis is not a reportable
disease in the United States, accurate prevalence
estimates are not available. Although the inter-
mediate host — snails of the Lymnaeidae family
— exists in the United States, most clinical
cases in the United States are diagnosed in im-
migrants and returning travelers.11,12 In areas
where F. hepatica infection is endemic, infection
is most common in children.2 In zones such as
the Bolivian Altiplano, where the infection is
hyperendemic, humans excrete sufficiently high
numbers of viable eggs to perpetuate the life
cycle of the liver fluke.2
Although the treatment of choice for other
trematodes is praziquantel, this agent is ineffec-
tive against F. hepatica. Triclabendazole has been
used in veterinary practice for fascioliasis since
1983, with demonstrated efficacy against imma-
ture and mature forms of the liver fluke. After
an outbreak of fascioliasis in Iran in 1989, a for-
mulation of triclabendazole for use in humans
was developed in Egypt and registered in De-
cember 1997.13 Triclabendazole is administered
as a single dose of 10 mg per kilogram; two
doses of 10 mg per kilogram, administered 12
to 24 hours apart, are given in severe cases.5 In
a case series of 24 asymptomatic persons with
positive tests for eggs in the stool who were
treated with triclabendazole, cure (defined by a
negative follow-up stool examination) was re-
ported in 19 persons (79%) after a single dose;
12 months after therapy, serologic tests were
negative in more than 90% of the patients who
were cured.14
In the present case, recognition of the causes
of marked eosinophilia and the implications of
the patient’s ingestion of freshwater plants while
she was traveling prompted consideration of
F. hepatica infection. Serologic testing confirmed
the diagnosis and led to prompt initiation of
therapy, with the resolution of symptoms and
eosinophilia and improvement in the parenchy-
mal abnormalities on imaging.
Dr. Oto reports receiving grant support from Guerbet and
Philips, grant support and advisory board fees from Profound
Healthcare, and consulting fees from AbbVie. No other poten-
tial conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Carol Semrad and Vijaya Rao for their critical
review of an earlier version of the manuscript.

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