The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Problem-Solving

Caren G. Solomon, M.D., M.P.H., Editor

Home Sweet Home

Maralyssa Bann, M.D., Daniel R. Kaul, M.D., Mahri Z. Haider, M.D., M.P.H.,
Sanjay Saint, M.D., M.P.H., and Zachary D. Goldberger, 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, sharing his or her reasoning with the reader (regular type).
The authors’ commentary follows.

A 25-year-old woman presented to the emergency department with a 2-day history From the Department of Medicine (M.B.,
of fever, chills, and sweats. These symptoms began abruptly and were accompanied M.Z.H., Z.D.G.) and the Divisions of
General Internal Medicine (M.B., M.Z.H.)
by malaise, headache, dry cough, myalgias, and decreased appetite. She reported no and Cardiology (Z.D.G.), University of
photophobia, neck stiffness, chest pain, flank pain, dyspnea, nausea, vomiting, ab- Washington School of Medicine, Harbor-
dominal pain, urinary urgency, or dysuria. view Medical Center, Seattle; and the De-
partment of Internal Medicine (D.R.K.,
S.S.) and Division of Infectious Disease
In a young, healthy person with relatively nonspecific symptoms, the likely diag- (D.R.K.), University of Michigan Medical
noses include viral illnesses and common conditions such as pyelonephritis. An School, and the Department of Veterans
Affairs Health Services Research and De-
infectious cause is highly likely given the abrupt onset of these nonspecific symp- velopment Center of Excellence (S.S.) —
toms. Further details of the patient’s medical history, including information on both in Ann Arbor. Address reprint re-
recent travel or exposures to ill persons, and a physical examination, will help de- quests to Dr. Goldberger at Harborview
Medical Center, Box 359748, Seattle, WA
termine whether further testing and empirical antimicrobial therapy is indicated. 98104, or at ­zgoldber@​­uw​.­edu.

N Engl J Med 2018;378:461-6.

Three weeks before presentation, the patient returned from a month-long trip DOI: 10.1056/NEJMcps1704731
through Southeast Asia, including Myanmar, Laos, Thailand, and the Philippines, Copyright © 2018 Massachusetts Medical Society.

where she had traveled through both rural and urban areas. She did not receive pro-
phylactic vaccinations or medications before travel. During the trip, she ate food that
she prepared herself as well as food purchased from markets and street vendors,
swam in both fresh water and salt water, and had direct exposure to animals, espe-
cially elephants. She noted insect bites that she believed to be from bedbugs and re-
ported an episode of self-limited, nonbloody diarrhea associated with fever and chills
while traveling.

Although it is possible that the patient’s symptoms are not related to her travel,
her travel history, which indicates multiple infectious exposures, and the absence
of vaccination or malaria prophylaxis warrant an urgent evaluation for potentially
life-threatening tropical infection. Testing to rule out malaria is required. Since
Southeast Asia has high rates of enteric fever and the patient ate local foods, blood
cultures to detect Salmonella typhi and S. paratyphi are indicated, although cultures
are often negative in persons with enteric fever. Scrub typhus is transmitted
through chigger bites largely in rural areas, and the patient reports bug bites; in
addition, murine typhus merits consideration as a cause of undifferentiated fever,
especially in travelers returning from Asia. A physical examination should include
a careful search for eschar or macular rash. Leptospirosis can be contracted from
water or soil contaminated by the urine of infected animals and can cause myalgia,

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 The n e w e ng l a n d j o u r na l
headache, and conjunctival suffusion. Melioido-
sis may be acquired in Southeast Asia through
percutaneous inoculation, inhalation, or, in rare
instances, ingestion of Burkholderia pseudomallei,
but infection with this bacterium is generally
manifested as cellulitis or pneumonia, neither
of which is present in this patient. Although the
patient did have exposure to mosquitoes, the
long incubation period of arboviruses such as
chikungunya, dengue, and Japanese encephalitis
argues against these diseases. Other tropical
diseases, such as acute schistosomiasis or tuber-
culosis, are possible. The abrupt onset makes
tuberculosis less likely, but chest radiography
would be useful.
The patient’s medical history is notable for recur-
rent urinary tract infections, for which she took
ciprofloxacin intermittently. Her last episode of
dysuria occurred approximately 2 weeks before
the current presentation, and she completed a
3-day course of ciprofloxacin. There is no family
history of rheumatologic disease or cancer. The
patient was employed as an office worker in a
manufacturing plant. She had no recent sick con-
tacts and reported no use of tobacco, alcohol, or
illicit drugs. During the past year she reported
having used condoms consistently with one male
partner and having no sexual contacts within the
preceding 3 months.
A complication of her recent urinary tract infec-
tion, such as pyelonephritis or renal abscess, is
possible. However, the absence of recurrent uri-
nary tract symptoms and flank pain makes these
conditions less likely. Her sexual history does
not suggest risk factors for acute infection with
the human immunodeficiency virus (HIV). Other
viral infections commonly seen in returning
travelers, such as acute infection with Epstein–
Barr virus or cytomegalovirus, are possible.
On physical examination, the patient’s tempera-
ture was 39.6°C, heart rate 112 beats per minute,
blood pressure 111/64 mm Hg, respiratory rate
16 breaths per minute, and oxygen saturation
98% while she was breathing ambient air. She
was uncomfortable but appeared well-nourished.
The pupils were 3 mm in diameter and equally
reactive to light. There was no scleral icterus or
conjunctival pallor. The neck was supple. No
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of m e dic i n e
lymphadenopathy was present. Mucous mem-
branes were dry. Regular tachycardia was pres-
ent, with no murmurs, rubs, or gallops. Lung
sounds were clear on auscultation, with no rales
or wheezes. The abdomen was soft, nondistended,
and nontender to deep palpation. Normal bowel
tones were present, and no hepatosplenomegaly
was detected. No costovertebral tenderness was
elicited. No joint effusions or rashes were present.
Neurologic examination revealed intact cranial
nerves. Motor strength was 5/5 in both legs, and
sensation in both arms and both legs was normal.
Gait and balance were normal. No deficits of cog-
nition or language were noted.
With the exception of tachycardia and fever, the
physical examination is normal. There is no
jaundice, confusion, or hepatosplenomegaly, as
might be present with severe malaria. The ab-
sence of cervical lymphadenopathy and flank
tenderness makes mononucleosis and pyelone-
phritis, respectively, unlikely. There is no rash or
eschar to suggest scrub typhus or murine typhus,
and no pneumonia or cellulitis, as would be ex-
pected with acute melioidosis. The absence of
conjunctival suffusion reduces the likelihood
of leptospirosis.
Laboratory studies revealed a white-cell count of
7310 per cubic millimeter (71% neutrophils, 21%
lymphocytes, 8% monocytes, and no eosinophils)
and a hemoglobin level of 14.3 g per deciliter. The
serum sodium level was 130 mmol per liter, po-
tassium 4.2 mmol per liter, chloride 96 mmol per
liter, bicarbonate 25 mmol per liter, urea nitrogen
10 mg per deciliter (3.6 mmol per liter), and cre-
atinine 0.88 mg per deciliter (77.8 μmol per liter).
The aspartate aminotransferase level was 53 U per
liter, and the alanine aminotransferase level was
52 U per liter (normal range for both, 9 to 38).
The total bilirubin level was 0.6 mg per deciliter
(10.3 μmol per liter; normal range, 0.2 to 1.3 mg
per deciliter [3.4 to 22.2 μmol per liter]). Urinaly-
sis showed trace protein, 1+ ketones, bacteria,
and squamous cells; tests for white cells, leuko-
cyte esterase, and nitrites were negative. Chest
radiography revealed clear lung fields. A rapid
diagnostic test for influenza was conducted with
a nasal swab, and the results were negative. Thin
and thick blood smears were negative for malaria.
Blood cultures were drawn.
 Clinical Problem-Solving

The absence of leukocytosis argues against a examination or the laboratory studies suggest a
routine bacterial infection, and the absence of routine cause. I would have expected more ini-
eosinophilia makes acute schistosomiasis (Kata- tial diarrhea in the presence of gram-negative
yama fever) very unlikely. The negative results on organisms that cause acute infection of the gas-
urinalysis and the normal creatinine level effec- trointestinal tract (e.g., campylobacter species
tively rule out leptospirosis. Much higher trans- and nontyphoidal salmonella species), but per-
aminase levels would be expected with viral haps the brief course of ciprofloxacin altered the
hepatitis. The absence of atypical lymphocytosis clinical presentation. The current presentation,
makes mononucleosis unlikely. The likelihood with systemic symptoms weeks after a mild diar-
of malaria is reduced given the initial negative rheal episode, is consistent with enteric fever.
results on smears, but false negative results are Maturation of the culture is likely to provide a
a possibility in the absence of technical expertise definitive cause.
or in the presence of very low levels of parasites
in the blood; rapid diagnostic testing improves During hospitalization, the patient continued to
the diagnostic yield. The hyponatremia may be have fever and sweats. Severe epigastric pain de-
related to dehydration, and ketones in the urine veloped, as did episodes of nonbloody diarrhea.
are common in acute illness in the absence of Her white-cell count decreased from 7500 to 3800
diabetes mellitus. Given the patient’s recent cells per cubic millimeter. Two additional sets of
travel and the high likelihood of enteric fever thin and thick smears for malaria were negative.
on the basis of clinical findings, an empirical Serologic tests for mononucleosis and HIV infec-
course of antibiotic treatment would be reason- tion were negative.
able. Whereas a fluoroquinolone is often the
first drug of choice for enteric fever, the patient’s Again, the constellation of gram-negative bacte-
recent use of a fluoroquinolone for her urinary remia and abdominal pain developing after a
symptoms and her recent return from Southeast prolonged, undifferentiated febrile illness in an
Asia, where intermediate and fluoroquinolone- otherwise healthy person returning from travel
resistant strains of S. typhi are circulating, sug- in Southeast Asia strongly suggests enteric fever.
gest that empirical azithromycin may be prefer- Epigastric pain can represent a general symptom
able in this case. or a more serious complication of typhoid fever,
such as intestinal perforation, but typically oc-
After the administration of 1 liter of intravenous curs after 1 to 3 weeks of fever. Mild elevations
fluid and oral acetaminophen, the patient defer- in transaminase levels and leukopenia may be
vesced and her symptoms resolved. She was dis- seen with this infection as well. Although drug
charged home. Within 24 hours after discharge, resistance is common in Southeast Asia, resis-
the blood cultures drawn previously revealed tance to third-generation cephalosporins is rare,
gram-negative rods. The patient was called and and ceftriaxone should be continued at this time
advised to return to the hospital. She presented until the final results of blood cultures are avail-
with a temperature of 38.5°C and a heart rate of able. If the patient were to become hemodynami-
90 beats per minute. Her blood pressure was cally unstable, repeat evaluation for the infec-
134/83 mm Hg and her respiratory rate 18 breaths tious source and a broadening of the antibiotics
per minute. The results of her physical examina- considered would be indicated.
tion were otherwise unchanged. The patient was
admitted to the hospital and treated empirically Blood cultures were positive for S. typhi, with
with intravenous ceftriaxone. intermediate resistance to ciprofloxacin. A course
of ceftriaxone was continued while the patient
Gram-negative bacilli are unlikely to be a con- remained in the hospital and was followed by a
taminant; the main consideration in this case is complete, 14-day course of oral azithromycin on
whether these gram-negative bacilli come from discharge, after which the patient fully recovered.
a fairly routine source (e.g., pyelonephritis or The case was reported to local public health offi-
cholangitis) or were acquired during the patient’s cials for appropriate follow-up as well as screen-
overseas travel. None of the findings on physical ing and monitoring of potential contacts.

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 The n e w e ng l a n d j o u r na l
C om men ta r y
Fever in the returning traveler is a commonly
encountered presentation. Making the correct
diagnosis requires careful consideration of ex-
posures during travel and a knowledge of the
specific pathogens present in the areas visited.
In a traveler with dietary and environmental ex-
posures returning from Southeast Asia with un-
differentiated fever, initial considerations include
malaria, enteric (typhoid or paratyphoid) fever,
scrub or murine typhus, leptospirosis, melioido-
sis, and diseases associated with arboviruses,
such as dengue or Japanese encephalitis.1 Rou-
tine illnesses not specifically associated with
travel, such as influenza or mononucleosis, must
be considered as well.
Identifying the causative organism is impor-
tant in order to guide appropriate supportive and
antimicrobial therapy. The presence of certain
findings on physical examination (e.g., eschar
in scrub typhus, conjunctival suffusion in lepto-
spirosis, and lymphadenopathy in infectious
mononucleosis) can help guide the differential
diagnosis.2,3 The incubation period can also be
helpful in guiding diagnosis; for example, den-
gue and influenza typically have short incuba-
tion times of approximately 7 days or less. The
general workup should include bacterial blood
cultures as well as parasitologic investigation for
malaria by means of microscopy (if appropriate
expertise is available) and rapid diagnostic test-
ing. If possible, positive results on rapid diag-
nostic testing should be confirmed on micros-
copy. Specialized testing should be pursued if
clinical suspicion of a specific pathogen is high.
Empirical treatment is often initiated, depend-
ing on the severity of illness as well as the avail-
ability or reliability of testing.
Typhoid fever is an infection caused by the
gram-negative bacillus S. typhi, which is transmit-
ted through the fecal–oral route in areas with
poor sanitation. Transmission may occur from
persons with acute infection or from asymptom-
atic, chronic carriers in whom the biliary tree
and gallbladder serve as a reservoir of infection.
Typhoid fever occurs throughout the developing
world, including Central America, South America,
the Caribbean, Africa, and Asia, with particularly
high prevalence in southern Asia. A recent sys-
tematic review estimated that 11.9 million cases
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of m e dic i n e
of typhoid disease occur annually in low- and
middle-income countries, accounting for 129,000
deaths.4 Improvements in public-health measures
have greatly reduced transmission in North
America and Europe. Only a few hundred cases
are identified in the United States each year, and
among these cases approximately 90% occur in
recent international travelers, with the majority
returning from India, Bangladesh, or Pakistan.5
After ingestion of the causative organism,
there is an asymptomatic incubation period of
6 to 30 days,1 during which bacteria invade the
mucosal lining of the small intestine and dis-
seminate through the lymphatic and reticuloen-
dothelial systems until they are released into the
bloodstream, triggering the symptomatic phase
of illness. As was the case in this patient, fever is
the prominent symptom; it may be accompanied
by other, nonspecific symptoms of insidious on-
set, including malaise, headache, nonproductive
cough, and generalized abdominal discomfort.
Diarrhea or constipation may occur during this
period, but some patients have neither of these
symptoms.6
Early findings on physical examination, such
as a maculopapular “rose spot” rash on the torso
and the arms and legs, hepatosplenomegaly, and
coated tongue are inconsistently present.6 Pulse–
temperature disassociation (relative bradycardia)
is sometimes seen, although this symptom is not
specific for typhoid fever and may also occur
with other intracellular infections, such as Q fever
and chlamydial infections. Laboratory evaluation
may reveal additional nonspecific findings, such
as anemia, thrombocytopenia, leukocytosis, leuko­
penia, or elevated transaminase levels. Gastro-
intestinal bleeding, one of the most commonly
reported complications, may develop after sev-
eral weeks of illness and is caused by inflamma-
tion and necrosis of Peyer’s patches, the small
intestinal sites of the organism’s entry. Intesti-
nal perforation resulting from necrotizing lymph-
adenitis is a rare complication that is associated
with a high fatality rate and merits urgent surgi-
cal intervention.7
Definitive diagnosis of typhoid fever can be
challenging, since the sensitivity of blood cul-
ture has been reported to be as low as 40% and
that of urine or stool culture to be lower.8 Sero-
logic tests for antibodies against S. typhi, such as
the Widal test, are problematic, since a positive
 Clinical Problem-Solving

reaction in areas where the organism is endem­
ic may represent previous infection.9 Given the
challenges associated with laboratory diagnosis,
prompt initiation of empirical antibiotic treat-
ment is generally warranted for patients in whom
typhoid fever is suspected, since this approach
has been associated with improved outcomes.10
The most commonly used oral agents for un-
complicated cases include fluoroquinolones
(except in instances when the likelihood of resis-
tance is thought to be high, which is particu-
larly the case in patients who have traveled from
southern Asia) and azithromycin.11 In one re-
port, more than 90% of U.S. travelers returning
from India and Bangladesh had either resistance
or intermediate sensitivity to ciprofloxacin.5 For
patients with severe illness, intravenous cepha-
losporins, such as ceftriaxone, are indicated. In
one small, placebo-controlled, randomized trial
of high-dose dexamethasone involving patients
presenting with severe disease and decreased
mental status or encephalopathy, mortality was
lower in the group taking dexamethasone with
chloramphenicol than in the group taking chlor-
amphenicol and placebo.12
Most patients with uncomplicated disease have
a good response to antibiotic therapy, although a
small number have clinical relapse 2 or 3 weeks
after symptom resolution and should be treated
with an additional course of antibiotics. Owing
to the intracellular nature of the bacterium, fever
can persist for several days, even after appropri-
ate antibiotic treatment has been instituted; there-
fore, the absence of immediate defervescence
should not prompt a change in the antibiotic
regimen.
Because antibiotic resistance is becoming par-
ticularly common, the prevention of typhoid
fever remains critical. Patient counseling before
travel should include discussion of frequent
handwashing and strict hygiene practices with
regard to the intake of food and water. The Cen-
ters for Disease Control and Prevention recom-
mends vaccination (parenteral capsular polysac-
charide or oral live-attenuated) against typhoid
fever for travelers to areas in which S. typhi is
endemic.13 Both forms of the vaccine have an
estimated efficacy of approximately 50% in nu-
merous international regions14 and 80% for U.S.
travelers returning from Southeast Asia.15 Inject-
able and oral vaccines offer 2 and 5 years of
protection, respectively; if longer-lasting immu-
nity is required, booster immunization is recom-
mended. The parenteral vaccine is not effective
against the related, nearly indistinguishable ill-
ness of paratyphoid fever (which is caused by
infection with S. enterica serotype paratyphi).
Immunocompromised patients should not re-
ceive the live oral vaccine.
Overall, typhoid fever is a treatable condition
that is uncommon in the United States. This pa-
tient presented with nonspecific symptoms that
invoked a broad differential diagnosis. This case
underscores the importance of taking a careful
history and considering the possibility of infec-
tion with a virus or bacterium that is endemic to
an area to which a febrile patient has recently
traveled.
Dr. Saint reports receiving consulting fees from Doximity and
Jvion. No other potential conflict of interest relevant to this ar-
ticle was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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 Clinical Problem-Solving

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clinical problem-solving series

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