Enteric Fever (Typhoid Fever)

Epidemiology and Etiology

Epidemiology

• Most prevalent in underdeveloped areas with poor sanitation
  • South-central and Southeast Asia
  • Southern Africa
• World Health Organization (WHO) estimates (worldwide):
  • Incidence: 11–20 million cases/year
  • Deaths: 128,000–161,000 deaths/year
• The incidence in developed countries is low and almost always associated with travel to a high-risk area (incidence in the United States: 200–300 cases/year).

Etiology

• Causative agent: S. enterica serotype Typhi or Salmonella Typhi
  • Motile, encapsulated, Gram-negative bacilli
  • Facultative intracellular within macrophages
  • Produces black colonies on Hektoen agar
  • Acid labile (requires a high inoculum) 
• Exam tip: While not commonly tested, Salmonella Paratyphi serotypes A, B, and C can also cause enteric fever (paratyphoid fever).

Pathophysiology

Transmission

• Fecal-oral transmission
  • Humans are the only reservoir.
  • Chronic carriers have gallbladder colonization (e.g., “Typhoid Mary”).
• Severity of disease is dependent on:
  • Infecting species (S. Typhi versus S. Paratyphi)
  • Infectious dose (high inoculum is required to survive exposure to gastric acids)

Pathogenesis

After ingestion of Salmonella Typhi:

• Bacteria must survive exposure to gastric acids.
• Bacteria adhere to and invade intestinal M cells of Peyer’s patches.
• After invasion, the bacteria replicate within macrophages in Peyer’s patches, mesenteric lymph nodes, and the spleen. This causes an inflammatory reaction with hypertrophy of Peyer’s patches and recruitment of mononuclear cells and lymphocytes.
• Bacteria spread hematogenously through the bloodstream and lymphatic system, causing:
  • Localized infection of the lymphoid tissue and small intestine
  • Bacteremia 

Clinical Presentation

Infection with S. Typhi results in typhoid (or enteric ) fever. Typhoid fever is a severe systemic illness associated with fever and abdominal pain. 

The incubation period is 5–21 days.

Diagnosis

Diagnosis is dependent on a high degree of suspicion as cultures are often negative, take many days, and may not be available in resource-poor areas.

• Confirmed by blood and stool cultures
  • Blood cultures will be positive for Salmonella species in 50%–70% of cases.
  • Stool cultures will be positive for Salmonella species in 30%–40% of cases.
• If other risk factors (e.g., recent travel to a high-risk) are present, clinical diagnosis is possible based on:
  • Prolonged fever (> 3 days)
  • Gastrointestinal (GI) symptoms
    • Abdominal pain
    • Diarrhea
    • Constipation

Management and Prevention

Management

• First-line treatment: fluoroquinolones (primarily ciprofloxacin)
• If fluoroquinolone resistance is suspected, azithromycin

Prevention

• Two vaccines are available for those traveling to high-risk areas:
  • Intramuscular, inactivated vaccine
    • Contains capsular polysaccharide
    • Must be > 2 years old
  • Oral, live-attenuated vaccine: must be > 6 years old
• Hand hygiene, food, and water safety are also key.
• Any infected individual must avoid preparing food for others.

Complications

Complications of typhoid are typically associated with untreated infection in 3rd phase (or week) of infection. The most common complications include:

• GI bleeding
• Ileal perforation
• Pericarditis
• Visceral abscesses
• Osteomyelitis
• Overwhelming sepsis

Another complication, usually associated with asymptomatic infection, is developing a chronic carrier state:

• Positive Salmonella in stool or urine cultures > 1 year after acute infection
  • More frequent in adult women and patients with cholelithiasis or other biliary tract abnormalities
  • Occurs in up to 6% of patients
  • Treatment: ciprofloxacin for at least 1 month
• Associated with an increased risk of carcinoma of the gallbladder
• Patients must avoid working in the food industry

Differential Diagnosis

• Amebic liver/hepatic abscess: 
  • Most common extraintestinal manifestation of amebiasis
  • As with typhoid fever, may present with pulmonary, cardiac, and central nervous system (CNS) manifestations
  • Different fever pattern
  • No rose-colored papular rash
• Appendicitis: 
  • As with typhoid fever, may present with abdominal pain and fever
  • Abdominal pain is localized to the right lower quadrant
• Toxoplasmosis:
  • As with typhoid fever, may present with headache, sore throat, malaise, fever, hepatosplenomegaly, and neurological symptoms
  • History of exposure to cats
  • Immunocompromised patients will have brain abscesses with multiple ring-enhancing lesions on magnetic resonance imaging (MRI).
• Tuberculosis (TB): 
  • As with typhoid fever, may present with abdominal pain, vomiting, diarrhea, malaise, fever, and weight loss
  • Infection is typically localized to the lungs with chest X-ray showing cavitations and mediastinal or hilar lymphadenopathy. 
• Leishmaniasis: 
  • As with typhoid fever, may present with hepatosplenomegaly, fever, anemia, and anorexia
  • Either skin ulcerations or a clinical history of spiking fevers, hepatosplenomegaly, and pancytopenia with exposure to sandflies
• Brucellosis: 
  • As with typhoid fever, may present with malaise, fatigue, fever, headache, lymphadenopathy, and myocarditis
  • History of ingesting raw or unpasteurized dairy products or direct contact with infected animals (goats, sheep, pigs, etc.)
• Malaria: 
  • As with typhoid fever, may present with headache, malaise, abdominal pain, paroxysmal high fever
  • Associated with travel history to an endemic region
  • Peripheral blood smear showing schizonts, hemolytic anemia, and thrombocytopenia