Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever

Author
Elizabeth L Hohmann, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Allyson Bloom, MD
Disclosures: Elizabeth L Hohmann, MD Nothing to disclose. Stephen B Calderwood, MD Patent Holder: Vaccine
Technologies Inc [Vaccines (Cholera vaccines)]. Equity Ownership/Stock Options: Pulmatrix [Infectious diseases (Inhaled
antimicrobials)]; PharmAthene [Anthrax (Antibody therapies)]. Allyson Bloom, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2016. | This topic last updated: Sep 26, 2013.
INTRODUCTION Typhoid fever is characterized by severe systemic illness with fever and abdominal
pain [1]. The organism classically responsible for the enteric fever syndrome is S. enterica serotype Typhi
(formerly S. typhi). Other Salmonella serotypes, particularly S. enterica serotype paratyphi A, B, or C, can
cause a similar syndrome; however, it is usually not clinically useful or possible to reliably predict the
causative organism based on clinical findings [2]. The term "enteric fever" is a collective term that refers
to both typhoid and paratyphoid fever.
The epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever will be reviewed
here. The pathogenesis, treatment and prevention of typhoid fever are discussed separately.
(See "Pathogenesis of typhoid fever" and "Treatment and prevention of typhoid fever" and "Immunizations
for travel".)
EPIDEMIOLOGY Typhoid fever is more common in children and young adults than in older patients
[3]. Worldwide, typhoid fever is most prevalent in impoverished areas that are overcrowded with poor
access to sanitation. Non-epidemic incidence estimates suggest that south-central Asia, Southeast Asia,
and southern Africa are regions with high incidence of S. typhi infection (more than 100 cases per
100,000 person years) [4]. Other regions of Asia and Africa, Latin America, the Caribbean, and Oceania
have a medium incidence of 10 to 100 cases per 100,000 person years. These estimates, though, are
limited by lack of consistent reporting from all areas of the world and are based on extrapolation of data
across regions and age groups. As an example, the incidence estimates within Africa are based upon
reports from Egypt and South Africa only and thus may not be accurately defined.
Because humans are the only reservoir for S. enterica serotype Typhi, a history of travel to settings in
which sanitation is poor or contact with a known typhoid case or carrier is useful for identifying people at
risk of infection outside of endemic areas, although a specific source or contact is identified in a minority
of cases.
Approximately 200 to 300 cases of S. typhi are reported in the United States each year [5]. About 80
percent of these cases occur among travelers to countries where typhoid fever is endemic, particularly
countries in South-Central Asia. In a study of 428 cases of typhoid fever reported among travelers from
resource rich countries through the multinational GeoSentinel Surveillance Network between 2006 and

2011, 67 percent of cases were acquired in south-central Asia (34, 13, 7, and 6 percent of total from India,
Nepal, Pakistan, and Bangladesh, respectively) (figure 1) [6]. Individuals visiting relatives in endemic
countries accounted for 28 percent of the typhoid cases.
Many travelers who subsequently develop typhoid fever have not received appropriate vaccination
despite guideline recommendations. Among 580 cases of vaccine-preventable diseases among returned
international travelers reported to the GeoSentinel Surveillance Network between 1997 and 2007,
confirmed or probable enteric fever (due mainly to S. typhi, but also S. paratyphi) was the most common
[7]. Only 38 percent of those with enteric fever had a pre-travel clinical encounter. However, the possibility
of S. typhi infection in returning travelers with a history of vaccine receipt should not be discounted, since
the vaccine is not completely effective. (See "Immunizations for travel", section on 'Typhoid vaccine'.)
Patients who acquire infection abroad are usually older than those who acquire disease in US outbreaks
and are more likely to have drug-resistant infection. S. typhi outbreaks in the United States are most often
foodborne; they are generally limited in size but can cause substantial morbidity [8,9].
The risk factors for the development of enteric fever due to typhoid or paratyphoid may differ. In an
Indonesian study, transmission of paratyphoid fever was more frequently observed outside the home (eg,
via consumption of food purchased from street vendors); transmission of typhoid fever was more
frequently observed within the household (eg, via sharing utensils, presence of a patient with typhoid, lack
of soap or adequate toilet facilities) [10]. S. paratyphi also appears to be an increasing cause of enteric
fever among vaccinated travelers, as the typhoid vaccine is ineffective against most S. paratyphi
infections [11,12].
Issues related to the epidemiology of drug resistance are discussed separately. (See "Treatment and
prevention of typhoid fever", section on 'Multidrug resistance'.)
Chronic carriage Chronic Salmonella carriage is defined as excretion of the organism in stool or urine
>12 months after acute infection. Rates of chronic carriage after S. typhi infection range from 1 to 6
percent [1,13,14]. Chronic carriage occurs more frequently in women and in patients with cholelithiasis or
other biliary tract abnormalities [15,16]. Chronic carriage in the urine is almost always associated with a
defect in the urinary tract (eg, urolithiasis, prostatic hyperplasia) or concurrent bladder infection with
Schistosoma [17].
Chronic carriers represent an infectious risk to others, particularly in the setting of food preparation. The
story of "Typhoid Mary," a cook in early 20th century New York who infected approximately 50 people
(three fatally), highlights the role of asymptomatic carriers in maintaining the cycle of person-to-person
spread [18]. For this reason, eradication of carriage when identified should be attempted. This is
discussed further separately. (See "Treatment and prevention of typhoid fever", section on 'Chronic
carriage'.)
The S. typhi carrier state may be an independent risk factor for carcinoma of the gallbladder as well as
other cancers [19,20]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and
diagnosis".)
MICROBIOLOGY The organism classically responsible for the enteric fever syndrome is S. enterica
serotype Typhi (formerly S. typhi). Other Salmonellae that can cause a similar clinical syndrome include
but are not limited to [21]:
Salmonella paratyphi A

Salmonella paratyphi B
Salmonella paratyphi C
Salmonella choleraesuis
These organisms are ingested and survive exposure to gastric acid before gaining access to the small
bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic
or hematogenous route. (See "Pathogenesis of typhoid fever".)
S. enterica serotype Typhi causes disease only in humans; it has no known animal reservoir. Infection
therefore implies direct contact with an infected individual or indirect contact via contaminated food or
water.
Infection due to Salmonella paratyphi species (also called S. enteritidis serotype paratyphi in older
reports) is less common than infection due to S. enterica serotype Typhi. Regional variation in prevalence
of S. paratyphi species has been described: S. paratyphi B is more frequently cultured than S. paratyphi
A; S. paratyphi C is rarely isolated [22,23]. S. paratyphi species are generally thought to cause milder
illnesses than S. typhi, although it is not possible to predict the causative organism based upon clinical
findings [2]. Among 609 cases of bacteremic enteric fever in Nepal (409 with S. typhi and 200 with S.
paratyphi A), the clinical syndromes caused by these two organisms were indistinguishable and of equal
severity [24].
"Nontyphoidal" Salmonellae may also cause severe illness consistent with enteric fever. In a study of 809
patients suspected of having enteric fever in Nigeria, for example, nontyphoidal Salmonellae (most
commonly S. enteritidis and S. typhimurium) were isolated in 7 percent of cases [22]. In Africa,
bacteremia with nontyphoidal Salmonellae is often associated with underlying HIV infection, which should
be considered in such patients. (See "Nontyphoidal Salmonella bacteremia", section on 'Epidemiology'.)
CLINICAL FEATURES Typhoid is a febrile illness with onset of symptoms 5 to 21 days after ingestion
of the causative microorganism in contaminated food or water. In general, lower inocula are associated
with longer incubation times. However, both the incubation period and inoculum needed to cause disease
vary depending upon host factors such as age, gastric acidity, and immunologic status.
(See "Pathogenesis of typhoid fever", section on 'Infectious dose'.)
The majority of patients with typhoid fever present with abdominal pain, fever, and chills.
Classic presentation Classic reports described the characteristic stages of typhoid fever in untreated
individuals [25]. In the first week of illness, rising ("stepwise") fever and bacteremia develop [26]. While
chills are typical, frank rigors are rare [11]. Relative bradycardia or pulse-temperature dissociation may be
observed. In the second week of illness, abdominal pain develops and "rose spots" (faint salmon-colored
macules on the trunk and abdomen) may be seen. During the third week of illness, hepatosplenomegaly,
intestinal bleeding, and perforation due to ileocecal lymphatic hyperplasia of the Peyer's patches may
occur, together with secondary bacteremia and peritonitis. Septic shock or an altered level of
consciousness may develop; among 300 cases of typhoid fever in Indonesia, these findings were
observed in approximately 15 percent of patients [27]. In the absence of acute complications or death
from overwhelming sepsis, symptoms gradually resolve over weeks to months.
Effect of antimicrobial therapy The clinical features of typhoid fever in the United States have
changed dramatically in the antibiotic era. When case series from the 1930s were compared with series

from the 1970s and 1980s, the prevalence of splenomegaly fell from 63 to 10 percent, and the prevalence
of rose spots fell from 30 to 1.5 percent [28]. Intestinal bleeding was also less frequent.
In the pre-antibiotic era, mortality rates were 15 percent or greater [25,29] and survivors experienced a
prolonged illness lasting weeks, with months of subsequent debilitation. Approximately 10 percent of
untreated patients relapsed, and up to 4 percent become chronic carriers of the organism.
In the post-antibiotic era, the average mortality rate from typhoid fever is estimated to be less than 1
percent [1], but this varies widely based upon site and resources, and may be 10- to 20-fold higher in the
most resource-limited settings. An epidemiological survey of about 1100 cases in Spain (1997-2005)
demonstrated a fatality rate of 0.9 percent [30]. A Centers for Disease Control and Prevention (CDC)
compilation of 10 hospital-based typhoid fever series reported a mean case-fatality rate of 2 percent
(range 0 to 14.8 percent), but noted that these series capture only the most severe and hospitalized
cases in those with access to care [31].
Other clinical manifestations The symptoms, signs, and complications of typhoid fever vary widely in
different series and may be related to age, geographic area, the causative organism, or the time at which
patients seek medical care.
Gastrointestinal manifestations Reports in the pre-antibiotic era suggested that constipation
occurred more frequently than diarrhea [25]. Subsequent 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 HIV infection [32,33]. Specifically, the incidence of diarrhea in children with culture proven
typhoid fever was 78 percent in a series from Australia [34] and 50 percent in a report from Vietnam [35].
Constipation occurs in approximately 30 percent of individuals [35,36], perhaps more frequently in adults.
Among 552 patients with culture-confirmed typhoid fever in Bangladesh, abdominal tenderness or
distension (57 percent) and rectal bleeding (9 percent) were equally distributed across age groups [37].
(See "Pathogenesis of typhoid fever", section on 'Gastrointestinal infection'.)
Intestinal perforation generally occurs more frequently among adults than children and is associated with
high mortality rates. Among 105 adults with typhoid fever in India, this complication was observed in 10
percent of patients [38]. In the Bangladesh study, intestinal perforation was observed in three percent of
patients overall, but in 25 percent of patients over 31 years old [37]. An outbreak of typhoid fever in
Uganda was detected specifically because of a high incidence of intestinal perforation, seen in patients of
all ages [39]. Over an 18-month period, 249 cases with a median age of 16 years were identified and 18
percent of them died.
Neurological manifestations Although headache is a frequent symptom reported in 44 to 94 percent
of cases [35,36,39,40], other neurological manifestations including disordered sleep patterns, acute
psychosis, myelitis, and rigidity have been observed but are uncommon [41], as are meningitis and focal
central nervous infections with S. typhi [42]. An outbreak of typhoid fever at the Malawi-Mozambique
border was notable for a relatively high incidence of associated neurological findings, found in 40 of 303
cases (13 percent) [40]. These included signs of upper motor neuron disease (eg, hyperreflexia,
spasticity, sustained clonus), ataxia, and Parkinsonism.
Patients with severe typhoid fever may develop "typhoid encephalopathy," with altered consciousness,
delirium, and confusion. This has been observed in up to 17 percent of patients, with no clear frequency
difference between children and adults [37]. In one study of 38 patients in Indonesia with typhoid fever,
delirium, obtundation, and stupor were grave prognostic signs, with a mortality rate as high as 55 percent

[27]. In this study, intravenous dexamethasone was administered in a randomized placebo-controlled

fashion as an adjunctive to antibiotic therapy; a reduction in mortality from 55 to 10 percent was observed.
In another series of 23 cases of typhoid encephalopathy from Bangladesh, the mortality rate was 13
percent; in a retrospective analysis of this series, survivors were more likely to have received IV
dexamethasone [43]. (See "Treatment and prevention of typhoid fever".)
Other extraintestinal manifestations Other protean symptoms have been reported to varying
degrees. Cough is not rare and has been observed in approximately 20 to 45 percent; arthralgias and
myalgias occur in about 20 percent [35,36,39,40]. Focal extraintestinal manifestations including
involvement of the hepatobiliary, cardiovascular, respiratory, genitourinary, musculoskeletal, and central
nervous systems have been described as a result of bacteremic seeding, but are observed infrequently
[44].
Laboratory abnormalities Patients with typhoid fever frequently have anemia and either leukopenia
or leukocytosis; leukopenia with left shift is typically seen in adults while leukocytosis is more common in
children. If observed in the third week of illness, leukocytosis should prompt suspicion for intestinal
perforation.
Abnormal liver function tests are frequently observed [28,45]. In an outbreak in 34 patients, abnormal liver
function tests were observed in all but one patient [28]. In some patients, the clinical and laboratory
picture may be suggestive of acute viral hepatitis [46]. In one study comparing 27 patients with
Salmonella hepatitis to 27 cases of viral hepatitis, Salmonella hepatitis was more frequently associated
with bradycardia (42 versus 4 percent) and fever >40C (44 versus 4 percent); serum aminotransferases
also tended to be lower (peak serum ALT 296 versus 3234 IU/L). A potential diagnostic challenge in
patients presenting with abnormal liver function tests is that the two infections may be present at once.
Cerebrospinal fluid studies are usually normal or reveal a mild pleocytosis (<35 cells/mm3), even in
patients with neuropsychiatric symptoms [42].
Special populations
Children Certain clinical manifestations associated with typhoid fever occur with different frequency in
children compared with adults; age differences were specifically examined in a review of 552 cultureconfirmed cases in Bangladesh [37]. Pneumonia and febrile seizures were overall infrequent but occurred
more commonly in children, whereas intestinal perforation was not seen in patients under five years old.
Younger patients also tended to have higher WBC counts; 14 of the 15 patients with a WBC count >20
x103/mm3 were younger than five years old.
Even among infants, there is variability in the severity of the disease. In a series from Chile, febrile infants
with typhoid fever had relatively mild illnesses not requiring hospitalization [47], while a study from
Bangladesh noted a fatality rate of 11 percent [37].
HIV-infected patients The severity of enteric fever does not appear to be markedly increased in the
setting of HIV infection, although nontyphoidal salmonellosis is known to be more complicated in HIV
infection. However, there is some evidence that immunocompromised patients fare poorly with typhoidal
infections. One study of four individuals with AIDS in Peru described atypically severe diarrhea or colitis
[32]. In a Tanzanian series of 104 cases of intestinal perforations due to typhoid fever treated surgically at
a university hospital, mortality was associated with HIV-positivity and low CD4 count at admission, among

other factors [48]. Other case reports have documented unusual manifestations of S. typhi infection such
as arteritis [49] or chorioamnionitis [50] in HIV-infected patients.
Chronic carriers In general, chronic carriers do not develop recurrent symptomatic disease. They
appear to reach an immunologic equilibrium in which they are chronically colonized and may excrete
large numbers of organisms, but have a high level of immunity and do not develop clinical disease [13,5153]. Chronic carriers frequently have high serum antibody titers against the Vi antigen, which is a clinically
useful test for rapid identification of such patients [14,54]. (See "Pathogenesis of typhoid fever", section
on 'Chronic carriage'.)
DIAGNOSIS The diagnosis of typhoid fever is made by culture of the causative microorganism in the
setting of a compatible clinical illness. Typhoid fever should be considered in a patient living in, traveling
from, or visiting from an endemic area who presents with abdominal pain, fever, and chills. In addition,
autochthonous cases or outbreaks can occur due to transmission via chronic carriers [55-57]. Serologic
tests are of limited clinical utility. In resource-limited settings, the diagnosis of typhoid fever is often based
upon clinical manifestations alone.
The differential diagnosis is broad and includes malaria, amebiasis, dengue fever, leishmaniasis, and
other causes of bacterial gastroenteritis. (See "Evaluation of fever in the returning traveler".)
Culture Blood cultures are positive in 40 to 80 percent of patients, depending upon the series and
culture techniques used. Blood cultures may require several days of incubation. The diagnosis can also
be made by culture of stool, urine, rose spots, or duodenal contents (via string capsule) [58]. Stool culture
is positive in up to 30 to 40 percent of cases, but is often negative by the time that systemic symptoms
bring patients to medical attention [47].
Bone marrow culture is the most sensitive routinely available diagnostic tool [59]. This may be particularly
important in complicated cases or when antimicrobial therapy has already been initiated and the
diagnosis remains uncertain. Bone marrow cultures may be positive in as many as 50 percent of patients
after as many as five days of antibiotics [33]. In one series of 44 patients with typhoid fever, S. typhi was
isolated from 98 percent of bone marrow cultures compared with 70 percent of blood cultures [60].
S. typhi isolates should be screened for resistance to nalidixic acid, or have formal sensitivity testing for
the clinically used fluoroquinolones [61,62]. Organisms with nalidixic acid resistance should be anticipated
to have reduced susceptibility to fluoroquinolones, even if fluoroquinolone sensitivity is reported by the
laboratory. (See "Treatment and prevention of typhoid fever", section on 'Fluoroquinolone resistance'.)
Serology Serologic tests such as the Widal test are of limited clinical utility in endemic areas because
positive results may represent previous infection. The Widal test detects anti-S. typhi antibodies, and the
minimal titers defined as positive for the O (surface polysaccharide) antigens and H (flagellar) antigens
must be determined for individual geographic areas; they are higher in developing regions than in the
United States [63]. When paired acute and convalescent samples are studied, a fourfold or greater
increase is considered positive. Positive results have been reported in 46 to 94 percent of cases [64]. In a
study of healthy blood donors performed in central India, seropositivity for typhoid fever using the S. typhi
O antigen or S. typhi H antigen was observed in 8 and 14 percent, respectively [64].
Newer serologic assays using enzyme-linked immunosorbent assay (ELISA) and dipstick techniques
perform somewhat better than the Widal test, but sensitivity and specificity are not adequate for routine

diagnostic use [65]. An ELISA for antibodies to the capsular polysaccharide Vi antigen is useful for
detection of carriers, but not for the diagnosis of acute illness [14,54].
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Basics topics (see "Patient information: Typhoid fever (The Basics)")
SUMMARY
Typhoid fever is transmitted by contaminated food or water. The organism classically responsible
for the enteric fever syndrome is S. enterica serotype Typhi (formerly S. typhi); other Salmonellae
may cause a similar clinical syndrome. (See 'Introduction' above.)
Typhoid fever is more common in children and young adults than in older patients. Humans are the
only reservoir for S. enterica serotype Typhi. In resource-rich settings, most cases of typhoid fever
occur in patients who have traveled to endemic regions, particularly south-central Asia. A history of
travel to settings in which sanitation is poor or history of contact with a known typhoid case or carrier
is useful for identifying patients at risk of infection, although a specific contact is identified in a
minority of cases. (See 'Epidemiology' above.)
Chronic Salmonella carriage is defined as excretion of the organism in stool or urine >12 months
after acute infection. Rates of chronic carriage after S. typhi infection range from 1 to 6 percent.
Chronic carriage occurs more frequently in women and in patients with cholelithiasis or other biliary
tract abnormalities. Chronic carriers represent an infectious risk to others, particularly in the setting
of food preparation. (See 'Chronic carriage' above.)
Typhoid fever usually presents with abdominal pain, fever, and chills approximately 5 to 21 days
after ingestion of the causative microorganism. Classic manifestations include relative bradycardia,
pulse-temperature dissociation, and "rose spots" (faint salmon-colored macules on the trunk and
abdomen). Hepatosplenomegaly, intestinal bleeding, and perforation may occur, leading to
secondary bacteremia and peritonitis. Laboratory findings may include anemia, leukopenia,
leukocytosis, and abnormal liver function tests. (See 'Clinical features'above.)
The diagnosis of typhoid fever is made by culture of the causative microorganism in the setting of a
compatible clinical illness. The organism can be cultured from blood, stool, urine, rose spots,
duodenal contents, or bone marrow. Serologic tests are of limited clinical utility given insufficient
sensitivity and specificity. (See 'Diagnosis' above.)
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Topic 2708 Version 12.0

Patient information: Typhoid fever (The Basics)

Written by the doctors and editors at UpToDate
What is typhoid fever? Typhoid fever is a fever caused by an infection with a type of bacteria called
Salmonella typhi. The fever usually happens along with belly pain and chills.
Typhoid fever is not very common in the United States or Europe, but it does occur in other parts of the
world, including:
South-central and Southeast Asia, which includes India, Pakistan, Bangladesh, and Nepal
Africa
The Philippines
El Salvador
Mexico
Haiti
In these places, the infection that causes typhoid fever spreads when people eat or drink things that have
the typhoid-causing bacteria in them. The bacteria can get into foods and drinks in different ways:
People who are infected can spread their germs to the food they cook if they do not wash their
hands before they touch the food.
Bacteria can get into the water supply through the bowel movements of infected people. Then, if
the water is not treated properly and is used in cooking or cleaning, it can spread the infection.
What are the symptoms of typhoid fever? The symptoms include:
Fever
Belly pain
Chills
Rose spots Faint, salmon-colored spots on the belly and trunk
Should I see a doctor or nurse? Yes. If you have symptoms of typhoid fever, see your doctor or
nurse.
Is there a test for typhoid fever? Yes. To find out if you are infected by the bacteria that cause
typhoid fever, your doctor or nurse can order a culture test on your blood. He or she might also order a
culture test on a sample of one of these things:
Bowel movement
Urine
Skin from one of the rose spots
How is typhoid fever treated? Treatment involves taking antibiotic pills for up to 2 weeks. If you are
put on antibiotics to treat typhoid fever, it is very important that stay on the medicines for as long as your
doctor recommends. Otherwise the infection could come back.
Can typhoid fever be prevented? Yes. There are 2 main ways to keep from getting typhoid fever:
Get the vaccine before you travel If you are planning a trip outside of the US and Europe, ask
your doctor or nurse if you need the typhoid vaccine or any other vaccines. There are 2 forms of the

vaccine. One comes in 4 pills that you take on different days. The other comes in a single shot. The
vaccine is not 100 percent effective. People can still get typhoid fever even if they got the vaccine.
Be careful what you eat and drink While traveling, you should:
Wash your hands with soap and water before eating or handling food.
Drink only bottled water or water that has been boiled for at least 1 minute.
Do not get ice in drinks and do not eat popsicles or flavored ice.
Eat food that has been completely cooked and is still hot.
Eat only fruits that have a peel and that you wash and peel yourself. Do not eat the peels.
Do not eat vegetables or salads.
Do not buy food or drinks from street vendors.