Typhoid Fever (Enteric Fever)

Definition

Etiology & Microbiology

• Causative organism: Salmonella typhi - a Gram-negative, facultative anaerobic bacillus
• Humans are the ONLY reservoir (unlike non-typhoidal Salmonella, which have animal reservoirs)
• Transmission: fecal-oral route via contaminated food or water; also from chronic carriers (often with gallbladder colonization/gallstones)
• S. Paratyphi A increasingly emerging in travelers from South/Southeast Asia

Epidemiology

• Estimated 9.2-21 million cases of typhoid fever and 110,000-280,000 deaths annually worldwide - Harrison's 22E
• Highest burden: Indian subcontinent (Pakistan, Bangladesh, Nepal, India), Eastern Mediterranean, Africa - incidences >1,000 cases/100,000 children in some urban areas
• Endemic in regions with poor sanitation and unsafe water
• In developed nations, most cases are imported
• Higher incidence in poor urban neighborhoods and among children/adolescents in endemic areas
• Risk factors: contaminated drinking water/ice, street food, raw produce fertilized with sewage, household contacts with illness, lack of handwashing

Pathogenesis

1. Ingested organisms penetrate intestinal epithelium via M cells overlying Peyer's patches
2. Engulfed by mononuclear cells in underlying lymphoid tissue
3. Peyer's patches in the terminal ileum enlarge into plateau-like elevations (up to 8 cm)
4. Mucosal shedding creates oval ulcers oriented along the long axis of the ileum
5. Unlike non-typhoidal Salmonella, S. Typhi can disseminate via lymphatic and blood vessels
6. Reactive hyperplasia of mesenteric lymph nodes; red pulp of spleen expands due to phagocyte hyperplasia
7. Typhoid nodules - small foci of parenchymal necrosis with macrophage aggregates - appear in liver, bone marrow, and lymph nodes - Robbins & Kumar Basic Pathology

Clinical Features

Classic Stepwise Progression

Key Signs

• Rose spots: pale red maculopapular rash on the trunk (chest/abdomen) - seen mainly in fair-skinned patients during the second week
• Relative bradycardia (Faget sign): pulse slower than expected for degree of fever - classic but may be absent
• Splenomegaly: develops as disease progresses
• "Pea soup" diarrhea: may appear in week 2-3, though 30% of patients present with constipation rather than diarrhea - Tintinalli's Emergency Medicine

Diagnosis

Complications

• Intestinal: small bowel perforation (most feared, typically terminal ileum - week 3), hemorrhage
• Hepatic: hepatitis, cholecystitis, gallbladder carrier state
• Neurological: encephalopathy, meningitis, psychosis, ataxia, seizures, deafness
• Cardiovascular: myocarditis, mycotic aneurysm
• Pulmonary: pneumonia
• Hematological: DIC, hemolytic anemia
• Other: septic arthritis, renal failure

Treatment

Antibiotics

• MDR strains: Resistant to chloramphenicol, ampicillin, trimethoprim - emerged in 1980s, now widespread
• Decreased susceptibility to ciprofloxacin (DSC): Major problem in South/Southeast Asia
• XDR (extensively drug-resistant) Typhi: First reported in Pakistan (2016-2019); resistant to all first-line agents + fluoroquinolones + third-generation cephalosporins; only azithromycin and carbapenems reliable
• A 2026 systematic review (PMID 41990105) confirms increasing antimicrobial resistance burden in Indian S. Typhi isolates from 1977-2024

Adjunctive Therapy

• Dexamethasone (3 mg/kg loading dose then 1 mg/kg q6h x 8 doses): indicated in severe typhoid with meningitis/encephalopathy or septic shock - improves survival
• IV rehydration and blood transfusion if needed for GI losses
• Surgery for bowel perforation

Carrier State

• Chronic carriers (>1 year of fecal excretion): treat with prolonged fluoroquinolone course (ciprofloxacin x 28 days); cholecystectomy if associated gallstones

Vaccines

• TCV (Typbar-TCV) is WHO prequalified and recommended for infants and children >6 months in endemic areas - preferred over older vaccines for broader protection and durability
• A 2025 meta-analysis (PMID 41125003) confirms real-world vaccine effectiveness of TCV in children and adolescents
• Important caveat: No current typhoid vaccine protects against S. Paratyphi - Goldman-Cecil Medicine
• Oral vaccine adherence may be as low as 70%

Prevention & Control (Public Health)

• Safe water supply and sewage disposal (most effective long-term measures)
• Food hygiene and handwashing
• Detection and management of chronic carriers
• Vaccination of travelers to endemic areas and children in high-burden countries
• WHO recommends introduction of TCV into routine immunization programs in high-burden countries

Differential Diagnosis

• Malaria (most important in tropics - always exclude first)
• Brucellosis, leptospirosis, rickettsia
• Infectious mononucleosis, viral hepatitis
• Lymphoma, miliary tuberculosis
• Other enteric infections

Recent Evidence Note: A 2026 meta-analysis (PMID 41990105, PLoS NTD) documents a growing burden of antimicrobial resistance among S. Typhi isolates in India from 1977-2024, reinforcing the need for culture and sensitivity testing before treatment. XDR typhoid is an emerging threat, particularly in South Asia. TCV introduction (PMID 41125003, Vaccine 2025) shows good real-world effectiveness.