ENTERIC FEVER

The classic syndrome of enteric fever is an acute illness, the first typical manifestations
of which are fever, headache, abdominal pain, relative bradycardia, splenomegaly, and
leukopenia. The prototype of the syndrome is typhoid fever caused by Salmonella
enterica serotype typhi (see Chapter 220 ). Fever is present in 75% to 100% of cases[1]
and is often initially of the remittent type, rising in a stepwise fashion during the first
week of illness, after which it becomes sustained.[2] [3] Typhoid fever is a major problem
for people living in developing areas with poor sanitation and fecal contamination of food
and water. It is estimated that there are at least 16 million new cases of typhoid fever each
year and 600,000 deaths.[4] In the United States, 2445 cases were reported to the Centers
for Disease Control and Prevention between 1985 and 1994, 72% of which were
imported, most frequently from Mexico or India.[5] In addition, 60 relatively small
outbreaks have been reported in the United States from 1960 to 1999 and their average
frequency per year appears to be decreasing.[6]
Pathogenesis

S. enterica serotype typhi and other bacteria that cause the enteric fever syndrome are
ingested and survive exposure to gastric acid before gaining access to the small bowel,
where they penetrate the intestinal epithelium possibly through microfold cells over
Peyers patches. During an incubation period of 7 to 14 days, they multiply in intestinal
lymphoid tissue and then disseminate by the lymphatic or hematogenous route.
Salmonella spp. grow intracellularly, primarily in reticuloendothelial cells in lymph
nodes, spleen, liver, and bone marrow. Animal models for this syndrome in which mice
are infected orally with Salmonella enteritidis or Yersinia enterocolitica have been
developed.[7]
Clinical Features

The organism classically responsible for the enteric fever syndrome is S. enterica
serotype typhi (formerly S. typhi). Other salmonellae, especially Salmonella paratyphi A,
Salmonella schottmuelleri (formerly S. paratyphi B), Salmonella hirschfeldii (formerly S.
paratyphi C), and Salmonella choleraesuis, may cause a similar clinical syndrome (
Table 941 ). Other diseases that may mimic enteric fever and that must be included in
the differential diagnosis of enteric fever are also summarized in Table 941 ; important
clinical and epidemiologic clues to these specific diagnoses are indicated.
Symptoms

Classic typhoidal fever begins with a remittent fever pattern that becomes sustained
over the first few days of illness. The frequencies of reported symptoms from several
series of patients infected by S. typhi and S. paratyphi A and S. schottmuelleri are
summarized in Table 942 . Most patients report fever and headache. Although reports
from the preantibiotic era suggest that constipation occurred more frequently than
diarrhea (79% versus 43%),[3] more recent reports suggest that these symptoms occur with
approximately equal frequency or that diarrhea may be more common, particularly in

young children and in adults with human immunodeficiency virus (HIV) infection.[8] [9] [11]
[12] [13]
Extraintestinal symptoms reported by patients include cough and conjunctivitis.
Although enteric fever caused by salmonellae other than S. typhi is usually less severe
and of shorter duration than typhoid fever, the syndromes are not sufficiently different to
permit clinical separation of individual cases.
Physical Findings

In evaluating patients with possible enteric fever syndrome, the physical examination
should focus on characteristics of the fever curve and accompanying pulse, skin, eyes,
oral cavity and oropharynx, chest, abdomen, and lymph nodes. The frequencies of
commonly reported physical findings are summarized in Table 942 . Fever is present in
most series in more than 90% of the cases. However, bacteriologic confirmation of
typhoid fever has been obtained in patients who were afebrile when the culture was
obtained. Classically, the fever is remittent during the first week, rising in a stepwise
fashion in both naturally acquired infection and volunteer studies[2] ; after the first week,
the fever usually becomes sustained. Deviations from this classic pattern frequently
occur, particularly in endemic areas. In studies from India, fever was remittent in 30%
and 60% of the cases, sustained in 22% to 25%, and intermittent in 15% to 46%.[1]
Relative bradycardia suggests the diagnosis of enteric fever. The presence of rose spots,
blanching erythematous maculopapular lesions 2 to 4 mm in diameter, although not
pathognomonic, is extremely helpful in confirming the impression of enteric fever;
however, they are observed in less than half of the patients and are even less common in
dark-skinned people.[3] Rose spots may be observed more frequently in infection caused
by S. typhi than in other forms of enteric fever.[14] [15] Conjunctivitis has been reported in up
to 44% of the patients with enteric fever, but it is usually less common.[3] Pharyngitis is
infrequent and usually not a prominent feature. Rales may be present on examination of
the chest. Abdominal tenderness may be diffuse or localized, most often in the right
lower quadrant. Splenomegaly is noted more frequently than hepatomegaly. Two
physical findings, lymphadenopathy and herpes simplex labialis, are useful in suggesting
alternative diagnoses because they rarely occur in patients with enteric fever.
Laboratory Findings

The definitive diagnosis of enteric fever is made by isolating S. typhi or another

Salmonella sp. from blood, bone marrow, stool, or urine. Cultures of blood as well as
stool and urine should be obtained before the initiation of antimicrobial therapy. If
multiple blood cultures are
* The authors thank Dr. Richard D. Pearson, who coauthored this chapter in previous editions, for his
important input.

1274

TABLE 94-1 -- Clinical, Epidemiologic, and Laboratory Clues to the Causes of

Enteric Fever and Conditions That May Mimic Enteric Fever
Etiologic Agent
or Disease

Clinical Clues in
Addition to Fever

Epidemiologic Clues

Laboratory Clues

Causes of Enteric Fever

Young adults, travel,
especially to India,
Mexico, and other
tropical areas, *
exposure to known
carrier

Salmonella
enterica
serotype Typhi

Salmonella
paratyphi A

Cultures (B, BM, U, F),

serology, leukopenia

Relative bradycardia,
splenomegaly, rose
spots, conjunctivitis

Salmonella schottmuelleri
Salmonella choleraesuis
Yersinia
enterocolitica

Chronic liver or other Older adults, pet

underlying disease, exposure
arthritis, erythema
nodosum

Cultures (B, F, J),

serology

Yersinia pseudotuberculosis
Campylobacter Stigmata or chronic
liver disease,
fetus
phlebitis

Older adults, farm or Cultures (B, F),

small-animal contact
serology

Brucellosis
(Brucella spp.)

Paucity of physical
findings

Occupation (abattoir
Cultures (B, BM),
employee, butcher),
serology, leukopenia
animal contact (goats,
sheep, cattle), diet
(unpasteurized cheese)

Typhoidal
tularemia
(Francisella
tularensis)

Severe prostration,
splenomegaly

Animal contact
Serology
(especially rabbits),
vector exposure (ticks)

Conditions That May Mimic Enteric Fever

Bacterial infections
Septicemic
Severe prostration
plague
(Yersinia pestis)

Rodent contact, vector Cultures (B), serology

exposure (fleas), travel

Intestinal
anthrax (

Travel, * diet
(undercooked meat)

Severe prostration

Cultures (B, F)

TABLE 94-1 -- Clinical, Epidemiologic, and Laboratory Clues to the Causes of

Enteric Fever and Conditions That May Mimic Enteric Fever
Etiologic Agent
or Disease

Clinical Clues in
Addition to Fever

Epidemiologic Clues

Laboratory Clues

Bacillus
anthracis)
Septicemia
melioidosis (
Burkholderia
pseudomallei)

Severe prostration,
pustular skin lesions

Travel, * especially
Southeast Asia

Cultures (B), serology,

chest radiograph

Acute
bartonellosis (
Bartonella
bacilliformis)

Severe prostration,
hemolysis, renal
failure

Travel to Andean
valleys in Peru,
Ecuador, and
Colombia, * vector
exposure (sand fly)

Cultures (B), blood

smear, acute hemolysis

Leptospirosis ( Relative bradycardia, Occupation (farmers,

Cultures (B, CSF, U),
Leptospira spp.) conjunctival
abattoir and sewer
serology, hepatorenal
suffusion
workers, veterinarians), dysfunction
animal contact
(especially cattle,
dogs), swimming
Relapsing fever Fever pattern,
( Borrelia
conjunctival
spp.)
suffusion,
splenomegaly, skin
rash

Travel, especially to
Blood smear
Southeast Asia, Far
East, Ethiopia, and the
western United States, *
vector exposure (louse,
tick)

Legionellosis ( Pneumonia, CNS

Legionella spp.) symptoms

Normal or
compromised host

Intestinal
Stigmata of
tuberculosis (
tuberculosis or AIDS
Mycobacterium
tuberculosis,
Mycobacterium
aviumintracellulare)

Exposure to known
Cultures (S, G, BM, L),
case travel * diet
radiograph (UGI,
SBFT)
(unpasteurized milk
and milk products),
malnourished children,
HIV infection

Abdominal
Abdominal mass,
actinomycosis ( fistula
Actinomyces
spp.)

Men

Chest radiograph,
purulent sputum, DFA
of sputum, urine
antigen

Culture (FD, A),

radiograph (UGI,
SBFT), CT with oral
contrast medium

TABLE 94-1 -- Clinical, Epidemiologic, and Laboratory Clues to the Causes of

Enteric Fever and Conditions That May Mimic Enteric Fever
Etiologic Agent
or Disease

Clinical Clues in
Addition to Fever

Intra-abdominal Spiking daily fever,

abscess
reduced
diaphragmatic
excursion,
intraabdominal or
diaphragmatic pain

Epidemiologic Clues
Previous surgery,
bowel or biliary tract
disease

Laboratory Clues
Leukocytosis, CT,
gallium scan,
sonography,
fluoroscopy

Rat bite fever

Rat bite or food-borne
Streptobacillus Headache, nausea,
vomiting, rash,
outbreak
moniliformis
myalgia, polyarthritis

Culture (B, J), serology

Rat bite
Spirillum minus Headache, nausea,
adenopathy, roseolarurticarial rash

Serology

Mycoplasma
pneumoniae

Cough, headache,
bullous myringitis

Children and
adolescents

Serology

Exposure to parrots,
Serology
Chlamydophila Headache, nausea,
vomiting, arthralgias, parakeets, related birds
psittaci
cough
Bacterial
pneumonia (
Streptococcus
pneumoniae,
Haemophilus
influenzae spp.)

Cough, sputum,
Older adults, smoking, Sputum Gram stain,
rales, headache,
underlying diseases
culture (S, B), chest
delirium, pulmonary
radiograph
infiltrates

Viral infections
Hepatitis

Jaundice, arthritis
(with hepatitis B)

Exposure to known
Liver dysfunction,
case, drug abuse, travel antibody and/or antigen
*
detection

Dengue

Relative bradycardia, Travel, * vector

myalgia, conjunctival exposure (mosquito)
suffusion, rash

Culture (B), serology,

leukopenia,
thrombocytopenia

Infectious
mononucleosis

Pharyngitis,
lymphadenopathy,
splenomegaly, rash

Young adults

Serology, lymphocyte
morphology

Travel, * vector

Serology, skin biopsy

Rickettsial infections
Rocky

Rash, headache,

TABLE 94-1 -- Clinical, Epidemiologic, and Laboratory Clues to the Causes of

Enteric Fever and Conditions That May Mimic Enteric Fever
Etiologic Agent
or Disease

Clinical Clues in
Addition to Fever

Epidemiologic Clues

Laboratory Clues

Mountain
spotted fever

myalgias

exposure (tick)

Epidemic
typhus

Conjunctival
suffusion, rash,
severe prostration

Travel, * vector
exposure (louse)

Serology

Brill-Zinsser
disease

Rash

Older adults, remote

travel * history

Serology

Endemic typhus Conjunctival

suffusion, rash,
splenomegaly

Rat contact, vector

exposure (flea)

Serology

Scrub typhus

Conjunctival
suffusion, rash,
lymphadenopathy

Travel, * vector
exposure (mites)

Serology

Q fever

Pneumonia, hepatitis Animal contact

(especially livestock),
travel, diet
(especially
unpasteurized milk)

Serology, chest
radiograph, liver
dysfunction

Ehrlichiosis

Headache, myalgia,
rash (occasional)

Travel, * vector
exposure (tick)

Serology, leukopenia,
thrombocytopenia

Travel, * animal contact

(chicken, birds, bats),
hobby (cave
exploration)

Culture (B, BM, L,

MM), biopsy (BM, L,
MM), chest radiograph,
urine antigen

Mycotic infections
Disseminated
histoplasmosis

Mucocutaneous
lesions, adrenal
insufficiency

Penicillium
marneffei

Umbilicated skin
Travel, * concurrent
lesions,
AIDS
lymphadenopathy,
cough, hepatomegaly

Culture (B, BM, LN),

chest radiograph

Parasitic Infections
Malaria

Fever pattern,
splenomegaly

Travel, * vector
exposure (mosquito)

Amebiasis

Colitis, liver abscess Travel *

Blood smear
Stool examination,
serology, liver scan,
sonography, CT, colon
biopsy

TABLE 94-1 -- Clinical, Epidemiologic, and Laboratory Clues to the Causes of

Enteric Fever and Conditions That May Mimic Enteric Fever
Etiologic Agent
or Disease

Clinical Clues in
Addition to Fever

Epidemiologic Clues

Paucity of physical
findings

Travel, * splenectomy,
vector exposure (tick)

Blood smear, serology

Toxoplasmosis Lymphadenopathy

Animal contact (cat);

diet (undercooked
pork)

Serology, biopsy
(lymph node)

Trichinosis

Diet (undercooked pork Serology, eosinophilia,

or bear meat)
biopsy (muscle)

Babesiosis

Periorbital edema,
muscle tenderness

Katayama fever Urticaria,

(acute
lymphadenopathy
schistosomiasis)
Visceral larva
migrans

Travel, * swimming or
other freshwater
exposure

Hepatosplenomegaly, Young children with

rash, bronchospasm, history of pica, animal
ocular lesions
contact (dog, cat)

Laboratory Clues

Eosinophilia, serology,
stool O&P
Serology, biopsy (L),
eosinophilia

Noninfectious causes
Malignancy

Adenopathy, anergy, Family history or prior Sonography, CT,

weight loss
malignancy
gallium scan, biopsy

Collagen
vascular or
granulomatous
disease (e.g.,
sarcoidosis,
granulomatous
hepatitis,
ulcerative
colitis, Crohns
disease, Stills
disease,
vasculitis, etc.)

Skin lesions,
arthritis, serositis,
multiple organ
involvement

Family history

Biopsy of involved
tissue, serology (ANA,
C), exclusion of other
causes

A, Abscess; AIDS, acquired immunodeficiency syndrome; ANA, antinuclear antibody;

B, blood marrow; C, complement; CNS, central nervous system; CSF, cerebrospinal
fluid; CT, computed tomography; DFA, direct fluorescent antibody test; F, feces; FD,
fistula drainage; G, gastric aspirate; HIV, human immunodeficiency virus; J, joint fluid;
L, liver; LN, lymph node;MM, mucous membrane; N, nasal;O&P, ova and parasite; S,
sputum;T, throat;U, urine; UGI, SBFT, upper gastrointestinal tract with small bowel
follow-through.
* Travel to endemic areas, either domestic or foreign.
Swimming in contaminated surface water

obtained, 73% to 97% of the cases are confirmed.[3] Patients with severe disease are the
most likely to have positive cultures. Culture of the blood clot after the serum is removed
and large volume (15 mL in adults) blood cultures improve culture sensitivity.[11] Bone
marrow cultures may be positive when blood cultures are negative, even after antibiotics
have been administered.[12] [13] Stool cultures are positive in less than half the patients, and
urine cultures are even less frequently positive.[3] [12] If patients have received antimicrobial
therapy, blood cultures are often negative. Cultures of biopsy specimens of rose spots
have been reported to be positive in nearly two thirds of patients, including some who
previously received antimicrobial therapy.[12]
The Widal test has been used to detect antiS. typhi antibodies for more than 100 years,
but its role in the diagnosis of typhoid fever is limited.[14] The minimal titers defined as
positive for the O (surface polysaccharide) antigens and H (flagellar) antigens must be
determined for individual geographic areas and are higher in developing regions than in
the United States.[11] Cross-reactions occur with both nonS. typhi group D salmonellae
and salmonellae from other groups. When paired acute and convalescent samples are
studied, a fourfold or greater increase is considered positive.
The Widal test has been reported to be positive in 46% to 94% of patients with typhoid
fever.[14] [16] The test is most reliable in areas in which data on the titers in control groups
without enteric fever are available; the sensitivity of the test can be improved when
diseases such as rheumatoid arthritis, which are associated with false-positive reactions,
are ruled out by other assays. Although the criteria vary, a single elevated titer for O
equal to or greater than 1:320 or H equal to or greater than 1:640 is considered positive.
A fourfold or greater titer rise demonstrated in paired serum specimens obtained 2 to 3
weeks apart is also diagnostic, but it is of no value in the acute setting. The potential for
either false-positive or false-negative responses limits the value of the Widal test in the
diagnosis of typhoid fever.[14] [16] Finally, the Widal test is not helpful in the diagnosis of
enteric fever caused by organisms other than S. typhi.
A number of other assays have been used to detect antibodies against other S. typhi
antigens or circulating antigens themselves. They include rapid tests for antibodies to
lipopolysaccharide or outer-membrane proteins.[17] [18] Finally, polymerase chain reaction
assays are now available in research settings but seem impractical in resource-poor
regions most affected by the disease.[15] [19]

1276

TABLE 94-2 -- Frequency of Symptoms and Physical Findings in Patients with

Enteric Fever

Typhoid Fever * (%)

Paratyphoid A and B
(%)

Fever

39100

92100

Headache

4390

60100

Nausea

2336

3358

Vomiting

2435

2245

Abdominal cramps

852

2992

Diarrhea

3057

1768

Constipation

1079

229

Cough

1186

1068

Fever

98100

100

Abdominal tenderness

3384

629

Splenomegaly

2365

074

Hepatomegaly

1552

1632

Relative bradycardia

1750

11100

Rose spots

246

03

Rales or rhonchi

484

287

Epistaxis

121

213

112

03

Symptoms

Physical findings

Meningismus
* Data from references , , , , ,
Data from references , [10] ,[14] , [15] .
[2]

[3] [5]

[10]

[11]

[12]

[13]

Additional laboratory tests that may be of value include the white blood cell count and
differential, liver function tests, urinalysis, and chest radiograph. Leukopenia is reported
in 16% to 46% of the cases. In some series, two thirds of patients had no eosinophils on
peripheral smear,[1] a finding that may be helpful in areas in which helminthic diseases are
prevalent and eosinophilia is common. Liver function tests may reveal a mildly elevated
bilirubin level and a slight to threefold elevation in alkaline phosphatase and
transaminase levels in one third to two thirds of the patients; on occasion, hepatic
manifestations may be prominent.[20] Urinalysis frequently reveals proteinuria, pyuria, and
casts[3] ; immune complex glomerulonephritis with red blood cell casts occasionally
occurs.[21] Coagulation abnormalities compatible with mild disseminated intravascular
coagulation are common, but the syndrome is rarely clinically apparent.[22] Chest

radiographic films reveal infiltrates in 2% to 11% of the cases.[3] In patients with diarrhea,
a methylene blue stain of a fresh stool specimen for fecal leukocytes may reveal
mononuclear cells.[23]
Epidemiology

Certain epidemiologic data may be of value in the diagnosis of enteric fever. Typhoid
fever is more common in children and young adults both in the United States[24] and
abroad. In the United States, cases occur throughout the year. Because humans are the
only reservoir for S. typhi, a history of being abroad in settings where sanitation is poor or
with a known typhoid case or carrier is useful, but a specific contact is identified in a
minority of cases.[5] The proportion of the cases in the United States that were acquired
abroad has increased dramatically; during 1985 to 1994, 72% of the cases were acquired
abroad.[5] Six countries accounted for 80% of the cases: Mexico (28%), India (25%), the
Philippines (10%), Pakistan (8%), El Salvador (5%), and Haiti (4%). The percentage of
cases associated with visiting Mexico decreased from 46% in 1985 to 23% in 1994,
whereas the percentage of cases associated with visiting the Indian subcontinent
increased from 25% in 1985 to 37% in 1994. The incidence among U.S. citizens traveling
to the Indian subcontinent was at least 18 times higher than that in people traveling to any
other geographic region.[5] Patients who acquire infection abroad are usually older than
those who acquire disease in the United States.
The importance of the microbiology laboratory as a source of domestic S. typhi infection
has also been recognized.[25] [26] In most laboratory-acquired cases, S. typhi had been used
for proficiency testing or research. Most patients with enteric fever caused by S.
paratyphi A or S. schottmuelleri acquire their infection abroad; S. schottmuelleri is only
occasionally and S. paratyphi A rarely isolated in the United States.
Differential Diagnosis
Enteric Feverlike Syndromes Caused by Other Bacteria

Y. enterocolitica, Yersinia pseudotuberculosis, and Campylobacter fetus can each

produce an illness characterized by fever, headache, and abdominal pain that may be
clinically indistinguishable from enteric fever caused by S. typhi or other salmonellae
(see Table 941 ). However, certain features of these infections may differentiate them
from true enteric fever. Acute diarrhea is often a prominent feature of enteric feverlike
illnesses caused by Y. enterocolitica [27] [28] and occasionally Y. pseudotuberculosis.[29] [30]
Diarrhea is less frequent in enteric feverlike illness caused by C. fetus; the acute
gastrointestinal symptoms of nausea, vomiting, abdominal cramps, and diarrhea were
present in only 27% of bacteremic illnesses caused by C. fetus.[31] A clue to the diagnosis
of Campylobacter infection is associated phlebitis.[31] [32]
The enteric feverlike syndromes caused by Y. enterocolitica, Y. pseudotuberculosis, and
C. fetus tend to occur in patients with significant underlying disease. Of 31 patients with
Y. enterocolitica bacteremia for whom information was available, 12 had cirrhosis of the
liver, 4 others had thalassemia, and 1 had kwashiorkor.[27] Only five were known to be free

of underlying disease. In another series, five of seven patients with the acute septicemic
or typhoidal form of Y. enterocolitica infection had evidence of liver disease; in addition,
all six patients with the subacute, localized form of the disease characterized by hepatic
and splenic abscesses had cirrhosis of the liver.[27] Of 20 patients with the enteric fever
like syndrome caused by Y. pseudotuberculosis, 11 had evidence of significant
underlying disease; the liver was involved in 10 of these patients.[29] In a series of patients
with bacteremia C. fetus illness, 73% had a significant underlying disease, frequently
involving the liver.[31]
Epidemiologic clues in differentiating true enteric fever from these enteric feverlike
syndromes include the patients age, residence, and recent travel history. Patients with
Salmonella-induced enteric fever are most often younger than 30 years, whereas the vast
majority of patients with non-Salmonella enteric feverlike syndromes are older than
40.[27] [28] [29] [30] [31] [32] As with typhoid fever, men are more frequently affected than women.
Patients with Salmonella-induced enteric fever frequently have a history of recent foreign
travel, most often to developing countries. Diseases caused by Y. enterocolitica and Y.
pseudotuberculosis appear to be common in Europe, particularly in Scandinavia,[33] and
are not frequently reported from developing countries. Infections caused by both Y.
enterocolitica and Y. pseudotuberculosis may be acquired in the United States as well.[34]
Although bacteremic C. fetus infection is relatively rarely documented, the majority of
cases have been reported from the United States, and foreign travel has not appeared to
be a significant predisposing factor.[31]
A pulse-temperature deficit similar to that observed in typhoid fever has been reported in
enteric feverlike illness caused by Y. enterocolitica[28] [34] [35] and Y. pseudotuberculosis [29]
but not in that caused by C. fetus.[31] An additional clue may be provided by the fever
pattern. In contrast to Salmonella-induced enteric fevers in which sustained fever is
common, intermittent fever throughout the illness caused by Y. enterocolitica has been
reported.[36] Because of the increased frequency of chronic liver disease in patients with
these enteric feverlike syndromes, physical examination is more likely to reveal
stigmata of chronic liver disease such as spider angiomas, gynecomastia, ascites, and
testicular atrophy. In addition, hepatomegaly is frequent and may be more pronounced
than in patients with typhoid fever.[28] Both erythema nodosum and polyarthritis may
occur in patients with illnesses caused by Y. enterocolitica and Y. pseudotuberculosis; in
one series, 55% of the patients with yersiniosis had arthritis, and 88% of those had
multiple joint involvement.[33] Nonsuppurative arthritis is more common in infections
caused by Y. enterocolitica (43%) than in those caused by Y. pseudotuberculosis (10%).[37]
Patients with bacteremic infection caused by Y. enterocolitica and C. fetus may also have
acute septic arthritis,[28] [31] [34] [35] a condition

1277

that is infrequently found in patients with classic enteric fever. Erythema nodosum has
been reported in 15% to 24% of patients with Yersinia and may be slightly more common
with Y. pseudotuberculosis infection than with Y. enterocolitica infection.[33] [37]

Thrombophlebitis has been reported in patients with C. fetus bacteremia and may be an
additional diagnostic clue.[31] [32]
As in the Salmonella-induced enteric fevers, blood cultures are the key to the diagnosis.
Each of the three organisms is more frequently isolated from blood than from other
specimens.[27] [28] [29] [30] [31] The isolation rate from stool cultures is improved if coldenrichment techniques are used for Yersinia[38] and if special selective media are used for
Campylobacter. However, because of its sensitivity to cephalosporins, C. fetus cannot be
cultured from stool on commonly used Campylobacter jejuniselective agars if they
contain cephalosporins. In addition, serologic tests are available for documenting
infection with Y. enterocolitica and Y. pseudotuberculosis and appear to be more
sensitive and more specific than those for Salmonella infection. Polymerase chain
reactionbased assays for Y. enterocolitica, Y. pseudotuberculosis, and C. fetus appear
promising, but they are available only in research settings.
Leukopenia is infrequent in patients with enteric feverlike syndromes; its presence
suggests that salmonellae are responsible. Findings on abdominal computed tomography
(CT) or ultrasonography suggestive of hepatic or splenic abscesses favor the diagnosis of
yersiniosis.[27] Glomerulitis complicating both typhoid fever and Y. enterocolitica has been
reported; therefore, the presence of protein, red blood cells, and red blood cell casts in the
urine is compatible with either of these syndromes.[21] [39]
Patients with typhoidal tularemia may be clinically indistinguishable from those with
enteric fever. The epidemiologic history may be of value. A history of rabbit or tick
exposure within 7 days before the onset of illness supports the diagnosis of tularemia.[40]
Although potentially dangerous, Francisella tularensis may be isolated from blood if the
appropriate medium is used. More often, serologic tests are used to confirm the diagnosis.
Acute brucellosis may manifest with fever, myalgias, and splenomegaly.[41] As in typhoid
fever, white blood cell counts are frequently normal or low. Skin lesions are uncommon
in brucellosis. Blood and bone marrow cultures and serologic testing permit separation of
these entities.
Systemic Infections That May Mimic Enteric Fever

A number of other serious infections may be initially confused with enteric fever. These
are particularly important because several are potentially fatal if not promptly recognized
and treated. Among the most common serious febrile illnesses associated with travel to
tropical areas is malaria, which should be considered even in individuals who claim to
have been compliant in avoiding mosquitoes and taking malarial prophylaxis. It is
characterized by fever, headache, myalgias, and, in some patients, gastrointestinal
complaints. Intestinal and extraintestinal amebiases may arise as acute or subacute febrile
illnesses. Dengue fever can begin up to 9 days after exposure in an endemic area. Other,
less common infectious causes of fever and enteric symptoms are discussed later. Some
are endemic in North America, whereas others are not. In addition, persons with
pneumococcal, Legionella, or Mycoplasma pneumonia may have enteric symptoms along
with respiratory complaints.

Septicemic plague can mimic enteric fever. The diagnosis of plague is suggested by a
sudden onset and rapid progression of illness. The history may again provide a clue to the
diagnosis; plague is present in wild rodents in the southwestern United States and in
endemic areas abroad. A history of travel to those areas, particularly if there is exposure
to rodents during the previous 2 weeks, supports the diagnosis of plague.[42] Blood
cultures, methylene blue stains of peripheral blood,[43] and serologic testing aid in the
diagnosis.
Intestinal anthrax may be characterized by fever and severe abdominal pain. It is typically
acute in onset and rapid in progression. Patients usually die during the first few days of
their illness. A history of ingesting raw or undercooked meat in an area where anthrax is
endemic suggests the diagnosis.[44]
Acute septicemic melioidosis may be confused clinically with enteric fever; this disease
is endemic in Southeast Asia. Physical findings that support the diagnosis of melioidosis
include pustular skin lesions.[45] The chest radiograph may reveal nodular pulmonary
densities. Blood cultures and serologic studies again permit differentiation from typhoid
fever.
Acute bartonellosis (Oroya fever) may manifest with fever, headache, and abdominal
pain. Because this disease occurs only in certain valleys in the Andes mountains of Peru,
Ecuador, and Colombia, a lack of travel in the preceding month is helpful in excluding
this possibility.[46] Evidence of acute hemolysis suggests the diagnosis. The causative
organisms may be seen on a stained peripheral blood smear. Because Oroya fever
predisposes to Salmonella-induced bacteremia, both infections may be encountered
simultaneously.[47] A fever surveillance study in Egypt identified brucellosis as an
important cause of prolonged fever that was frequently mistaken clinically as typhoid
fever; 87% of patients with brucellosis were diagnosed with and treated for typhoid.[48]
Rat-bite fever caused by Streptobacillus moniliformis may mimic enteric fever when the
rat puncture site is not clinically evident or when the infection is foodborne.[49] This illness
may also mimic enteric feverlike syndromes. History of a recent rat bite suggests the
diagnosis.[49] Cultures of blood and joint fluid may confirm the diagnosis; serologic tests
may also be helpful. The other cause of rat-bite fever, Spirillum minus, causes subacute
fever, headache, nausea, and vomiting, often with an urticarial rash (sodoku), 1 to 4
weeks after a rat bite. There is usually regional adenopathy.[50] [51] Spirillary fever causes a
false-positive serologic test for syphilis in the majority of cases. S. minus requires mouse
inoculation for its isolation or demonstration of the 2- to 5-m twisted gram-negative rod
in tissue or blood for diagnosis. Like syphilis and relapsing fever, spirillary fever is often
associated with a Herxheimer reaction when treatment with penicillin G is initiated.
Leptospirosis frequently manifests with fever and headache and is most prevalent in
young adults. Abdominal pain occurs in approximately 30% of cases.[52] Diarrhea and
constipation are less frequent. Muscle pain and tenderness occur in nearly 70% of the
patients, more frequently than in enteric fever. Additional differentiating features are the
fever curve and clinical course; leptospirosis is characteristically a biphasic illness.[53]

Evidence of liver dysfunction is present in approximately 50% of the patients with

leptospirosis.[52] Although conjunctival suffusion is characteristic of leptospirosis and is
reported in one third of patients, conjunctivitis occurs in enteric fever as well. Two
findings that would favor the diagnosis of leptospirosis are azotemia (26% of cases) and
cerebrospinal fluid pleocytosis (47% of cases).[52] Serologic tests are of value in
confirming the diagnosis of leptospirosis.
Relapsing fever caused by Borrelia hermsii may be confused with enteric fever. A history
of travel during the previous 3 weeks to an area where louse-borne relapsing fever is
endemic (Ethiopia, South America, Far East) raises the possibility of this diagnosis. Tickborne relapsing fever can also be acquired in the western United States.[54] Conjunctivitis,
rash, and hepatosplenomegaly are common. However, in contrast to patients with enteric
fever, patients with tick-borne relapsing fever have a fever that resolves in a crisis during
the first week only to recur later.[55] Giemsa or Wright stain of peripheral blood during a
febrile episode may confirm the presence of spirochetes.
Patients with intestinal tuberculosis may have fever and findings referable to the
gastrointestinal tract. The areas most commonly affected are jejunoileum and ileocecum.
Radiologic studies of the terminal ileum may show evidence of a terminal ileitis that can
be confused with the terminal ileitis of typhoid fever or Y. enterocolitica infection.
Imaging features that suggest tuberculosis include cecal amputation, ileocecal thickening
and inflammation, mesenteric adenopathy, and evidence of associated peritonitis.[56]
Intestinal tuberculosis, once a rare disease in the United States, has become more
common as a consequence of the acquired immunodeficiency syndrome (AIDS)
epidemic, and it remains an important problem in developing

1278

areas.[57] Evidence of active pulmonary tuberculosis, which is present in approximately

20% of cases, and a positive purified protein derivative test support the diagnosis.
Abdominal actinomycosis may also mimic enteric fever. Physical examination may
reveal an abdominal mass; the presence of a draining sinus tract strongly favors this
diagnosis.[58] The diagnosis is confirmed by culture.
Intra-abdominal pyogenic abscesses can pose difficult diagnostic challenges and remain
high on the list of undiagnosed causes of fever.[59] They should be suspected when fever
persists or recurs and may be detected by sonography, CT, or magnetic resonance
imaging.
Patients with Mycoplasma pneumoniae infection rarely have a course suggestive of
enteric fever. Fever and headache may be prominent. The presence of tracheobronchitis
with severe, nonproductive cough or pneumonia identified by physical examination or on
the chest radiograph suggests this diagnosis, although infiltrates may also occur in
patients with enteric fever caused by S. typhi. The presence of bullous myringitis suggests

M. pneumoniae infection.[60] The appearance of upper or lower respiratory illness in

friends or members of the patients family also favors this diagnosis. Serologic studies
can be used to confirm M. pneumoniae infection.
Patients with psittacosis frequently have an illness characterized by fever, headache,
myalgia, abdominal pain, vomiting, and diarrhea. On physical examination a faint
macular rash may be noted; splenomegaly occurs in some patients.[61] A history of
exposure to birds suggests the diagnosis, and serologic testing is helpful in confirmation.
Several rickettsial infections, especially epidemic typhus, Brill-Zinsser disease, endemic
typhus, Rocky Mountain spotted fever, and scrub typhus as well as Q fever, are
characterized by fever, headache, myalgia, and, except in Q fever, skin rash. Of these,
Rocky Mountain spotted fever is the most likely to be encountered in the United States.[62]
[63]
The gastrointestinal manifestations of Rocky Mountain spotted fever include
abdominal pain, diarrhea, vomiting, and upper gastrointestinal tract bleeding, and a
diagnosis of appendicitis, cholecystitis, or gastroenteritis may initially be considered.[64] [65]
[66]
A history of recent tick exposure suggests the diagnosis. Although failure of the
characteristic rash to develop may lead to a fatal delay in diagnosis and treatment, once
the characteristic rash associated with these illnesses appears, the diagnostic confusion is
lessened. Serologic testing provides documentation of rickettsial infections. In addition,
fluorescent antibody techniques can be used to demonstrate Rickettsia rickettsii in biopsy
specimens of involved skin.[67] Sporadic cases of epidemic typhus associated with flying
squirrels have been reported in the United States since 1976.[68] [69] The majority of these
have occurred in southeastern states during the winter months. Q fever is associated with
cattle and sheep exposure or the ingestion of unpasteurized milk.[70]
Monocytotropic and granulocytotropic ehrlichiosis, other tick-borne diseases, may also
arise with typhoid-like symptoms including fever, myalgias, vomiting, diarrhea,
headache, and, in some cases, rash, with elevated liver enzyme levels, leukopenia, and
anemia.[71] [72] A history of tick exposure in an endemic area is helpful. The diagnosis can
be confirmed by serologic tests.
Legionella infections in normal or immunocompromised hosts may arise with
gastrointestinal symptoms of abdominal pain, nausea, vomiting, or diarrhea that is usually
watery and noninflammatory.[73] Patients with disseminated histoplasmosis may have
fever, abdominal pain, nausea, vomiting, and diarrhea.[74] The diagnosis may be suggested
by the presence of mucous membrane lesions or adrenal insufficiency. Biopsy specimens
and cultures of liver, blood, urine, and bone marrow may be useful in confirming the
diagnosis.
Several acute viral infections have gastrointestinal manifestations. Abdominal pain,
nausea, and vomiting are frequent symptoms in patients with hepatitis. However, the
severity of jaundice and the extent of elevation of transaminase levels are much greater
than those observed in enteric fever. Influenza (particularly type B) may manifest with
fever, headache, and abdominal pain. Serologic studies and, in the case of influenza,
nasopharyngeal swabs are useful in distinguishing these illnesses. Infectious

mononucleosis may mimic enteric fever, particularly when acute pharyngitis is not
prominent. Examination of the peripheral blood smear and studies for heterophil or
Epstein-Barr virusspecific antibodies are helpful in differentiating this illness from
enteric fever.
In dengue fever, an important mosquito-borne viral disease in the tropics, headache,
severe myalgias, and leukopenia are common. The maculopapular skin rash that
characteristically appears on the trunk on the third to fifth day of illness and subsequently
spreads peripherally, the biphasic clinical course, and a history of recent travel (within
the previous 9 days) to areas in which dengue is endemic suggest the diagnosis.
A number of protozoal and helminthic infections can also mimic typhoid fever. Malaria is
endemic in many areas of the world in which typhoid fever is also relatively common.
Both diseases may arise with fever, headache, abdominal pain, and other gastrointestinal
symptoms. Two thirds of 25 cases of malaria in one series presented with prominent
gastrointestinal symptoms (nausea, vomiting, abdominal pain, or diarrhea) that might
have misled physicians from an early diagnosis of malaria.[75] When present, intermittent
fever suggests the diagnosis of malaria, but it is not observed in the majority of
nonimmune individuals with the disease. Peripheral blood smears confirm the diagnosis
of malaria.
Fever, chills, and hemolytic anemia in a person with exposure to an area with Ixodes
scapularis ticks and white-footed mice (Peromyscus spp.) or white-tailed deer
(Odocoileus virginianus) may be due to infection with Babesia microti, especially in an
asplenic patient.[76] [77]
Either intestinal or hepatic amebiasis may mimic acute enteric fever. In patients with
hepatic abscesses, documentation of a single abscess cavity favors the diagnosis of
amebiasis.[78] The diagnosis may be confirmed by means of a positive indirect
hemagglutination test. Patients with visceral leishmaniasis frequently present with fever,
malaise, hepatosplenomegaly, weight loss, anemia, thrombocytopenia, and leukopenia.
Massive splenomegaly suggests visceral leishmaniasis. The diagnosis is made by
identifying leishmanial amastigotes within mononuclear phagocytes in aspirates of the
spleen or bone marrow or by culturing leishmania from those specimens.
Several helminthic infections may cause an enteric feverlike syndrome, but they are
usually associated with eosinophilia as discussed later. Patients with trichinosis typically
present with fever, headache, myalgias, abdominal pain, diarrhea, periorbital edema, and
rash. The presence of eosinophilia, rather than the eosinopenia frequently noted in enteric
fever, helps in the differentiation. The history of recent ingestion of raw or undercooked
pork suggests trichinosis. It can be confirmed by acute and convalescent serologic tests or
biopsy, but the latter is seldom necessary.
Patients with visceral larva migrans may also have fever and hepatomegaly. In more
severe infections, splenomegaly, rash, and pneumonitis may also occur. In contrast to
enteric fever, visceral larva migrans is typically associated with pronounced eosinophilia.

The diagnosis is suggested by a history of pica. Serologic tests may confirm the diagnosis
of Toxocara spp. infection.
Patients with acute schistosomiasis (Katayamas fever) may also present with an enteric
fever syndrome. Again, eosinophilia is helpful in separating these possibilities. The
history of swimming in fresh water during the previous month in areas where
schistosomiasis is endemic further suggests schistosomiasis. The diagnosis is suggested
by serologic tests and confirmed by the eventual identification of ova in the stool.
Noninfectious causes of fever and abdominal pain such as eosinophilic gastroenteritis,
hematologic and other malignancies involving abdominal lymph nodes or the intestine,
vasculitides, and granulomatous diseases must also be considered. Diagnosis in such
cases often requires radiographic studies, biopsy of involved tissues, and the exclusion of
other processes as discussed later. See Chapter 48 for a discussion of the differential
diagnosis of fever of unknown origin.
Therapy for Enteric Fever

In patients with the enteric fever syndrome, it is advisable to consider empirical

antimicrobial therapy for typhoid fever before the diagnosis is confirmed by culture.
Multiple-drugresistant isolates of S. typhi unresponsive

1279

to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol are increasingly

prevalent around the world.[79] [80] [81] Fluoroquinolones, such as ciprofloxacin or ofloxacin,[82]
[83] [84]
are now widely used, but resistance to them has been reported in a number of
areas.[85] [86] [87] The fluoroquinolones achieve high concentration in phagocytic cells and in
bile. They are usually well tolerated and, provided the infecting strain is sensitive, result
in faster defervescence than cephalosporins. Fluoroquinolones are not approved for use in
children in the United States because of their potential to damage cartilage and tendons,
but accumulating evidence of their safe use with children with typhoid, bacillary
dysentery, and cystic fibrosis has led to their increased use in this population.[88] [89] [90] For
uncomplicated quinolone-resistant typhoid, therapy with azithromycin is considered firstline therapy.[4] Thirdgeneration cephalosporins, such as ceftriaxone,[91] [92] [93] and the
monobactam aztreonam are also effective. [94] For sensitive S. typhi, ampicillin,
trimethoprim-sulfamethoxazole, or chloramphenicol can be used. Strains may
occasionally acquire resistance during therapy. A patients recent travel and exposure
history should be considered in selecting additional empirical antimicrobial drugs to
cover other possible causes of the enteric syndrome, pending the results of cultures and
other diagnostic tests.

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