Pathogenesis of Enteric Fever - Step by Step

1. Ingestion

• Contaminated food or water ingested
• Infective dose: typically >10^5 organisms (lower if gastric acidity is reduced)
• S. Typhi is the main agent; S. Paratyphi A, B, C cause milder disease

2. Gastric Acid Barrier

• Most organisms are killed by gastric acid (pH <2)
• Surviving organisms proceed to the small intestine
• Risk increases with: achlorhydria, antacid/PPI use, prior antibiotics (which reduce competing flora), large inoculum

3. Intestinal Penetration (Two Pathways)

• Via M cells overlying Peyer's patches in the terminal ileum (primary route)
• Via CFTR-mediated uptake by enterocytes (explains why CFTR mutations confer partial protection)

4. Peyer's Patches (Terminal Ileum)

• Bacteria enter the submucosa
• Taken up by mononuclear phagocytes/macrophages within Peyer's patches
• Bacteria survive and multiply intracellularly (resist killing inside phagosomes)
• Peyer's patches undergo hypertrophy then necrosis - the basis for ulceration and later perforation

5. Mesenteric Lymph Nodes

• Infected macrophages drain to mesenteric lymph nodes
• Further intracellular multiplication

6. Primary (Silent) Bacteremia - Incubation Phase (Days 1-14)

• Via the thoracic duct → bloodstream
• This is transient and silent - patient is asymptomatic or has mild prodrome
• Corresponds to the incubation period (mean 10-14 days, range 5-21 days)

7. Seeding of Reticuloendothelial System (RES)

• S. Typhi seeds the liver, spleen, bone marrow, and gallbladder
• Massive intracellular multiplication inside tissue macrophages
• Bone marrow is the most sensitive culture site even after antibiotics

8. Secondary (Sustained) Bacteremia - Symptomatic Phase (Week 1-2)

• Organisms released back into bloodstream in large numbers
• Cytokine storm: TNF-α, IL-1β, IL-6 released by activated macrophages
• Clinical features: stepwise rising fever (39-40.5°C), relative bradycardia (Faget's sign), headache, myalgia, malaise, anorexia
• Rose spots on abdomen/chest in ~30% of light-skinned patients (salmon-colored maculopapules - S. Typhi can be cultured from them)
• Hepatosplenomegaly in ~50%

9. Gallbladder Colonization → Intestinal Reseeding (Week 2-3)

• Gallbladder becomes infected (bile is an excellent culture medium)
• Organisms re-enter intestine via bile
• Re-infection of Peyer's patches → worsening diarrhea, GI symptoms more prominent in second week
• Stool cultures become positive at this stage

10. Complications (Week 2-4, untreated)

11. Chronic Carrier State

• 1-5% of patients become chronic carriers (>1 year shedding)
• Gallbladder is the reservoir (especially with cholelithiasis)
• Detected by anti-Vi antibody serology
• These carriers are the main human reservoir maintaining transmission

Diagnostic Correlation with Pathogenesis