1. Enteric fever, or typhoid fever, is a severe systemic disease that is classically caused by Salmonella ser.
Typhi (Salmonella typhi) and is found mainly in developing countries, but it is encountered worldwide
because of international travel.
181.2Enteric Fever
Etiology.
Enteric fever, or typhoid fever, is caused by S. ser Typhi, S. ser. Paratyphi A, S. ser. Paratyphi B
(Schottmuelleri), and S. ser. Paratyphi C (Hirschfeldii). Rarely, other Salmonella serotypes can
cause a similar prolonged febrile illness.
Typhoid fever is a systemic disease characterized by fever and abdominal pain and caused by
dissemination of S. Typhi or S. Paratyphi. The disease was initially called typhoid fever because of its
clinical similarity to typhus. However, in the early 1800s, typhoid fever was clearly defined pathologically
as a unique illness on the basis of its association with enlarged Peyer's patches and mesenteric lymph
nodes. In 1869, given the anatomic site of infection, the term enteric fever was proposed as an
alternative designation to distinguish typhoid fever from typhus
Epidemiology.
The incidence, mode of transmission, and consequences of enteric fever differ significantly in
developed and developing countries. The incidence has decreased markedly in developed
countries. In developing countries, S. ser. Typhi is often the most common Salmonella isolate,
with an incidence that can reach 500 cases/ 100,000 population (0.5%) and a high mortality rate.
The World Health Organization has estimated that at least 12.5 million cases occur annually
worldwide.
Because humans are the only natural reservoir of S. ser. Typhi, direct or indirect contact with an
infected person (sick or chronic carrier) is necessary for infection. Ingestion of foods or water
contaminated with human feces is the most common mode of transmission. Water-borne
outbreaks due to poor sanitation and direct fecal-oral spread due to poor personal hygiene are
encountered, mainly in developing countries. Oysters and other shellfish cultivated in water
contaminated by sewage are also a source of widespread infection. Congenital transmission of
enteric fever can occur by transplacental infection from a bacteremic mother to her fetus.
Intrapartum transmission is also possible, occurring by a fecal-oral route from a carrier mother.
In contrast to other Salmonella serotypes, the etiologic agents of enteric fever—S. Typhi and S.
Paratyphi serotypes A, B, and C—have no known hosts other than humans.
Pathogenesis.
In younger children, the morphologic changes of S. ser. Typhi infection are less prominent than
in older children and adults. Hyperplasia of Peyer patches with necrosis and sloughing of
overlying epithelium produces ulcers that may bleed. The mucosa and lymphatic tissue of the
intestinal tract are severely inflamed and necrotic. Ulcers heal without scarring. Strictures and
intestinal obstruction virtually never occur after typhoid fever. The inflammatory lesion may
occasionally penetrate the muscularis and serosa of the intestine and produce perforation. The

2. mesenteric lymph nodes, liver, and spleen are hyperemic and generally reveal areas of focal
necrosis. Hyperplasia of reticuloendothelial tissue with proliferation of mononuclear cells is the
predominant finding. A mononuclear response may be seen in the bone marrow in association
with areas of focal necrosis. Inflammation of the gallbladder is focal, inconstant, and modest in
proportion to the extent of local bacterial multiplication. Bronchitis is common. Inflammation
also may be observed in the form of localized abscesses, pneumonia, septic arthritis,
osteomyelitis, pyelonephritis, endophthalmitis, and meningitis.
The inoculum size required to cause enteric fever in volunteers is 105–109 S. ser. Typhi
organisms. These estimates may be higher than in naturally acquired infection because the
volunteers ingested the organisms in milk; stomach acidity is an important determinant of
susceptibility to Salmonella. The bacteria invade through the Peyer patches. Organisms are
transported to intestinal lymph nodes, where multiplication takes place within the mononuclear
cells. Monocytes, unable to destroy the bacilli early in the disease process, carry these organisms
into the mesenteric lymph nodes. Organisms then reach the bloodstream through the thoracic
duct, causing a transient bacteremia. Circulating organisms reach the reticuloendothelial cells in
the liver, spleen, and bone marrow and may seed other organs. After proliferation in the
reticuloendothelial system, bacteremia recurs. The gallbladder is particularly susceptible to being
infected. Local multiplication in the walls of the gallbladder produces large numbers of
salmonellae, which reach the intestine through the bile.
Several virulence factors seem to be important. Invasion of Peyer patches is encoded by genes
closely related to the invasion genes of Shigella and enteroinvasive E. coli. However, S. ser.
Typhi possesses a number of additional genes not found in Shigella that are responsible for the
features of typhoid fever. The surface Vi capsular antigen found in S. ser. Typhi interferes with
phagocytosis by preventing the binding of C3 to the surface of the bacterium. The ability of
organisms to survive within macrophages after phagocytosis is an important virulence trait
encoded by the phoP regulon; it may be related to metabolic effects on host cells. Circulating
endotoxin, a lipopolysaccharide component of the bacterial cell wall, is thought to cause the
prolonged fever and toxic symptoms of enteric fever, although its levels in symptomatic patients
are low. Alternatively, endotoxin-induced cytokine production by human macrophages may
cause the systemic symptoms. The occasional occurrence of diarrhea may be explained by
presence of a toxin related to cholera toxin and E. coli heat-labile enterotoxin.
Cell-mediated immunity is important in protecting the human host against typhoid fever.
Decreased numbers of T lymphocytes are found in patients who are critically ill with typhoid
fever. Carriers show impaired cellular reactivity to S. ser. Typhi antigens in the leukocyte
migration inhibition test. In carriers, a large number of virulent bacilli pass into the intestine
daily and are excreted in the stool, without entering the epithelium of the host.
Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal pain—
are variable. While fever is documented at presentation in >75% of cases, abdominal pain is reported in
only 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a
person presents with fever and a history of recent travel to a developing country.

3. The incubation period for S. Typhi averages 10–14 days but ranges from 3 to 21 days, with the duration
likely reflecting the inoculum size and the host's health and immune status. The most prominent
symptom is prolonged fever (38.8°–40.5°C; 101.8°–104.9°F), which can continue for up to 4 weeks if
untreated. S. Paratyphi A is thought to cause milder disease than S. Typhi, with predominantly
gastrointestinal symptoms. However, a prospective study of 669 consecutive cases of enteric fever in
Kathmandu, Nepal, found that the infections were clinically indistinguishable. In this series, symptoms
reported on initial medical evaluation included headache (80%), chills (35–45%), cough (30%), sweating
(20–25%), myalgias (20%), malaise (10%), and arthralgia (2–4%). Gastrointestinal symptoms included
anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%)
more commonly than constipation (13–16%). Physical findings included coated tongue (51–56%),
splenomegaly (5–6%), and abdominal tenderness (4–5%).
Early physical findings of enteric fever include rash ("rose spots"), hepatosplenomegaly (3–6%),
epistaxis, and relative bradycardia at the peak of high fever. Rose spots (Fig. 146-2) make up a faint,
salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash is
evident in ~30% of patients at the end of the first week and resolves without a trace after 2–5 days.
Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of
these lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.
The development of severe disease (which occurs in ~10–15% of patients) depends on host
factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain
virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (10–20%)
and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness
and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer's patches at the initial
site of Salmonella infiltration. Both complications are life-threatening and require immediate
fluid resuscitation and surgical intervention, with broadened antibiotic coverage for
polymicrobial peritonitis (Chap. 121) and treatment of gastrointestinal hemorrhages, including
bowel resection. Neurologic manifestations occur in 2–40% of patients and include meningitis,
Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as "muttering
delirium" or "coma vigil"), with picking at bedclothes or imaginary objects.
Rare complications whose incidences are reduced by prompt antibiotic treatment include
disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and
splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis,
glomerulonephritis, pyelonephritis and hemolytic uremic syndrome, severe pneumonia, arthritis,
osteomyelitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2–3
weeks of fever resolution and in association with the same strain type and susceptibility profile.
Up to 10% of untreated patients with typhoid fever excrete S. Typhi in the feces for up to 3
months, and 1–4% develop chronic asymptomatic carriage, shedding S. Typhi in either urine or
stool for >1 year. Chronic carriage is more common among women, infants, and persons with
biliary abnormalities or concurrent bladder infection with Schistosoma haematobium. The

4. anatomic abnormalities associated with the latter conditions presumably allow prolonged
colonization.
Clinical Manifestations.
The incubation period is usually 7–14 days, but it may range from 3–30 days, depending mainly
on the size of the ingested inoculum. The clinical manifestations of enteric fever depend on age.
SCHOOL-AGED CHILDREN AND ADOLESCENTS.
The onset of symptoms is insidious. Initial symptoms of fever, malaise, anorexia, myalgia,
headache, and abdominal pain develop over 2–3 days. Although diarrhea having a pea soup
consistency may be present during the early course of the disease, constipation later becomes a
more prominent symptom. Cough and epistaxis may ensue. Severe lethargy may develop in
some children. Temperature, which increases in a stepwise fashion, becomes an unremitting and
high fever within 1 wk, often reaching 40°C.
During the 2nd week of illness, high fever is sustained, and fatigue, anorexia, cough, and
abdominal symptoms increase in severity. Patients appear acutely ill, disoriented, and lethargic.
Delirium and stupor may be observed. Physical findings include a relative bradycardia, which is
disproportionate to the high fever. Hepatomegaly, splenomegaly, and distended abdomen with
diffuse tenderness are very common. In about 50% of patients with enteric fever, a macular or
maculopapular rash (rose spots) appears on about the 7th–10th day. Lesions are usually discrete,
erythematous, and 1–5 mm in diameter; the lesions are slightly raised and blanch on pressure.
They appear in crops of 10–15 lesions on the lower chest and abdomen and last 2–3 days. They
leave a slight brownish discoloration of the skin on healing. Cultures of the lesions have a 60%
yield for Salmonella organisms. Rhonchi and scattered rales may be heard on auscultation of the
chest. Nausea and vomiting if occurring in the 2nd or 3rd week suggest a complication. If no
complications occur, the symptoms and physical findings gradually resolve within 2–4 wk, but
malaise and lethargy may persist for an additional 1–2 mo. Patients may be emaciated by the end
of the illness. Enteric fever caused by nontyphoidal Salmonella is usually milder, with a shorter
duration of fever and a lower rate of complications.
INFANTS AND YOUNG CHILDREN (<5 YR).
Enteric fever is relatively rare in this age group in endemic areas. Although clinical sepsis can
occur, the disease is surprisingly mild at presentation, making the diagnosis difficult. Mild fever
and malaise, misinterpreted as a viral syndrome, occur in infants with culture-proven typhoid
fever. Diarrhea is more common in young children with typhoid fever than in adults, leading to a
diagnosis of acute gastroenteritis.
NEONATES.
In addition to its ability to cause abortion and premature delivery, enteric fever during late
pregnancy may be transmitted vertically. The neonatal disease usually begins within 3 days of
delivery. Vomiting, diarrhea, and abdominal distention are common. Temperature is variable but

5. may be as high as 40.5°C. Seizures may occur. Hepatomegaly, jaundice, anorexia, and weight
loss can be marked.
Complications.
Severe intestinal hemorrhage and intestinal perforation occur in 1–10% and 0.5–3% of the
patients, respectively. These and most other complications usually occur after the 1st week of the
disease. Hemorrhage, which usually precedes perforation, is manifested by a decrease in
temperature and blood pressure and an increase in the pulse rate. Perforations, which are usually
pinpoint size but may be as large as several centimeters, typically occur in the distal ileum and
are accompanied by a marked increase in abdominal pain, tenderness, vomiting, and signs of
peritonitis. Sepsis with various enteric aerobic gram-negative bacilli and anaerobes may develop.
Although disturbed liver function test results are found for many patients with enteric fever,
overt hepatitis and cholecystitis are considered complications. An increase in serum amylase
levels may sometimes accompany clinically obvious pancreatitis.
Pneumonia caused by superinfection with organisms other than Salmonella is more common in
children than in adults. In children, pneumonia or bronchitis is common (approximately 10%).
Toxic myocarditis with fatty infiltration and necrosis of the myocardium may be manifested by
arrhythmias, sinoatrial block, ST-T changes on the electrocardiogram, or cardiogenic shock.
Thrombosis and phlebitis occur rarely. Neurologic complications include increased intracranial
pressure, cerebral thrombosis, acute cerebellar ataxia, chorea, aphasia, deafness, psychosis, and
transverse myelitis. Peripheral and optic neuritis have been reported. Permanent sequelae are
rare. Other reported complications include fatal bone marrow necrosis, pyelonephritis, nephrotic
syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis. Although
osteomyelitis and suppurative arthritis can occur in a normal host, they are more common in
children with hemoglobinopathies.
Diagnosis.
Culturing the Salmonella strain involved is usually the basis for confirming the diagnosis.
Results of blood cultures are positive in 40–60% of the patients seen early in the course of the
disease, and stool and urine cultures become positive after the 1st week. The stool culture result
is also occasionally positive during the incubation period. Because of the intermittent and low-
level bacteremia, repeated blood cultures should be obtained in suspect cases. Cultures of bone
marrow often yield positive results during later stages of the disease, when blood cultures may be
sterile; although seldom obtained, cultures of mesenteric lymph nodes, liver, and spleen may also
have positive results at this point. A culture of bone marrow is the single most sensitive method
of diagnosis (positive in 85–90%) and is less influenced by prior antimicrobial therapy. Stool and
sometimes urine cultures are positive in chronic carriers. In suspected cases with negative results
of stool cultures, a culture of aspirated duodenal fluid or of a duodenal string capsule may be
helpful in confirming infection. However, the duodenal string culture test cannot be performed
on those too young or too ill to cooperate.
Direct detection of S. ser. Typhi-specific antigens in the serum or S. ser. Typhi Vi antigen in the
urine has been attempted by immunologic methods, often using monoclonal antibodies.
Polymerase chain reaction has been used to amplify specific genes of S. ser. Typhi in the blood

6. of patients, enabling diagnosis within a few hours. This method is specific and more sensitive
than blood cultures, given the low level of bacteremia in enteric fever. Serology is of little help
in establishing the diagnosis, but it may be useful in epidemiologic studies. The classic Widal
test measures antibodies against O and H antigens of S. ser. Typhi. Because many false-positive
and false-negative results occur, diagnosis of typhoid fever by Widal test alone is prone to error.
A normochromic, normocytic anemia often develops after several weeks of illness and is related
to intestinal blood loss or bone marrow suppression. Blood leukocyte counts are frequently low
in relation to the fever and toxicity, but there is a wide range in counts; leukopenia, usually not
less than 2,500 cells/mm3, is often found after the 1st or 2nd week of illness. When pyogenic
abscesses develop, leukocytosis may reach 20,000–25,000/mm3. Thrombocytopenia may be
striking and persist for as long as 1 wk. Liver function test results are often disturbed. Proteinuria
is common. Fecal leukocytes and fecal blood are very common.
Diagnosis
Since the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be
considered in any febrile traveler returning from a developing country, especially the Indian
subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in
these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections,
leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 117). Other than a positive
culture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopenia
and neutropenia are detectable. Leukocytosis is more common among children, during the first
10 days of illness, and in cases complicated by intestinal perforation or secondary infection.
Other nonspecific laboratory findings include moderately elevated liver function tests and
muscle enzyme levels.
The definitive diagnosis of enteric fever requires the isolation of S. Typhi or S. Paratyphi from
blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The yield of
blood cultures is quite variable; sensitivity is as high as 90% during the first week of infection
and decreases to 50% by the third week. A low yield in infected patients is related to low
numbers of salmonellae (<15 organisms/mL) and/or to recent antibiotic treatment. Since almost
all S. Typhi organisms in blood are associated with the mononuclear-cell/platelet fraction,
centrifugation of blood and culture of the buffy coat can substantially reduce the time to isolation
of the organism but does not increase sensitivity.
Unlike blood culture, bone marrow culture remains highly (90%) sensitive despite 5 days of
antibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive duodenal
string test) can be positive despite a negative bone marrow culture. If blood, bone marrow, and
intestinal secretions are all cultured, the yield is >90%. Stool cultures, while negative in 60–70%
of cases during the first week, can become positive during the third week of infection in
untreated patients.
Several serologic tests, including the classic Widal test for "febrile agglutinins," are available.
None of these tests is sufficiently sensitive or specific to replace culture-based methods for the

7. diagnosis of enteric fever in developed countries. Polymerase chain reaction and DNA probe
assays to detect S. Typhi in blood are being developed.
DIFFERENTIAL DIAGNOSIS.
During the initial stage of enteric fever, the clinical diagnosis may mistakenly be gastroenteritis,
viral syndrome, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosis
includes sepsis with other bacterial pathogens; infections caused by intracellular
microorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsial
diseases; viral infections, such as infectious mononucleosis and anicteric hepatitis; and
malignancies, such as leukemia and lymphoma.
Treatment.
Antimicrobial therapy is essential in treating enteric fever. Because of increasing antibiotic
resistance, however, choosing the appropriate empirical therapy is problematic and controversial.
Although antibiotic resistance of S. ser. Typhi isolates in the United States is relatively low (3–
4%), most infections are acquired abroad, where resistance occurs. Increasing rates of plasmid-
mediated antibiotic resistance of S. ser. Typhi have been reported from Southeast Asia, Mexico,
and certain countries in the Middle East. Reports from India describe multiresistance to
chloramphenicol, ampicillin, and TMP-SMX in 49–83% of S. ser. Typhi isolates. Resistant
strains are usually susceptible to third-generation cephalosporins. Quinolones are efficacious but
are not approved for children. Most antibiotic regimens are associated with a 5–20% recurrence
risk. Chloramphenicol (50 mg/kg/24 hr divided qid PO or 75 mg/kg/24 hr divided q 6 hr
IV), ampicillin (200 mg/kg/24 hr divided q 4–6 hr IV), amoxicillin (100 mg/kg/24 hr
divided tid PO), and trimethoprim-sulfamethoxazole (10 mg of TMP and 50 mg of
SMZ/kg/24 hr divided bid PO) have demonstrated good clinical efficacy. Although
chloramphenicol therapy is associated with a more rapid defervescence and sterilization of
blood, the rate of relapse is somewhat higher, and this agent can cause potentially serious
adverse effects. Most children become afebrile within 7 days; treatment of uncomplicated cases
should be continued for at least 14 days, or 5–7 days after defervescence. Data suggest that very
short courses of therapy may be adequate with oral cefixime (20 mg/kg/24 hr divided bid for 7
days), ceftriaxone (50 mg/kg/24 hr once daily IM for 5 days) or oral ofloxacin
(15 mg/kg/24 hr for 2 days). Chloramphenicol remains the gold standard.
In adults, ciprofloxacin at a dose of 500 mg bid for 7–10 days is effective and associated with a
low relapse rate. In children with suspected resistant strains, empirical therapy with ceftriaxone
(or cefotaxime) is appropriate until antibiotic susceptibility patterns are available.
In addition to antibiotic therapy, a short course of dexamethasone (3 mg/kg for the initial dose,
followed by 1 mg/kg q 6 hr for 48 hr) improves the survival rate of patients with shock,
obtundation, stupor, or coma. Supportive treatment and maintenance of appropriate fluid and
electrolyte balance are essential. When intestinal hemorrhage is severe, blood transfusion is
needed. Surgical intervention and broad-spectrum antibiotics are recommended for intestinal
perforation. Surgical resection of 10 cm on each side of the perforation has been reported to
improve survival. Platelet transfusions have been suggested for the treatment of

8. thrombocytopenia that is sufficiently severe to cause intestinal hemorrhage in patients for whom
surgery is contemplated.
Although attempts to eradicate chronic carriage of S. ser. Typhi are recommended for public
health considerations, eradication is difficult despite in vitro susceptibility to the usual
antibiotics. A course of 4–6 wk of high-dose ampicillin (or amoxicillin) plus probenecid or
TMP-SMZ results in an approximately 80% cure rate of carriers if no biliary tract disease is
present. Ciprofloxacin has been used successfully in adults. In the presence of cholelithiasis or
cholecystitis, antibiotics alone are unlikely to be successful; cholecystectomy within 14 days of
antibiotic treatment is recommended.
Enteric (Typhoid) Fever: Treatment
Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric
fever and results in a case-fatality rate of <1%. The initial choice of antibiotics depends on the
susceptibility of the S. Typhi and S. Paratyphi strains in the area of residence or travel (Table
146-1). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effective
class of agents, with cure rates of ~98% and relapse and fecal carriage rates of <2%. Experience
is most extensive with ciprofloxacin. Short-course ofloxacin therapy is similarly successful
against infection caused by nalidixic acid–susceptible strains. However, the increased incidence
of nalidixic acid–resistant (NAR) S. Typhi in Asia, which is probably related to the widespread
availability of fluoroquinolones over the counter, is now limiting the use of this drug class for
empirical therapy. Patients infected with NAR S. Typhi strains should be treated with
ceftriaxone, azithromycin, or high-dose ciprofloxacin. However, high-dose fluoroquinolone
therapy for NAR enteric fever has been associated with delayed resolution of fever and high
rates of fecal carriage during convalescence.
Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever,
including NAR and fluoroquinolone-resistant strains. These agents clear fever in ~1 week, with
failure rates of ~5–10%, fecal carriage rates of <3%, and relapse rates of 3–6%. Oral
azithromycin results in defervescence in 4–6 days, with rates of relapse and convalescent stool
carriage of <3%. Despite efficient in vitro killing of Salmonella, first- and second-generation
cephalosporins as well as aminoglycosides are ineffective in treating clinical infections.
Patients with persistent vomiting, diarrhea, and/or abdominal distension should be hospitalized
and given supportive therapy as well as a parenteral third-generation cephalosporin or
fluoroquinolone, depending on the susceptibility profile. Therapy should be administered for at
least 10 days or for 5 days after fever resolution.
In a randomized, prospective, double-blind study of critically ill patients with enteric fever (i.e.,
those with shock and obtundation) in Indonesia in the early 1980s, the administration of
dexamethasone (3-mg initial dose followed by eight doses of 1 mg/kg every 6 h) with
chloramphenicol was associated with a substantially lower mortality rate than treatment with
chloramphenicol alone (10% vs 55%). Although this study has not been repeated in the "post-
chloramphenicol era," severe enteric fever remains one of the few indications for glucocorticoid
treatment of an acute bacterial infection.

9. The 1–5% of patients who develop chronic carriage of Salmonella can be treated for 4–6 weeks
with an appropriate oral antibiotic. Treatment with oral amoxicillin, trimethoprim-
sulfamethoxazole (TMP-SMX), ciprofloxacin, or norfloxacin is ~80% effective in eradicating
chronic carriage of susceptible organisms. However, in cases of anatomic abnormality (e.g.,
biliary or kidney stones), eradication often requires both antibiotic therapy and surgical
correction.
Prognosis.
The prognosis for a patient with enteric fever depends on prompt therapy, the age of the patient,
previous state of health, the causative Salmonella serotype, and the appearance of complications.
In developed countries, with appropriate antimicrobial therapy, the mortality rate is less than 1%.
In developing countries, the mortality rate is higher than 10%, usually because of delays in
diagnosis, hospitalization, and treatment. Infants and children with underlying debilitating
disorders are at higher risk. The appearance of complications, such as gastrointestinal perforation
or severe hemorrhage, meningitis, endocarditis, and pneumonia, is associated with high
morbidity and mortality rates.
Relapse after the initial clinical response occurs in 4–8% of the patients who are not treated with
antibiotics. In patients who have received appropriate antimicrobial therapy, the clinical
manifestations of relapse become apparent about 2 wk after stopping antibiotics and resemble the
acute illness. The relapse, however, is usually milder and of shorter duration. Numerous relapses
may occur. Individuals who excrete S. ser. Typhi for ≥3 mo after infection usually become
chronic carriers. The risk of becoming a carrier is low in children and increases with age; of all
patients with typhoid fever, 1–5% become chronic carriers. The incidence of biliary tract
diseases is higher in chronic carriers than in the general population. Although chronic urinary
carriage may also occur, it is rare and found mainly in individuals with schistosomiasis.
Multidrug-resistant (MDR) strains of S. Typhi emerged in 1989 in China and Southeast Asia and
have since disseminated widely (Fig. 146-1). These strains contain plasmids encoding resistance
to chloramphenicol, ampicillin, and trimethoprim—antibiotics long used to treat enteric fever.
With the increased use of fluoroquinolones to treat MDR enteric fever, strains of S. Typhi and S.
Paratyphi with reduced susceptibility to ciprofloxacin [minimal inhibitory concentration (MIC),
0.125–1.0 g/mL] have emerged in India and Vietnam and have been associated with clinical
treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic acid
detects most but not all strains with reduced susceptibility to ciprofloxacin.
Prevention.
In endemic areas, improved sanitation and clean running water are essential to control enteric
fever. To minimize person-to-person transmission and food contamination, personal hygiene
measures, handwashing, and attention to food preparation practices are necessary. Efforts to
eradicate S. ser. Typhi from carriers are recommended, because humans are the only reservoir of
S. ser. Typhi. When such efforts are unsuccessful, carriers should be prevented from working in
food- or water-processing activities, in kitchens, and in occupations related to patient care. These

10. individuals should be made aware of the potential contagiousness of their condition and of the
importance of handwashing and attentive personal hygiene.
VACCINE.
Two vaccines against S. ser. Typhi are commercially available in the United States. An oral, live-
attenuated preparation of the Ty21a strain of S. ser. Typhi have been shown to have good
efficacy (67–82%). Four enteric-coated capsules are given on alternate days, and the entire series
is repeated every 5 yr. Significant adverse effects are rare. The oral vaccine is recommended for
persons ≥6 yr of age. Infants and toddlers do not develop immune responses with this
preparation. It should not be used in persons with immunodeficiency syndromes. The Vi capsular
polysaccharide can be used in persons ≥2 yr of age. It is given as a single intramuscular dose,
with a booster every 2 yr.
Typhoid vaccination is recommended to travelers to endemic areas, especially Latin America,
Southeast Asia, and Africa. Such travelers need to be cautioned that the vaccine is not a
substitute for personal hygiene and careful selection of foods and drinks, because none of the
vaccines has efficacy approaching 100%. Vaccination is also recommended to individuals with
intimate exposure to a documented carrier and for control of outbreaks.
Prevention and Control
Theoretically, it is possible to eliminate the salmonellae that cause enteric fever since they
survive only in human hosts and are spread by contaminated food and water. However, given the
high prevalence of the disease in developing countries that lack adequate sewage disposal and
water treatment, this goal is currently unrealistic. Thus, travelers to developing countries should
be advised to monitor their food and water intake carefully and to consider vaccination.
Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S. Typhi
vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a parenteral
vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in 1 dose, with
a booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A and B vaccine is
no longer licensed, largely because of significant side effects (see below). An acetone-killed
whole-cell vaccine is available only for use by the U.S. military. The minimal age for
vaccination is 6 years for Ty21a and 2 years for Vi CPS. Currently, there is no licensed vaccine
for paratyphoid fever.
A large-scale meta-analysis of vaccine trials comparing whole-cell vaccine, Ty21a, and Vi CPS
in populations in endemic areas indicates that, while all three vaccines are similarly effective for
the first year, the 3-year cumulative efficacy of the whole-cell vaccine (73%) exceeds that of
both Ty21a (51%) and Vi CPS (55%). In addition, the heat-killed whole-cell vaccine maintains
its efficacy for 5 years, whereas Ty21a and Vi CPS maintain their efficacy for 4 and 2 years,
respectively. However, the whole-cell vaccine is associated with a much higher incidence of side
effects (especially fever: 16% vs 1–2%) than the other two vaccines.
Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell–
independent properties. In the recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic

11. recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2- to 4-year-
olds, two injections of Vi-rEPA induced higher T-cell responses and higher levels of serum IgG
antibody to Vi than did Vi CPS in 5- to 14-year-olds. In a two-dose trial in 2- to 5-year-old
children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 88% efficacy at 43
months and was very well tolerated. Similar results were obtained in a trial in Cambodia. This
vaccine is not yet commercially available in the United States. At least three new live vaccines
are in clinical development and may prove more efficacious and longer-lasting than previous live
vaccines.
Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy
rates may be substantially lower than those for local populations in endemic areas. Both the CDC
and the World Health Organization recommend typhoid vaccination for travelers to typhoid-
endemic countries. Recent analyses from the CDC found that 16% of travel-associated cases
occurred among persons who stayed at their travel destination for 2 weeks. Thus,
vaccination should be strongly considered even for persons planning short-term travel to high-
risk areas such as the Indian subcontinent. In the United States, persons who have intimate or
household contact with a chronic carrier or laboratory workers who frequently deal with S. Typhi
also should receive typhoid vaccine.
Enteric fever is a notifiable disease in the United States. Individual health departments have their
own guidelines for allowing ill or colonized food handlers or health care workers to return to
their jobs. The reporting system enables public health departments to identify potential source
patients and to treat chronic carriers in order to prevent further outbreaks. In addition, since 1–
4% of patients with S. Typhi infection become chronic carriers, it is important to monitor
patients (especially child-care providers and food handlers) for chronic carriage and to treat this
condition if indicated.s
Morphology. Infection causes Peyer's patches in the terminal ileum to enlarge into sharply
delineated, plateau-like elevations up to 8 cm in diameter. Draining mesenteric lymph nodes are
also enlarged. Neutrophils accumulate within the superficial lamina propria, and macrophages
containing bacteria, red blood cells, and nuclear debris mix with lymphocytes and plasma cells in
the lamina propria. Mucosal shedding creates oval ulcers, oriented along the axis of the ileum,
that may perforate. The draining lymph nodes also harbor organisms and are enlarged due to
phagocyte accumulation.
The spleen is enlarged and soft, with uniformly pale red pulp, obliterated follicular markings,
and prominent phagocyte hyperplasia. The liver shows small, randomly scattered foci of
parenchymal necrosis in which hepatocytes are replaced by macrophage aggregates, called
typhoid nodules, that may also develop in the bone marrow and lymph nodes.