Typhoid and paratyphoid fever

Typhoid and paratyphoid fever are infectious diseases caused by the bacteria Salmonella typhi and Salmonella paratyphi. Transmission occurs via the fecal-oral route. The incubation period is typically 7–21 days, although it may be as long as 30 days. Typhoid and paratyphoid fever classically have three clinical stages. In the first week of symptoms, body temperature rises gradually and relative bradycardia, as well as diarrhea or constipation, may occur. The second week of illness is characterized by persistent fever, rose-colored spots on the abdomen, nonspecific abdominal pain, and profuse diarrhea. During the third week, complications such as hepatosplenomegaly, intestinal bleeding, and/or perforation with secondary bacteremia and peritonitis may occur. Symptoms begin to subside in the fourth week. Pathogen detection in blood and stool cultures confirms the diagnosis. The treatment of choice includes fluoroquinolones such as ciprofloxacin. Up to 6% of patients become chronic Salmonella carriers after symptoms have resolved.

• There are an estimated 11–21 million cases per year worldwide.
• Most prevalent in resource-limited regions with poor sanitation in East and Southeast Asia, Africa, and Central and South America
• In the United States, approx. 300 culture-confirmed cases of typhoid fever and 100 cases of paratyphoid fever are reported annually, mostly in individuals who have traveled to endemic regions.

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen
  • Salmonella enterica serotype Typhi: typhoid fever
    • Gram-negative rod
    • Facultative anaerobe with peritrichous flagella
    • Produces hydrogen sulfide (H₂S) on TSI agar
    • Oxidase-negative
    • Cannot ferment lactose
  • Salmonella enterica serotype Paratyphi: paratyphoid fever
    • Salmonella enterica serotype Paratyphi A
    • Salmonella enterica serotype Paratyphi B
    • Salmonella enterica serotype Paratyphi C
    • Salmonella enterica serotype Choleraesuis
• Reservoir
  • Salmonella enterica serotype Typhi: humans
  • Other Salmonella species: humans and animals
• Transmission: fecal-oral
  • Direct: person-to-person contact; asymptomatic carriers frequently involved (e.g., the pathogen may be transferred from contaminated stool via handshake to the next person)
  • Indirect: contaminated food and water (e.g., if drinking water and sewage systems are not properly separated or a carrier prepares food)

Humans are the main reservoir for S. typhi.

Salmonella has flagella.

References:^[3]

Lifecycle

1. Oral uptake of pathogen: A relatively large number of organisms (∼ 10⁵) is needed to cause infection (high infective dose), unlike, e.g., in Shigella infection, where as few as ∼ 10 organisms suffice to infect the host.
2. Migration into the Peyer patches of the distal ileum; : If the pathogen manages to reach the distal ileum, it migrates via M cells through the epithelium and into the Peyer patches.
3. Infection of macrophages → nonspecific symptoms
4. Spread from macrophages to the bloodstream → septicemia → systemic disease
5. Migration back to intestine → excretion in feces

Virulence factors

The cell wall of the typhoid pathogens contains endotoxins; , which are responsible for the neurological symptoms associated with typhoid and paratyphoid fever (see the “Bacteria overview” article for more information).

References:^[3][4]

General

• Incubation period: 5–30 days (most commonly 7–14 days)
• If left untreated, three different disease stages, each lasting a week, classically occur.
• After 3 weeks of disease: slow regression of symptoms; patients may become chronic Salmonella carriers (see “Complications” below).

Typhoid fever is a systemic disease and it is not limited to the gastrointestinal system.

Typhoid fever must always be considered in cases of persistent fever of unknown origin and a history of travel to an endemic region.

Progression of illness

Week 1

• Body temperature rises gradually.
• Relative bradycardia
• Constipation or diarrhea
• Headache

Week 2

• Persistent fever , but no chills; mostly unresponsive to antipyretics
• Rose-colored spots; : a small, speckled, rose-colored exanthem that appears on the lower chest and abdomen (most commonly around the navel) in approx. 30% of affected individuals
• Typhoid tongue: greyish/yellowish-coated tongue with red edges
• Nonspecific abdominal pain and headache
• Yellow-green diarrhea; , comparable to pea soup (caused by purulent, bloody necrosis of the Peyer patches), or obstipation and bowel obstruction (as a result of swollen Peyer patches in the ileum)
• Neurological symptoms (delirium, coma)

Week 3

• Clinical features of week 2
• Additional possible complications include:
  • Gastrointestinal ulceration with bleeding and perforation
  • Hepatosplenomegaly
  • In rare cases: sepsis, meningitis, myocarditis, and renal failure

References:^[3]

• Laboratory tests
  • Anemia
  • Leukopenia or leukocytosis
    • Absolute eosinopenia ^[5]
    • Relative lymphocytosis ^[6]
  • Abnormal liver function tests
• Pathogen detection ^[3]
  • Blood cultures: Bacteremia is detectable starting in week 1 of the disease.
  • Stool cultures
  • Bone marrow cultures (most sensitive modality, but rarely performed) ^[7]
  • Serology (Widal test)

Blood culture is the most important diagnostic tool at disease onset, as stool cultures are often negative despite active infection.

• First-line treatment: fluoroquinolones (e.g., ciprofloxacin)
• Azithromycin, if resistance to fluoroquinolones is suspected (e.g., in patients with infection acquired from certain regions, such as South Asia)
• Third-generation cephalosporins (e.g., ceftriaxone) are preferred for severe infection.
• Antibiotics prolong the duration of fecal excretion of bacteria.

References:^[8]

Chronic Salmonella carriage

• Definition: positive stool cultures 12 months after overcoming the disease
• Incidence: 2–5% of patients become chronic carriers (S. typhi colonizes the gallbladder). ^[9]
• Clinical features: typically asymptomatic
• Treatment: fluoroquinolones (e.g., ciprofloxacin) administered for at least 1 month
• Complication: increased risk for gallbladder cancer

References:^[8]

We list the most important complications. The selection is not exhaustive.

Food and water

Vaccination is not entirely effective. Measures must therefore be implemented to avoid exposure (see "Food and water safety").

Vaccination

• Indication: The WHO recommends typhoid fever vaccination to those traveling to high-risk areas (East and Southeast Asia, South and Central America, Africa).
• Administration: A parenteral, inactivated vaccine and an oral, live vaccine are available for active immunization, and both provide similar levels of protection. ^[10]
  • Inactivated vaccine contains Vi polysaccharide (part of S. typhi capsule): administered intramuscularly
  • Live-attenuated vaccine contains live attenuated S. typhi: administered orally
  • See “Vaccines before travel” for details.

Overcoming an infection with S. typhi or S. paratyphi does not confer lifelong immunity. Vaccination is not entirely protective.

Reporting requirements

Typhoid/paratyphoid fever are nationally notifiable diseases.

References:^[2][8][11]