Typhoid Fever (Enteric Fever)

Definition & Etiology

Epidemiology

• Estimated 9.2–21 million cases of typhoid fever and ~110,000–280,000 deaths per year globally
• Highest burden: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, and sub-Saharan Africa; can exceed 1,000 cases/100,000 children in some urban areas
• In the US, ~5,700 cases/year; 78% travel-associated, predominantly from South Asia
• Most affected: young children, adolescents, and travelers to endemic areas
• Risk factors: contaminated drinking water, street food, raw produce fertilized with sewage, prior H. pylori infection (associated with reduced gastric acidity)

• MDR strains (resistant to chloramphenicol, ampicillin, TMP-SMX) emerged in the 1980s
• Decreased susceptibility to ciprofloxacin (DSC) / fluoroquinolone resistance — especially from South/Southeast Asia (clone H58)
• XDR (extensively drug-resistant) S. Typhi emerged in Pakistan in 2016, also resistant to third-generation cephalosporins and fluoroquinolones

Pathogenesis

1. Ingestion of contaminated food/water → organisms reach the distal ileum
2. Entry via M cells overlying Peyer's patches → phagocytosed by mononuclear cells in lymphoid tissue
3. Peyer's patches enlarge (plateau-like elevations up to 8 cm diameter) in the terminal ileum; mucosal shedding creates oval ulcers oriented along the long axis of the ileum
4. Unlike non-typhoidal Salmonella, S. Typhi disseminates via lymphatics and bloodstream → bacteremia
5. Hematogenous seeding of liver, spleen, bone marrow, gallbladder, and other organs
6. Typhoid nodules (small foci of parenchymal necrosis with macrophage aggregates) may appear in liver, spleen, bone marrow, and lymph nodes
7. Red pulp of the spleen expands due to prominent phagocyte hyperplasia
8. Gallbladder colonization → chronic carrier state (associated with gallstones)

Clinical Course

Incubation Period

Classic Weekly Progression

Key Clinical Features

• Fever — present at initial evaluation in >75%; prolonged, sustained, up to 4 weeks untreated
• Relative bradycardia — pulse-temperature dissociation (classic but present in <50%)
• Rose spots — faint, salmon-colored, blanching maculopapular rash on trunk/chest; appear at end of week 1 in ~30% of patients; 2–5 day duration; difficult to see in darker skin

Rose spots of enteric fever — faint, salmon-colored maculopapular lesions on the trunk (Harrison's, p. 1360)

• Hepatosplenomegaly (3–6%), coated tongue (51–56%)
• Leukopenia or normal WBC (not leukocytosis — key distinguishing feature from bacterial sepsis)
• GI: anorexia, nausea, vomiting; diarrhea (22–28%) or constipation (13–16%)

Diagnosis

Complications

• Intestinal perforation — most feared; typically in the distal ileum at necrotic Peyer's patches; occurs in ~3% (up to 10% in some series); presents as acute abdomen

Multiple ileal perforations at emergency laparotomy (A–E) secondary to typhoid fever

• Intestinal hemorrhage — from ulcerated Peyer's patches
• Hepatitis with focal necrosis
• Cholecystitis, gallbladder colonization → chronic carrier state
• Neuropsychiatric: encephalopathy, meningitis, psychosis, ataxia, seizures (typhoid encephalopathy)
• Myocarditis, endocarditis, pneumonia
• Septic arthritis, osteomyelitis (especially in sickle cell disease)
• DIC, renal failure
• Deafness (sequela)

Treatment

Antibiotic Selection (Based on Susceptibility)

• Fluoroquinolone resistance is now predominant in travelers returning from South/Southeast Asia — empiric fluoroquinolone monotherapy is unreliable for these patients
• For severe disease (typhoid encephalopathy/meningitis, shock): add dexamethasone (3 mg/kg IV loading dose, then 1 mg/kg q6h × 48 hours) alongside antibiotics
• Supportive: IV fluid rehydration, blood transfusion if significant GI blood loss
• Relapse occurs in 5–10%, usually milder; re-treat with same antibiotic

Mortality

• Pre-antibiotic era: 10–20%
• With appropriate treatment: <1%

Chronic Carrier State

Prevention & Vaccination

• Vaccines do not cover S. Paratyphi — important limitation given rising paratyphoid incidence
• Revaccination required as protection wanes

Key Differentials

• Malaria (exclude first in febrile traveler)
• Dengue fever
• Leptospirosis
• Brucellosis
• Viral hepatitis
• Rickettsial infections

Clinical Pearl: In any traveler returning from South Asia or Africa with fever lasting >10 days, typhoid should be high on the differential. Blood culture is the diagnostic cornerstone. Fluoroquinolone resistance is now so prevalent from the Indian subcontinent that empiric ceftriaxone or azithromycin is preferred pending susceptibility results.