Enteric Fever (Typhoid Fever)

Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Up to 20 million new cases of typhoid fever occur each year worldwide, most commonly in undeveloped areas with poor sanitation. Transmission occurs through the fecal-oral route, and humans are the only known reservoir. Complications of typhoid fever include intestinal hemorrhage, pericarditis, visceral abscesses, and septicemia. Treatment is with fluoroquinolones. Prevention of typhoid fever is available through vaccination, hand hygiene, and safe food and water practices.

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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: Salmonella Typhimurium
    • 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).
Salmonella typhi

S. Typhimurium

Image: “Salmonella typhi“ by Roinujs. License: CC BY-SA 4.0

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. Typhimurium versus S. paratyphi)
    • Infectious dose (high inoculum is required to survive exposure to gastric acids)

Pathogenesis

After ingestion of S. Typhimurium:

  • 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 
Salmonella typhi photomicrograph

This photomicrograph reveals some of the histopathology exhibited in a lymph node tissue specimen in a case of typhoid fever. Macrophages are present amongst the normal lymphocytes. Note the S. Typhimurium bacterial invasion of macrophages. These macrophages also contain erythrocytes and degenerated lymphocytes.

Image: “2213” by CDC/ Armed Forces Institute of Pathology, Charles N. Farmer. License: Public Domain

Clinical Presentation

Infection with S. Typhimurium 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.

Three-phase or -week progression (if untreated)
Clinical courseSubjective findings
Week 1Bacteremia
  • Gradually rising fever
  • Relative bradycardia
  • Pulse-temperature dissociation
  • Constipation
Week 2
  • Progressing illness
  • Patients appear acutely ill
  • Persistent fever: for > 3 days, unresponsive to antipyretics
  • Abdominal pain
  • “Rose spots”: small, speckled, rose-colored exanthem most commonly on the lower chest/abdomen
  • Yellow-green, “pea soup” diarrhea or constipation
  • Prostration
  • Typhoid tongue: greyish/yellow coated tongue with erythematous edges
Week 3
  • Ileocecal lymphatic hyperplasia of Peyer’s patches
  • Secondary bacteremia
  • Peritonitis
Clinical features of week 2 plus:
  • Hepatosplenomegaly
  • Intestinal bleeding
  • Altered mental status

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

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