Typhoid and paratyphoid fever

Typhoid and paratyphoid fever (sometimes referred to together as enteric fever) are infectious diseases caused by the bacteria Salmonella Typhi and Salmonella Paratyphi. Transmission occurs via the fecal-oral route. The incubation period is highly variable but typically ranges from 6 to 30 days. Typhoid and paratyphoid fever classically have three clinical stages. In the first week of symptoms, body temperature rises gradually, and relative bradycardia, diarrhea, and/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 after the third week. Pathogen detection in blood or stool cultures confirms the diagnosis. The choice of empiric antibiotic therapy depends on the risk of pathogen resistance. The most commonly used agents include ceftriaxone and azithromycin. Some individuals 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. 400 culture-confirmed cases of typhoid fever and 100 cases of paratyphoid fever are reported annually, mostly in individuals who have traveled to endemic regions.

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 Salmonella Typhi.

Salmonella has flagella.

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).

General

• Incubation period: 6–30 days (most commonly 7–14 days) ^[1]
• 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”).

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. ^[1]
• Relative bradycardia (not seen in children) ^[3][4]
• 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

Suspect typhoid or paratyphoid fever in patients with fever and gastrointestinal concerns (e.g., diarrhea) who have traveled to endemic areas. In adults and children, diagnosis is confirmed with the detection of Salmonella Typhi or Salmonella Paratyphi in cultures. ^[3][5][6]

Routine laboratory studies ^[5]

Not typically indicated, but if performed may show some of the following findings.

• CBC with differential ^[5][6]
  • Anemia
  • Leukopenia or leukocytosis ^[5][7]
    • Eosinopenia ^[8]
    • Relative lymphocytosis ^[9]
  • Thrombocytopenia
• Inflammatory markers: ↑ CRP
• Liver chemistries: ↑ AST and/or ALT
• BMP: may show abnormalities in patients with severe diarrhea
  • ↑ BUN, ↑ creatinine ^[10]
  • Electrolyte disturbances
  • See “Laboratory findings in dehydration and hypovolemia.”

Confirmatory studies ^[1][10][11]

• Microbiology
  • Blood cultures: indicated for all patients
    • Most important diagnostic tool to identify current infection ^[1][11]
    • May be positive starting in week 1 of the disease ^[12]
  • Stool cultures: to increase chance of pathogen detection or to identify chronic Salmonella carriage
    • Recommended for all pediatric patients and for individuals who traveled with an infected patient. ^[3]
    • Lower sensitivity than blood cultures ^[10][3]
    • May be positive starting in week 2 ^[1]
  • Urine cultures: low sensitivity
  • Bone marrow cultures: most sensitive modality, but rarely performed ^[3][5][11]
  • Bile or duodenal fluid cultures may be used. ^[3][6]
• Serology (e.g., Widal test, rapid antibody diagnostics): not recommended because of low sensitivity and specificity and the inability to distinguish current infection from previous infection or vaccination ^[3]

Typhoid and paratyphoid fever are nationally notifiable diseases in the US. Notify the state or local health department if a case is confirmed. ^[1]

General principles ^[1][3]

• Consult infectious diseases (ID) for guidance.
• Antibiotic treatment should be based on antibiotic susceptibility testing, as resistance is widespread.
• In patients with severe infection (e.g., delirium, coma, shock): ^[12]
  • Provide supportive care, e.g., fluid resuscitation.
  • Manage complications, e.g., management of GI perforation or management of GI bleeding.
  • Consider administration of corticosteroids, e.g., dexamethasone (off-label). ^[3][13]
• Monitor for response to therapy (e.g., fever resolution in 3–5 days, infection relapse) and complications (e.g., chronic Salmonella carriage).

Antibiotic therapy ^[1][6][14]

Start empiric antibiotic treatment based on disease severity and the risk of extremely drug-resistant (XDR) pathogens; tailor further treatment based on antimicrobial susceptibility testing. ^[10]

• Uncomplicated infection: azithromycin (off-label) ^[3][13]
• Complicated infection ^[1][3][14]
  • Low-risk for XDR pathogens: third-generation cephalosporins, e.g., ceftriaxone (off-label)
  • High risk for XDR infection (no travel or recent travel to Iraq or Pakistan): carbapenems

Targeted antibiotic therapy

The following antibiotics should only be given after confirming susceptibility as resistance is common. ^[1]

• Adults: fluoroquinolones, e.g., ciprofloxacin
• Children: amoxicillin, trimethoprim/sulfamethoxazole, or ciprofloxacin (off-label) ^[3]

Due to high resistance in the US, fluoroquinolones should not be used until susceptibility data is available.

Antibiotics prolong the duration of fecal excretion of bacteria.

Relapse is common and may necessitate retreatment. ^[3]

Acute complications ^[12]

• Gastrointestinal and hepatobiliary
  • Bowel perforation
  • GI hemorrhage
  • Cholecystitis
  • Hepatitis
• Cardiac: myocarditis
• Respiratory
  • Pneumonia
  • Bronchitis
• Neurologic
  • Altered mental status (e.g., encephalopathy, delirium)
  • Meningitis

Chronic Salmonella carriage ^[14]

• Definition: positive stool cultures 12 months after resolution of symptoms
• Incidence: 2–5% of patients become chronic carriers (Salmonella Typhi colonizes the gallbladder). ^[15]
• Clinical features: typically asymptomatic
• Treatment: : fluoroquinolones (e.g., ciprofloxacin) administered for at least 1 month if susceptible
• Complication: increased risk for gallbladder cancer

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

Typhoid fever vaccination ^[1][16]

• Indications ^[6]
  • Travelers to high-risk areas (e.g., South and Southeast Asia, South and Central America, Africa)
  • Close contact with a documented chronic carrier
  • Laboratory personnel exposed to typhoid
• Vaccine types: A parenteral, inactivated vaccine and an oral, live vaccine are available for active immunization, and both provide similar levels of protection. ^[16][17]
  • Inactivated vaccine containing Vi polysaccharide (part of Salmonella Typhi capsule): administered intramuscularly
  • Live-attenuated vaccine containing live-attenuated Salmonella Typhi: administered orally
• Indications and schedule: See “Vaccines before travel” for details.

Overcoming an infection with Salmonella Typhi or Salmonella Paratyphi does not confer lifelong immunity, and vaccination is not 100% protective. ^[1]

Other prevention strategies ^[1]

Vaccination is not 100% effective. Measures must therefore be implemented to avoid exposure.

• Food and water safety while traveling
• Hand hygiene ^[11]
  • Wash hands with soap and water before preparing food, before eating, and after using the bathroom.
  • Use hand sanitizer with ≥ 60% alcohol if soap and/or water are not available.