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🦠 Enteric Fever (Typhoid) - Complete Microbiology Exam Guide

Sources: Harrison's Principles of Internal Medicine 22E (2025), Jawetz Melnick & Adelberg's Medical Microbiology 28E, Park's Textbook of Preventive & Social Medicine

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1. THE ORGANISM (Microbiology of Salmonella Typhi)

• Family: Enterobacteriaceae
• Gram-negative, short rod (bacillus)
• Non-lactose fermenter
• Motile (peritrichous flagella)
• Facultative anaerobe
• Produces H₂S gas
• Does NOT form spores or capsule (except Vi antigen = virulence capsular antigen)

• On MacConkey / EMB agar: pale/colorless colonies (non-lactose fermenter)
• On Bismuth sulfite agar: black colonies (H₂S production)
• On Salmonella-Shigella (SS) agar / HE agar / XLD agar: selective media
• On TSI (Triple Sugar Iron) slant: K/A, Gas, H₂S positive (ferments glucose only, not lactose or sucrose)
• Enrichment broth: Selenite F or Tetrathionate broth (inhibits normal flora, allows Salmonella to multiply)

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2. EPIDEMIOLOGY

• ~9.2-21 million cases of typhoid fever per year worldwide
• ~5 million cases of paratyphoid fever per year
• 110,000-280,000 deaths annually
• Highest incidence: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, Africa - exceeding 1,000 cases per 100,000 children in some urban areas
• In developed countries (USA, Western Europe), enteric fever is rare and mostly travel-associated

• Fecal-oral route - the ONLY route
• S. Typhi and S. Paratyphi are strictly human pathogens (no animal reservoir - unlike non-typhoidal Salmonella)
• Sources:
  • Fecally contaminated drinking water or ice (causes explosive epidemics)
  • Contaminated food from chronic carriers (most important ongoing source)
  • Street food, raw fruits/vegetables from sewage-fertilized fields
  • Sexual transmission (male-to-male, documented)
  • Health care workers from infected patients/cultures

• Poor sanitation, mixing of drinking water with sewage
• No handwashing, limited toilet access
• Young children and adolescents in endemic areas
• Prior H. pylori infection (reduces gastric acidity = lower barrier)
• Travel to endemic regions

• 3% of typhoid survivors become permanent (chronic) carriers
• Organisms persist in the gallbladder and biliary tract (especially if gallstones present)
• Convalescent carriers shed organisms in stool/urine for weeks after recovery
• Carriers working as food handlers = major source of outbreaks

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3. PATHOGENESIS

Ingestion of S. Typhi (inoculum ~10⁵ organisms)
        ↓
Survive gastric acid → reach small intestine
        ↓
Penetrate intestinal epithelium via M-CELLS overlying Peyer's patches
(M-cells in ileum = specialized sampling cells of gut-associated lymphoid tissue)
        ↓
Enter intestinal lymphatics → Peyer's patches multiply → local hyperplasia
        ↓
PRIMARY BACTEREMIA (1st week) - spreads to liver, spleen, bone marrow
        ↓
Bacteria multiply intracellularly within macrophages (reticuloendothelial system)
        ↓
SECONDARY BACTEREMIA (2nd week) - high fever plateau, systemic illness
        ↓
Re-seeding of intestine via bile from gallbladder
→ Necrosis of Peyer's patches → ulceration

• Hyperplasia then necrosis of Peyer's patches (ileum) - hallmark
• Enlarged mesenteric lymph nodes
• Hepatitis + focal necrosis of liver
• Splenomegaly
• Inflammation of gallbladder (organisms persist here)
• Rose spots = bacterial emboli in dermal capillaries

• S. Typhi survives inside macrophages (intracellular pathogen) - resists killing
• Vi antigen inhibits complement activation and phagocytosis

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4. CLINICAL FEATURES

• Relative bradycardia (Faget's sign) = pulse lower than expected for the fever temperature
• Rose spots: faint, salmon-colored, blanching maculopapular rash on trunk/chest; 2-4mm; appear in ~30% of patients; disappear in 3-4 days
• Coated tongue (51-56%)
• Splenomegaly + hepatomegaly
• Dicrotic pulse

• Leukopenia (WBC normal or low) - NOT elevated as in typical bacterial sepsis - classic exam point!
• Elevated liver enzymes

• Intestinal hemorrhage (sudden temperature drop + shock + blood in stool)
• Intestinal perforation (3rd week - most dangerous)
• Pneumonia, myocarditis, cholecystitis, nephritis, osteomyelitis, typhoid psychosis

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5. LABORATORY DIAGNOSIS

Summary Table

1. Sample (blood, stool, urine, bone marrow)
2. Inoculate into enrichment broth (selenite F / tetrathionate) for stool
3. Subculture on differential media (MacConkey, EMB, bismuth sulfite)
4. Subculture on selective media (SS agar, HE agar, XLD agar)
5. Identify suspect colonies by biochemical reactions (TSI, urease, oxidase)
6. Confirm by slide agglutination with specific antisera

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6. WIDAL TEST (Tube Dilution Agglutination Test)

What it is:

Principle:

Antibody appearance timing:

• O antibodies: appear day 6-8 after onset
• H antibodies: appear day 10-12 after onset
• Serum agglutinins rise sharply during weeks 2-3 of infection

Interpretation:

• Need 2 serum samples at 7-10 day intervals to show a rising titer (4-fold rise is significant)
• Single significant titers (used in endemic areas):
  • O agglutinin ≥ 1:160 = significant
  • H agglutinin ≥ 1:160 = significant
• A rising titer is more meaningful than a single titer

Limitations (very high-yield exam content):

• False positives caused by:
  • Cross-reaction with other Salmonella serotypes sharing O/H antigens
  • Cross-reacting epitopes with other Enterobacteriaceae
  • Malaria, typhus, bacteremia, liver cirrhosis, immunological conditions
  • Previous vaccination
• False negatives caused by:
  • Prior antibiotic therapy (blunts antibody response)
  • Early disease (too early for antibody rise)
  • Immunocompromised patients
  • Up to 30% of culture-proven typhoid cases can be Widal-negative!
• Difficult to interpret in endemic areas (background titers are high)
• CDC does NOT recommend Widal test for diagnosis of acute typhoid

Newer alternatives to Widal:

• IDL Tubex® test: detects IgM antibodies against O9 antigen; results in minutes
• Typhidot®: detects IgM + IgG against 50kD antigen of S. Typhi; takes 3 hours
• Typhidot-M®: detects IgM only (more specific for acute infection)
• Dipstick test: detects S. Typhi-specific IgM antibodies against LPS antigen
• PCR/NAAT: direct detection; still being evaluated for routine use

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7. DRUG RESISTANCE

History of resistance:

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8. TREATMENT

Antibiotic Therapy (Harrison's 2025 Table):

• Mortality drops from 10-30% (untreated) to <1% with prompt treatment
• Fluoroquinolones now unreliable for Indian subcontinent strains
• Azithromycin is now a preferred oral option
• Chronic carriers: Ampicillin + cholecystectomy (if gallstones present)

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9. PROPHYLAXIS (Prevention)

Non-pharmacological (environmental):

• Safe drinking water supply and proper sewage treatment
• Food safety - thorough cooking of poultry/eggs/meat
• Hand hygiene (handwashing with soap)
• Avoid raw fruits/vegetables from sewage-fertilized fields
• Exclude carriers from food handling jobs
• Identify and treat chronic carriers

Pharmacological (chemoprophylaxis):

• Not routinely recommended
• Pre-travel vaccination is the primary strategy

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10. VACCINES

Currently available vaccines:

Key vaccine facts for exam:

• Both Ty21a and Vi CPS have 50-80% efficacy
• Ty21a contraindicated in: immunocompromised patients, pregnancy, <6 years, during antibiotic use
• Vi antigen is the basis of the injectable vaccine - it is the capsular polysaccharide that confers immunity
• TCV is WHO-recommended for routine immunization in children in high-burden countries
• Vaccination recommended for travelers to endemic regions, especially rural areas
• Only 3% of US typhoid cases had received vaccine in the prior 5 years!

Mechanism of immunity:

• O and Vi antibodies = resistance to infection (circulating antibodies)
• Secretory IgA = prevents attachment to intestinal epithelium
• Reinfection possible but usually milder
• Relapses occur in 2-3% despite antibodies (organisms sequestered intracellularly)

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11. QUICK EXAM SUMMARY TABLE

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12. HIGH-YIELD MNEMONICS

• Week 1: rising fever + blood culture positive
• Week 2: plateau fever + rose spots + Widal turns positive
• Week 3: complications (perforation/hemorrhage) + stool culture positive

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