Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused

primarily by Salmonella enterica, subspecies enterica serovar typhi and, to a lesser extent,
related serovars paratyphi A, B, and C.
The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The
classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated,
typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal
hemorrhage, bowel perforation, and death within 1 month of onset. Survivors may be left with
long-term or permanent neuropsychiatric complications.
S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor
sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at
the end of the Pelopennesian War.[1] The name S typhi is derived from the ancient Greek typhos,
an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced
stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics
have markedly reduced the frequency of typhoid fever in the developed world, it remains
endemic in developing countries.[2]
S paratyphi causes the same syndrome but appears to be a relative newcomer. It may be taking
over the typhi niche, in part, because of immunological naivete among the population and
incomplete coverage by vaccines that target typhi.
Note that some writers refer to the typhoid and paratyphoid fever as distinct syndromes caused
by the typhi versus paratyphi serovars, while others use the term typhoid fever for a disease
caused by either one. We use the latter terminology. We refer to these serovars collectively as
typhoidal salmonella.
Pathophysiology
All pathogenic Salmonella species, when present in the gut are engulfed by phagocytic cells,
which then pass them through the mucosa and present them to the macrophages in the lamina
propria. Nontyphoidal salmonellae are phagocytized throughout the distal ileum and colon. With
toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-

associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages

and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8),
causing inflammation and suppressing the infection.[3, 4]
In contrast to the nontyphoidal salmonellae, S typhi and paratyphi enter the host's system
primarily through the distal ileum. They have specialized fimbriae that adhere to the epithelium
over clusters of lymphoid tissue in the ileum (Peyer patches), the main relay point for
macrophages traveling from the gut into the lymphatic system. The bacteria then induce their
host macrophages to attract more macrophages.[3]
S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation,
while the most common paratyphi serovar, paratyphi A, does not. This may explain the greater
infectivity of typhi compared with most of its cousins.[5]
Typhoidal salmonella co-opt the macrophages' cellular machinery for their own reproduction [6] as
they are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and
then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph
nodes. Once there, they pause and continue to multiply until some critical density is reached.
Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to
invade the rest of the body.[4]
The bacteria then infect the gallbladder via either bacteremia or direct extension of infected bile.
The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer
patches. Bacteria that do not reinfect the host are typically shed in the stool and are then
available to infect other hosts.[2, 4] See the image below.
Life cycle of Salmonella typhi.

Chronic carriers are responsible for much of the transmission of the organism. While
asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms
sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps,

intracellularly, within the epithelium itself.[7] The bacteria excreted by a single carrier may have
multiple genotypes, making it difficult to trace an outbreak to its origin.[8]
Risk factors
Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms of
typhi causes infection in more than 50% of healthy volunteers.[9] Paratyphi requires a much
higher inoculum to infect, and it is less endemic in rural areas. Hence, the patterns of
transmission are slightly different.
The following are modes of transmission of typhoidal salmonella:

Oral transmission via food or beverages handled by an often asymptomatic individuala

carrierwho chronically sheds the bacteria through stool or, less commonly, urine

Hand-to-mouth transmission after using a contaminated toilet and neglecting hand

hygiene

Oral transmission via sewage-contaminated water or shellfish (especially in the

developing world). [10, 11, 12]

Paratyphi is more commonly transmitted in food from street vendors. It is believed that some
such foods provide a friendly environment for the microbe.
Paratyphi is more common among newcomers to urban areas, probably because they tend to be
immunologically nave to it. Also, travellers get little or no protection against paratyphi from the
current typhoid vaccines, all of which target typhi.[13, 14]
Typhoidal salmonella are able to survive a stomach pH as low as 1.5. Antacids, histamine-2
receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria
decrease stomach acidity and facilitate S typhi infection.[4]

HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection;

however, the data and opinions in the literature as to whether this is true for S typhi or paratyphi
infection are conflicting. If an association exists, it is probably minor.[15, 16, 17, 18]
Other risk factors for typhoid fever include various genetic polymorphisms. These risk factors
often also predispose to other intracellular pathogens. For instance, PARK2 and PACGR code for
a protein aggregate that is essential for breaking down the bacterial signaling molecules that
dampen the macrophage response. Polymorphisms in their shared regulatory region are found
disproportionately in persons infected with Mycobacterium leprae and S typhi.[11]
On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to
cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut
membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del, which
is associated with a decreased susceptibility to typhoid fever, as well as to cholera and
tuberculosis. The homozygous F508del mutation in CFTR is associated with cystic fibrosis.
Thus, typhoid fever may contribute to evolutionary pressure that maintains a steady occurrence
of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.[19, 20]
As the middle class in south Asia grows, some hospitals there are seeing a large number of
typhoid fever cases among relatively well-off university students who live in group households
with poor hygiene.[21] American clinicians should keep this in mind, as members of this cohort
often come to the United States for advanced degrees.
Epidemiology
Frequency
United States
Since 1900, improved sanitation and successful antibiotic treatment have steadily decreased the
incidence of typhoid fever in the United States. In 1920, 35,994 cases of typhoid fever were
reported. In 2006, there were 314.

Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had been outside
of the country within the preceding 30 days. Two thirds of these individuals had just journeyed
from the Indian subcontinent. The 3 known outbreaks of typhoid fever within the United States
were traced to imported food or to a food handler from an endemic region. Remarkably, only
17% of cases acquired domestically were traced to a carrier.[22]
International
Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are
poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but
80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or
Vietnam.[23] Within those countries, typhoid fever is most common in underdeveloped areas.
Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and
kills an estimated 200,000 people every year.[24]
In the United States, most cases of typhoid fever arise in international travelers. The average
yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of
departure was as follows:[22]

Canada - 0

Western Hemisphere outside Canada/United States - 1.3

Africa - 7.6

Asia - 10.5

India - 89 (122 in 2006)

Total (for all countries except Canada/United States) - 2.2

Mortality/Morbidity

With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile
illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and
a 0.2% risk of mortality.[22] Untreated typhoid fever is a life-threatening illness of several weeks'
duration with long-term morbidity often involving the central nervous system. The case fatality
rate in the United States in the pre-antibiotic era was 9%-13%.[25]
Race
Typhoid fever has no racial predilection.
Sex
Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006
involved males.[22]
Age
Most documented typhoid fever cases involve school-aged children and young adults. However,
the true incidence among very young children and infants is thought to be higher. The
presentations in these age groups may be atypical, ranging from a mild febrile illness to severe
convulsions, and the S typhi infection may go unrecognized. This may account for conflicting
reports in the literature that this group has either a very high or a very low rate of morbidity and
mortality.[21, 26
History
A severe nonspecific febrile illness in a patient who has been exposed to typhoidal salmonella
should always raise the diagnostic possibility of typhoid fever (enteric fever).
Classic typhoid fever syndrome
The clinical syndromes associated with S typhi and paratyphi are indistinguishable. Typhoid
fever begins 7-14 days after ingestion of the organism . The fever pattern is stepwise,

characterized by a rising temperature over the course of each day that drops by the subsequent
morning. The peaks and troughs rise progressively over time.
Over the course of the first week of illness, the notorious gastrointestinal manifestations of the
disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce
colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the
bowel lumen, causing constipation that lasts the duration of the illness. The individual then
develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise.[2]
At approximately the end of the first week of illness, the fever plateaus at 103-104F (39-40C).
The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules
usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days. [2]
These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or
nontyphoidal salmonellosis.[27]
During the second week of illness, the signs and symptoms listed above progress. The abdomen
becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse
(double beat, the second beat weaker than the first) may develop.
In the third week, the still febrile individual grows more toxic and anorexic with significant
weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and
crackles over the lung bases. Abdominal distension is severe. Some patients experience foul,
green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid
state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches
may cause bowel perforation and peritonitis. This complication is often unheralded and may be
masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal
hemorrhage may cause death.
If the individual survives to the fourth week, the fever, mental state, and abdominal distension
slowly improve over a few days. Intestinal and neurologic complications may still occur in
surviving untreated individuals. Weight loss and debilitating weakness last months. Some
survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria
indefinitely.[21, 28, 29, 2, 4]

Various presentations of typhoid fever

The clinical course of a given individual with typhoid fever may deviate from the above
description of classic disease. The timing of the symptoms and host response may vary based on
geographic region, race factors, and the infecting bacterial strain. The stepladder fever pattern
that was once the hallmark of typhoid fever now occurs in as few as 12% of cases. In most
contemporary presentations of typhoid fever, the fever has a steady insidious onset.
Young children, individuals with AIDS, and one third of immunocompetent adults who develop
typhoid fever develop diarrhea rather than constipation. In addition, in some localities, typhoid
fever is generally more apt to cause diarrhea than constipation.
Atypical manifestations of typhoid fever include isolated severe headaches that may mimic
meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or
fever alone. Some patients, especially in India and Africa, present primarily with neurologic
manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or GuillainBarr syndrome. Other unusual complications include pancreatitis,[30] meningitis, orchitis,
osteomyelitis, and abscesses anywhere on the body.[2]
Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever [2, 31, 32, 33, 34,
35]

(Open Table in a new window)

Incubatio

Week 1

Week 2

Week 3

Very

Very common

Week 4

Post

Recover

10%-20%

n
Systemic
Stepladder

fever

pattern or insidious
onset fever
Acute high fever
Chills
Rigors
Anorexia
Diaphoresis
Neurologic
Malaise

commona

or death 3%-4%
(15% of chronic

Very rareb
Almost allc
Uncommon
Almost all
Very common
Almost

y phase relapse;

Almost

untreate
d cases)

Typhoid

carriers;

all
Insomnia

all
Very

Confusion/delirium

common
Very

Common
d

Psychosis
Catatonia
Frontal
headache

Very rare
Very rare
Very

state

long-term

(common

neurologic

sequelae
(extremel

common
Common

rare);

common
gallbladde
(usually

mild)

cancer

(RR=167;
carriers)

Meningeal signs
Parkinsonism
Ear, nose, and throat
Coated tongue

Raree
Very rare

Rare

Very
common

Sore throatf
Pulmonary
Mild cough
Bronchitic cough
Rales
Pneumonia

Common
Common
Common
Rare

Rare

Common

(lobar)

(basal)

Cardiovascular
Dicrotic pulse
Myocarditis
Pericarditis

Rare
Rare
Extremel

Common

y rareg
Thrombophlebitis
Gastrointestinal

Very rare

Constipation

Very

Common

Diarrhea
Bloating

common
Rare
Very

Common (pea soup)

with

tympany

common

Diffuse

mild

(84%)[35]
Very

abdominal pain
Sharp right lower

common
Rare

quadrant pain
Gastrointestinal

Very rare; Very common

hemorrhage

usually
trace

intestinal
perforation
Hepatosplenomegal

Rare
Common

y
Jaundice
Common
Gallbladder pain
Very rare
Urogenital
Urinary retention
Common
Hematuria
Rare
Renal pain
Rare
Musculoskeletal
Myalgias
Very rare
Arthralgias
Very rare
Rheumatologic
Arthritis
(large Extremely rare
joint)
Dermatologic
Rose spots
Miscellaneous
Abscess (anywhere)
a

Rare
Extremel

Extremel

Extremel

y rare
y rare
y rare
Very common: Symptoms occur in well over half of cases (approximately 65%-95%).

Very

rare:

Almost

Symptoms

all:

Common:

Rare:

occur

Symptoms

Symptoms

Symptoms

in

less

occur

occur

occur

than

in

in

in

5%

of

cases.

almost

all

cases.

35%-65%

of

cases.

5%-35%

of

cases.

Blank cells: No mention of the symptom at that phase was found in the literature.

Extremely

rare:

Symptoms

have

been

described

in

occasional

case

reports.

Treated typhoid fever

If appropriate treatment is initiated within the first few days of full-blown illness, the disease
begins to remit after about 2 days, and the patient's condition markedly improves within 4-5
days. Any delay in treatment increases the likelihood of complications and recovery time.