Definition and Etiology

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.

S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor
sanitation, crowding, and social chaos.

Epidemiology
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.
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]

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.

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 ,
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.

Typhoidal salmonella use the macrophages' cellular machinery for their own reproduction 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. Afterward, the bacteria induce
macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body.
The bacteria then infect the gallbladder via either bacteremia or direct extension of infected
bile.

Clinical presentation

Classic typhoid fever syndrome

Typhoid fever begins 7-14 days after ingestion of the organism . The fever is characterized by a
rising temperature over the course of each day that drops by the subsequent morning. Then it
rises 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

The individual then develops a dry cough, dull frontal headache and malaise.

The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules
usually 1-4 cm wide and fewer than 5 in number.

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,individual becomes 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.

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.
Investigations

8 rCulture

The criterion standard for diagnosis of typhoid fever has long been culture isolation of the
organism. Cultures are widely considered 100% specific.

Culture of bone marrow aspirate is 90% sensitive until at least 5 days after commencement of
antibiotics. However, this technique is extremely painful, which may outweigh its benefit. [36]

Blood, intestinal secretions (vomitus or duodenal aspirate), and stool culture results are positive
for S typhi in approximately 85%-90% of patients with typhoid fever who present within the
first week of onset. They decline to 20%-30% later in the disease course. In particular, stool
culture may be positive for S typhi several days after ingestion of the bacteria secondary to
inflammation of the intraluminal dendritic cells. Later in the illness, stool culture results are
positive because of bacteria shed through the gallbladder.

Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Large-volume (10-30 mL) blood
culture and clot culture may increase the likelihood of detection. [37]

Stool culture alone yields a sensitivity of less than 50%, and urine culture alone is even less
sensitive. Cultures of punch-biopsy samples of rose spots reportedly yield a sensitivity of 63%
and may show positive results even after administration of antibiotics. A single rectal swab
culture upon hospital admission can be expected to detect S typhi in 30%-40% of patients. S
typhi has also been isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric lymph
nodes, resected intestine, pharynx, tonsils, abscess, and bone, among others.

Bone marrow aspiration and blood are cultured in a selective medium (eg, 10% aqueous oxgall)
or a nutritious medium (eg, tryptic soy broth) and are incubated at 37°C for at least 7 days.
Subcultures are made daily to one selective medium (eg, MacConkey agar) and one inhibitory
medium (eg, Salmonella-Shigella agar). Identification of the organism with these conventional
culture techniques usually takes 48-72 hours from acquisition.

Polymerase chain reaction

Polymerase chain reaction (PCR) has been used for the diagnosis of typhoid fever with varying
success. Nested PCR, which involves two rounds of PCR using two primers with different
sequences within the H1-d flagellin gene of S typhi, offers the best sensitivity and specificity.
Combining assays of blood and urine, this technique has achieved a sensitivity of 82.7% and
reported specificity of 100%. However, no type of PCR is widely available for the clinical
diagnosis of typhoid fever.
Imaging Studies

Radiography: Radiography of the kidneys, ureters, and bladder (KUB) is useful if bowel
perforation (symptomatic or asymptomatic) is suspected.

CT scanning and MRI: These studies may be warranted to investigate for abscesses in the liver
or bones, among other sites.

TREATMENT AND PREVENTION

Medical Care

If a patient presents with unexplained symptoms described in Table 1 within 60 days of

returning from an typhoid fever (enteric fever) endemic area or following consumption of food
prepared by an individual who is known to carry typhoid, broad-spectrum empiric antibiotics
should be started immediately. Treatment should not be delayed for confirmatory tests since
prompt treatment drastically reduces the risk of complications and fatalities. Antibiotic therapy
should be narrowed once more information is available.

Compliant patients with uncomplicated disease may be treated on an outpatient basis. They
must be advised to use strict handwashing techniques and to avoid preparing food for others
during the illness course. Hospitalized patients should be placed in contact isolation during the
acute phase of the infection. Feces and urine must be disposed of safely.

Surgical Care

Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple
closure of the perforation with drainage of the peritoneum. Small-bowel resection is indicated
for patients with multiple perforations.

If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be
resected. Cholecystectomy is not always successful in eradicating the carrier state because of
persisting hepatic infection.
Consultations

An infectious disease specialist should be consulted. Consultation with a surgeon is indicated

upon suspected gastrointestinal perforation, serious gastrointestinal hemorrhage, cholecystitis,
or extraintestinal complications (arteritis, endocarditis, organ abscesses).

Diet

Fluids and electrolytes should be monitored and replaced diligently. Oral nutrition with a soft
digestible diet is preferable in the absence of abdominal distension or ileus.

Activity

No specific limitations on activity are indicated for patients with typhoid fever. As with most
systemic diseases, rest is helpful, but mobility should be maintained if tolerable. The patient
should be encouraged to stay home from work until recovery

Prognosis

The prognosis among persons with typhoid fever depends primarily on the speed of diagnosis
and initiation of correct treatment. Generally, untreated typhoid fever carries a mortality rate
of 10%-20%. In properly treated disease, the mortality rate is less than 1%.

An unspecified number of patients experience long-term or permanent complications, including

neuropsychiatric symptoms and high rates of gastrointestinal cancers.