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Typhoid Fever & Paratyphoid A, B, C - Complete Guide

Sources: Harrison's Principles of Internal Medicine 22E (2025), Tintinalli's Emergency Medicine, Park's Textbook of Preventive and Social Medicine, CDC Guidelines

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1. DEFINITION & CAUSATIVE ORGANISMS

• Man is the ONLY reservoir - no animal reservoir exists for any of these organisms (unlike non-typhoidal Salmonella)
• Gram-negative, facultative anaerobic, motile bacilli
• Killed by drying, pasteurization, and common disinfectants
• S. Paratyphi A thought to cause milder disease, but a large prospective study (Kathmandu, Nepal, n=669) found typhoid and paratyphoid clinically indistinguishable

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2. EPIDEMIOLOGY

• Global burden: 9.2-21 million cases of typhoid and ~5 million cases of paratyphoid per year; 110,000-280,000 deaths/year
• Highest burden: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, sub-Saharan Africa, Southeast Asia, some Pacific regions
• Incidence can exceed 1,000 cases per 100,000 children in some urban areas
• High correlation with mixing of drinking water and human sewage
• In endemic regions: more common in poor urban neighborhoods, children, and adolescents
• Peak age: 5-19 years; incidence falls after age 20 (immunity acquired from subclinical infection)
• Males more commonly infected; carrier rate higher in females

• Contaminated drinking water or ice
• Food from street vendors
• Raw fruits/vegetables grown in sewage-fertilized fields
• Ill household contacts
• Poor hand hygiene
• Prior H. pylori infection (reduced gastric acidity)
• International travel (78% of US cases are travel-associated, mainly from Indian subcontinent)

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3. TRANSMISSION & PATHOGENESIS

1. Ingestion of organism - gastric acid is a major barrier (reduced gastric acid = higher susceptibility)
2. Penetration of small intestinal mucosa via M cells overlying Peyer's patches
3. Uptake by macrophages - survive and replicate intracellularly (this is why cell-mediated immunity is the primary defense)
4. Spread to mesenteric lymph nodes → thoracic duct → bloodstream = primary bacteremia (end of incubation)
5. Seeding of reticuloendothelial system (liver, spleen, bone marrow) and gallbladder
6. Secondary bacteremia - produces clinical illness
7. In the third week - Peyer's patches become necrotic and ulcerate, risking perforation and hemorrhage
8. Organisms can persist in gallbladder for years (chronic carrier state)

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4. CLINICAL FEATURES (WEEK BY WEEK)

Week 1 - Onset

• Step-ladder fever rising to 38.8-40.5°C (101.8-104.9°F)
• Headache (80%), chills (35-45%), malaise
• Cough (30%), myalgia (20%), arthralgia
• Relative bradycardia (pulse slow relative to the height of fever - "Faget's sign") - present in <50% of cases
• Anorexia (55%), nausea (18-24%), vomiting (18%)
• Constipation more common than diarrhea in early stages
• Coated tongue (51-56%)

Week 2 - Full Illness

• High continuous fever, now well established
• "Rose spots" - faint, salmon-colored, blanching, maculopapular rash on the trunk and chest
  • Appear in ~30% of patients at end of week 1 to beginning of week 2
  • 2-4 mm, blanch on pressure, fade without scarring
  • Seen best in fair-skinned individuals
  • Represent Salmonella-infected macrophages in the skin

• Splenomegaly and hepatomegaly (5-6%)
• Abdominal distension, diarrhea (22-28%) or constipation (13-16%)
• Epistaxis in some patients

Week 3-4 - Complications or Recovery

• Severe: intestinal hemorrhage or perforation
• Neurological manifestations possible
• Without treatment: fever persists for up to 4 weeks

• Milder course with shorter duration
• More prominent gastrointestinal symptoms from the start
• Lower complication and fatality rates

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5. LABORATORY DIAGNOSTICS

Blood Tests

• Leukocytosis can occur in children and with intestinal perforation (should raise suspicion for complication)

Microbiological Cultures (Gold Standard)

• Blood cultures are the most practical first-line test
• Bone marrow culture is the definitive test - organism can be recovered even after antibiotic treatment has begun
• Stool cultures become positive in weeks 2-3 as organisms shed via bile into the gut

Serological Tests

• Detects agglutinating antibodies against O (somatic) and H (flagellar) antigens of S. Typhi
• O antibodies - appear in week 1, rise in weeks 2-3, fall quickly after recovery - indicates active infection
• H antibodies - appear later, persist for months/years - may reflect past infection or vaccination
• Diagnostic criteria: 4-fold rise in paired sera (taken 2 weeks apart) OR single titre ≥1:160 (O) in a non-endemic area
• Limitations: Low sensitivity and specificity; false positives in other Salmonella infections, malaria, liver disease, and in vaccinated individuals; results vary by lab
• Not reliable for diagnosis in endemic areas where baseline titres may be elevated
• For paratyphoid: similar test using Paratyphi A (AO, AH), B (BO, BH) antigens

• IgM and IgG ELISA against a specific 50-kDa outer membrane protein of S. Typhi
• Typhidot-M (detects IgM only) is more specific - eliminates IgG that persists from previous infection
• Results available in 3-4 hours
• Better than Widal in endemic areas

• Detects IgM antibodies to O9 antigen of S. Typhi
• Rapid test, good specificity
• Does not cross-react with vaccination

• High sensitivity, identifies organisms even after antibiotic initiation
• Not universally available

Key Diagnostic Approach Summary

1. Culture blood in week 1 (best yield)
2. Culture stool + urine from week 2
3. Bone marrow culture if blood culture negative and high clinical suspicion
4. Widal test - supportive evidence only (not definitive in endemic areas)
5. Rapid tests (Typhidot, Tubex) for resource-limited settings

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6. DIFFERENTIAL DIAGNOSIS

• Malaria - most important; always exclude first in travelers
• Brucellosis
• Leptospirosis
• Typhus / Rickettsiosis
• Dengue fever
• Sepsis from other causes
• Viral hepatitis
• Tuberculosis (in chronic fever)

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7. COMPLICATIONS (10-15% of hospitalized patients)

Gastrointestinal

Cardiovascular

• Myocarditis - ECG changes, arrhythmias
• Mycotic aneurysm (rare)

Hematological

• DIC (Disseminated Intravascular Coagulopathy)
• Severe anemia (from GI blood loss + hemolysis)
• Thrombocytopenia

Neurological ("Typhoid Encephalopathy")

• Altered consciousness, confusion, delirium
• Meningismus, seizures
• Psychosis
• Ataxia, cranial nerve palsies
• Deafness (sensorineural - a specific sequela)
• Occurs in 1-10% of severe cases

Respiratory

• Pneumonia (bronchopneumonia)
• Pleural effusion

Renal

• Glomerulonephritis, renal failure (rare)

Other

• Septic arthritis
• Osteomyelitis (especially in sickle cell disease)
• Pancreatitis

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8. RELAPSE

• Occurs in ~10% of inadequately treated patients (and some adequately treated)
• Typically 1-3 weeks after clinical recovery (CDC) / "2-3 weeks after recovery" (MSF 2024)
• Relapse illness is usually milder than the primary attack
• Usually NOT due to antibiotic resistance
• Re-treatment with the same antibiotic is usually effective
• Second relapse possible (rare)

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9. CARRIER STATE

• Chronic carrier: Excretion of S. Typhi in stool or urine for >1 year after infection
• Affects 1-4% of typhoid fever cases (Park: 2-5%)
• Organisms persist in the gallbladder and biliary tract
• More common in women, elderly, and those with pre-existing gallbladder disease
• The famous historical case: "Typhoid Mary" (Mary Mallon) - caused >1,300 cases over her lifetime
• Faecal carriers more frequent than urinary carriers
• Chronic urinary carrier state often associated with urinary tract abnormalities
• Vi antibody detected in ~80% of chronic carriers (useful screening test)

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10. TREATMENT

General Principles

• Antibiotics shorten clinical course, reduce complication risk, and lower mortality
• Treatment decisions complicated by high rates of antimicrobial resistance
• Susceptibility testing should guide treatment whenever possible

Antibiotic Resistance Profile

Antibiotic Regimens

• Dexamethasone 3 mg/kg IV loading dose, then 1 mg/kg every 6 hours for 48 hours (for typhoid shock or encephalopathy)
• Reduces mortality in severe disease with neurological involvement

Supportive Treatment

• IV rehydration
• Antipyretics (paracetamol; avoid NSAIDs due to GI bleeding risk)
• Blood transfusion if significant GI blood loss
• Nutritional support
• Close monitoring for complications (abdominal exam, stool examination)

Treatment of Complications

Treatment of Chronic Carriers

• Ampicillin or Amoxicillin 4-6 g/day + Probenecid 2 g/day for 6 weeks (concentrated in bile; eradicates carrier state in ~70%)
• Ciprofloxacin 750 mg BD for 4 weeks (preferred if susceptible)
• Cholecystectomy with concurrent antibiotic therapy - reserved for carriers with gallstones when medical treatment fails
• Chloramphenicol is ineffective at clearing the carrier state

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11. PARATYPHOID A, B, C - SPECIFIC NOTES

• Paratyphoid fever accounts for ~5 million cases/year globally
• S. Paratyphi A is the most common paratyphoid
• Paratyphoid is slightly more common in older adults (median age 29 vs 23 for typhoid in US data)
• Complications occur less frequently but are otherwise the same in type
• The two diseases cannot be distinguished on clinical grounds - only culture separates them

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12. PROGNOSIS & MORTALITY

• With early diagnosis and appropriate treatment, mortality is ~1%
• Without treatment: disease lasts ~4 weeks; historical mortality 10-30%

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13. PREVENTION & CONTROL

Vaccination

• No vaccine covers paratyphoid - vaccines only protect against S. Typhi
• WHO recommends TCV for routine use in children >6 months in endemic countries
• Vaccines are not 100% effective - food and water precautions remain essential

Sanitation & Control

• Safe water supply and sewage treatment are the most important measures
• The "weakest link" in transmission is sanitation (most amenable to control)
• Food handling hygiene, hand washing
• Identification and treatment of chronic carriers
• Isolation of cases until 3 bacteriologically negative stool and urine samples obtained
• Disinfection: 5% cresol for 2 hours (stools and urine); 2% chlorine for soiled linen

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Summary Table - At a Glance

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🦠 Typhoid Fever & Paratyphoid A, B — Complete Clinical Guide

Based on Harrison's Principles of Internal Medicine 22E (2025), Tintinalli's Emergency Medicine, Park's Textbook of Preventive & Social Medicine, CDC Guidelines 2024

---

1. DEFINITION & CAUSATIVE ORGANISMS

• Gram-negative, facultative anaerobic, motile bacilli
• Man is the ONLY reservoir - no animal reservoir
• Killed by drying, pasteurization, and common disinfectants
• Survive for weeks in water and ice
• Virulence factors include the Vi (virulence) capsular polysaccharide antigen, which inhibits complement activation and phagocytosis

---

2. EPIDEMIOLOGY

• Global burden: 9.2-21 million typhoid cases + ~5 million paratyphoid cases annually; 110,000-280,000 deaths/year
• Highest incidence: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, sub-Saharan Africa, Southeast Asia
• Can exceed 1,000 cases per 100,000 children in some urban slum areas
• Peak age: 5-19 years (incidence falls after 20 due to acquired immunity)
• Males more commonly infected; carrier rate higher in females
• Correlates strongly with mixing of drinking water and sewage

• Contaminated water or ice
• Street food vendors
• Raw fruits/vegetables grown in sewage-fertilized soil
• Ill household contacts
• Poor hand hygiene, no toilet access
• Prior H. pylori infection (reduced gastric acid = easier bacterial colonization)
• International travel (78% of US cases are travel-associated, mainly Indian subcontinent)

---

3. TRANSMISSION & PATHOGENESIS

Route of Transmission — the "5 Fs"

• Primary sources: feces and urine of cases or chronic carriers
• Secondary sources: contaminated water, food, flies, fingers

Pathogenesis (Step by Step)

Ingestion (10³–10⁹ organisms)
        ↓
Gastric acid barrier (1st defense — reduced acidity increases susceptibility)
        ↓
Penetration of small bowel mucosa via M cells overlying Peyer's patches
        ↓
Uptake by macrophages → survive intracellularly (cell-mediated immunity is primary defense)
        ↓
Mesenteric lymph nodes → thoracic duct → PRIMARY BACTEREMIA (silent, end of incubation)
        ↓
Seeding of reticuloendothelial system: liver, spleen, bone marrow, gallbladder
        ↓
Replication in macrophages → SECONDARY BACTEREMIA → clinical illness begins
        ↓
Week 3-4: Peyer's patches enlarge, necrose, ulcerate
        ↓
Risk of intestinal perforation and hemorrhage

• Organisms persist in the gallbladder (chronic carrier state)
• Intracellular survival explains why bacteremia can recur and why treatment requires bacteriostatic agents with intracellular penetration

---

4. CLINICAL FEATURES — WEEK BY WEEK

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WEEK 1 — Prodrome / Onset

• Fever character: Begins low, rises progressively in a step-ladder pattern, becomes continuous by end of week 1
• Relative bradycardia (Faget's sign): Pulse unusually slow for the height of fever — present in <50% of cases; when present, strongly suggestive
• Coated tongue: 51-56%

---

WEEK 2 — Full Illness

• Fever now sustained, high (40-40.5°C)
• "Rose spots" — pathognomonic rash
  • Faint, salmon-colored, blanching maculopapular rash
  • Located primarily on trunk and chest
  • 2-4 mm diameter, fade without scarring
  • Appear in ~30% of patients, more visible in fair-skinned individuals
  • Represent Salmonella-infected macrophages in the skin
  • Resolve spontaneously in 2-5 days

• Hepatosplenomegaly (5-6%)
• Abdominal distension and tenderness (4-5%)
• Diarrhea (22-28%) — "pea-soup" diarrhea; or persistent constipation
• Epistaxis in some patients
• Toxemic facies — patient appears acutely unwell

---

WEEK 3-4 — Complications or Resolution

• If untreated: fever persists for up to 4 weeks
• Maximum risk of intestinal perforation and hemorrhage
• "Typhoid state" — profound toxemia, muttering delirium, picking at bedclothes
• Neurological features may emerge
• With treatment: defervescence begins within 3-5 days; clinical improvement in 4-5 days

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Paratyphoid A & B - Specific Features

• Clinically identical to typhoid (a large prospective study of 669 consecutive cases in Kathmandu found them indistinguishable)
• Paratyphoid A traditionally considered milder with more GI-predominant symptoms
• Rose spots can occur
• Complications occur less frequently
• Cannot be distinguished from typhoid by clinical examination alone — only culture differentiates

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5. LABORATORY DIAGNOSTICS

A. Routine Blood Tests

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B. Microbiological Cultures (Gold Standard)

• Never delay blood culture - it is the most important and practical test
• 3 blood cultures in 24 hours before antibiotics significantly increases yield
• Bone marrow culture is the gold standard - should be used when:
  • Blood culture is negative but clinical suspicion is high
  • Patient has already received antibiotics
  • Carrier state investigation
• Cultures must be incubated for 7-10 days before reporting as negative

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C. Serological Tests

1. Widal Test (Tube Agglutination Test)

• AO, AH - Paratyphi A agglutinins
• BO, BH - Paratyphi B agglutinins

• Significant titer: Single titer ≥1:160 (O antigen) in a non-endemic area
• Definitive diagnosis: 4-fold rise in paired sera taken 10-14 days apart
• In endemic areas, baseline titers may be elevated — single titer is unreliable

• False positives: malaria, other Salmonella infections, liver disease, autoimmune conditions, prior vaccination
• False negatives: early disease (before antibody production), immunocompromised patients, early antibiotic treatment
• Does not differentiate acute from past infection reliably in endemic areas
• Not recommended as sole diagnostic test by WHO

2. Typhidot Test

• Detects IgM and IgG against a specific 50 kDa outer membrane protein of S. Typhi
• Typhidot-M (detects IgM only) is more specific — eliminates cross-reactivity from past infection IgG
• Results in 3-4 hours
• Better performance in endemic areas than Widal test

3. TUBEX Test

• Detects IgM against O9 antigen of S. Typhi
• Rapid colorimetric test
• Good specificity; does NOT cross-react with typhoid vaccination
• Semi-quantitative

4. Blood Culture PCR / Molecular Tests

• High sensitivity; can identify organisms even after antibiotic initiation
• Not widely available in endemic regions
• Multiplex PCR panels can differentiate S. Typhi from S. Paratyphi

5. Vi Antibody Test

• Vi agglutinins present in ~80% of chronic carriers
• Used to screen for chronic carrier state
• Not useful for acute diagnosis

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D. Summary: Diagnostic Approach by Week

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6. COMPLICATIONS

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A. Gastrointestinal Complications

1. Intestinal Perforation (Most Feared)

• Incidence: 1-3%
• Usually in the terminal ileum, near the ileocecal valve (at Peyer's patch ulcers)
• Presents with: sudden worsening of abdominal pain, rigid abdomen ("board-like"), absent bowel sounds, rebound tenderness
• X-ray/CT: free air under the diaphragm
• Mortality: 10-32% even with surgery
• Management: emergency laparotomy (primary repair or resection + anastomosis), broad-spectrum IV antibiotics

2. Intestinal Hemorrhage

• Incidence: 1-5%
• From erosion of a blood vessel at the base of an ulcerated Peyer's patch
• Presents with: melena or bright red rectal bleeding, sudden drop in temperature and fever, tachycardia
• Management: IV fluids, blood transfusion, conservative initially; surgery if massive or uncontrolled

3. Hepatitis

• Mild jaundice and elevated transaminases in up to 40% of patients
• Usually self-limiting

4. Cholecystitis

• Acute or chronic
• Gallbladder is the site of persistence in chronic carriers
• May require cholecystectomy in refractory carriers

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B. Neurological Complications ("Typhoid Encephalopathy") — 1-10%

• Altered consciousness, confusion, stupor, coma
• Muttering delirium ("typhoid state")
• Meningismus (meningeal irritation without meningitis)
• Seizures
• Sensorineural deafness (a specific recognized sequela)
• Ataxia, cranial nerve palsies
• Psychosis, behavioral changes

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C. Cardiovascular Complications

---

D. Hematological Complications

---

E. Respiratory Complications

• Pneumonia / Bronchopneumonia — from bacteremia seeding the lungs, or superinfection
• Pleural effusion (uncommon)

---

F. Renal Complications

• Glomerulonephritis (immune complex deposition)
• Acute tubular necrosis / Acute kidney injury
• Urinary tract infection

---

G. Other Complications

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H. Relapse

• Occurs in ~10% of inadequately treated patients
• Onset 1-3 weeks after apparent clinical recovery
• Usually milder than primary illness
• Generally NOT due to antibiotic resistance
• Re-treatment with the same antibiotic is effective
• Second relapse possible but rare

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7. TREATMENT

A. Antibiotic Resistance Landscape (Critical Context)

• Always perform antimicrobial susceptibility testing when culture is obtained
• A thorough travel history guides empiric choices while awaiting results

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B. Treatment Regimens

Uncomplicated Typhoid/Paratyphoid (Oral, Outpatient)

Severe / Complicated Typhoid (IV, Inpatient)

Adjuvant Dexamethasone (For Severe Toxicity)

• Dexamethasone 3 mg/kg IV loading dose, then 1 mg/kg every 6 hours for 48 hours
• Shown to reduce mortality in severe disease with neurological involvement
• Do not use for uncomplicated disease (may prolong carrier state and increase relapse risk)

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C. Supportive Treatment

---

D. Treatment of Complications

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E. Treatment of Chronic Carriers

• Chloramphenicol is ineffective for clearing the carrier state
• Follow-up stool/urine cultures at 3-4 months and 12 months post-treatment

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8. PARATYPHOID A & B — SPECIFIC COMPARISON

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9. CHRONIC CARRIER STATE

• Definition: Excretion of S. Typhi in stool or urine for >1 year after infection
• Affects 1-4% of typhoid fever cases
• Organisms persist in gallbladder and biliary tract (bile concentrations remain high)
• Higher risk: women, elderly, pre-existing gallbladder disease
• Faecal carriers more common than urinary carriers
• Chronic urinary carrier state associated with urinary tract abnormalities
• Vi antibody positive in ~80% of chronic carriers (screening test)
• Famous example: "Typhoid Mary" (Mary Mallon) - caused >1,300 cases over her lifetime while remaining asymptomatic

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10. PROGNOSIS

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11. PREVENTION

Vaccines

• No vaccine protects against paratyphoid - vaccines only cover S. Typhi
• WHO recommends TCV for children >6 months in endemic countries
• Vaccines are NOT 100% effective — food/water precautions are always necessary

Sanitation (Most Important)

• Safe drinking water and sewage treatment — the most impactful public health measure
• Hand hygiene (before eating, after toilet use)
• Safe food handling
• Pasteurization of dairy products

Control of Cases & Carriers

• Case isolation until 3 consecutive negative stool and urine cultures
• Notification to public health authorities (mandatory in most countries)
• Disinfection of stools and urine with 5% cresol for 2 hours
• Soiled linen: 2% chlorine solution or steam sterilization
• Carrier identification and treatment
• Exclusion of carriers from food handling and patient care

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QUICK REFERENCE SUMMARY TABLE

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Typhoid Fever & Paratyphoid A, B — Complete Detailed Guide

Sources: Harrison's Principles of Internal Medicine 22E (2025), Tintinalli's Emergency Medicine, Park's Textbook of Preventive & Social Medicine, CDC Clinical Guidance 2024

---

1. DEFINITION & CAUSATIVE ORGANISMS

• Gram-negative, non-spore-forming, facultative anaerobic, motile bacilli
• Man is the ONLY reservoir - no animal reservoir (unlike non-typhoidal Salmonella)
• Killed by drying, pasteurization, and common disinfectants
• Survive weeks in water and ice
• Key virulence factor: Vi (virulence) capsular polysaccharide - inhibits complement and phagocytosis
• The disease was called "typhoid" for its clinical similarity to typhus; the term "enteric fever" was proposed in 1869 based on the anatomic site of infection

---

2. EPIDEMIOLOGY

• Global burden: 9.2-21 million typhoid cases + ~5 million paratyphoid cases per year; 110,000-280,000 deaths/year
• Highest incidence: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, sub-Saharan Africa, Southeast Asia
• Can exceed 1,000 cases per 100,000 children in some urban areas
• Peak age group: 5-19 years (incidence falls after age 20 due to acquired immunity from repeated subclinical exposure)
• Males more commonly infected (greater exposure); carrier rate higher in females
• Strong correlation with mixing of drinking water and human sewage

• Contaminated drinking water or ice
• Street food vendors
• Raw fruits/vegetables grown in sewage-fertilized soil
• Ill household contacts
• Poor hand hygiene and lack of toilet access
• Prior H. pylori infection (chronically reduced gastric acid lowers the infective dose needed)
• International travel (78% of US cases are travel-associated, predominantly from India, Pakistan, Bangladesh)

---

3. TRANSMISSION

Route - the "5 Fs"

Feces/Urine (of cases or carriers)
      ↓
Food — Fingers — Fomites — Flies — Fluids (Water)
      ↓
New host (fecal-oral route)

• Primary sources: feces and urine of cases or chronic carriers
• Secondary sources: contaminated water, food, flies, dirty fingers
• Transmission is dose-dependent - severity varies with the size of the inoculum
• No evidence that organisms are excreted in sputum or milk

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4. PATHOGENESIS (Step by Step)

STEP 1: Ingestion of organisms
        Gastric acid is the first barrier — reduced acidity increases susceptibility

STEP 2: Organisms reach small bowel mucosa
        Penetrate via M cells overlying Peyer's patches

STEP 3: Uptake by submucosal macrophages
        Survive and replicate INTRACELLULARLY
        (This is why cell-mediated immunity — not antibody — is the primary defense)

STEP 4: Spread to mesenteric lymph nodes → thoracic duct
        → PRIMARY (SILENT) BACTEREMIA — marks end of incubation period

STEP 5: Seeding of reticuloendothelial system
        Liver, spleen, bone marrow, GALLBLADDER

STEP 6: Organisms replicate in macrophages of these organs
        → SECONDARY BACTEREMIA → Clinical illness begins

STEP 7: Week 3-4 — Peyer's patches enlarge, become necrotic, ULCERATE
        → Risk of intestinal perforation and hemorrhage

STEP 8: Organisms may persist in gallbladder indefinitely
        → CHRONIC CARRIER STATE

---

5. CLINICAL FEATURES — WEEK BY WEEK

---

WEEK 1 — Onset / Prodrome

• Pulse is abnormally slow relative to the height of fever
• Present in <50% of cases
• When present, is strongly suggestive of enteric fever
• May be absent in elderly or those with cardiac disease

---

WEEK 2 — Full Illness / Peak

• Fever now sustained and high (40-40.5°C), truly continuous
• "Rose Spots" - the pathognomonic rash:
  • Faint, salmon-colored, blanching, maculopapular spots
  • Located on trunk and chest
  • 2-4 mm in diameter; fade without scarring in 2-5 days
  • Present in approximately 30% of patients
  • More visible in fair-skinned individuals
  • Represent Salmonella-infected macrophages in the skin
  • Can occur in both typhoid and paratyphoid

• Hepatosplenomegaly (5-6%); abdominal distension
• Diarrhea (22-28%) - classically described as "pea-soup diarrhea" - OR constipation (13-16%)
• Abdominal tenderness (4-5%)
• Epistaxis in some patients
• Toxemic facies - patient appears acutely unwell, drowsy, expressionless

---

WEEK 3-4 — Complications or Defervescence

• Maximum risk of intestinal perforation and hemorrhage (Peyer's patches at peak ulceration)
• "Typhoid state" in severe untreated cases: profound toxemia, muttering delirium, picking at bedclothes, incontinence
• Neurological features can emerge (see complications)
• Without treatment: fever persists for up to 4 weeks
• With treatment: fever begins to resolve within 3-5 days of starting appropriate antibiotics; clinical improvement within 4-5 days

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Paratyphoid A & B - Specific Points

• A prospective study of 669 consecutive cases in Kathmandu, Nepal found typhoid and paratyphoid clinically indistinguishable
• Paratyphoid A traditionally considered milder with more GI-predominant (gastroenteritis-like) onset
• Rose spots and relative bradycardia can occur in paratyphoid
• Complications occur less frequently and mortality is roughly half that of typhoid
• Cannot be distinguished from typhoid clinically - only culture differentiates them

---

6. LABORATORY DIAGNOSTICS

A. Routine Blood Tests

---

B. Microbiological Cultures (Gold Standard)

• Take blood cultures before starting antibiotics - sensitivity drops dramatically thereafter
• Take 3 blood cultures within 24 hours to maximize yield
• Bone marrow culture is the definitive test when blood culture is negative - organisms are recoverable even 5-7 days after antibiotics have been started
• Cultures must be incubated for 7-10 days before reporting as negative
• Organism identification confirms the diagnosis AND allows susceptibility testing to guide treatment

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C. Serological Tests

1. Widal Test (Tube Agglutination Test)

• Paratyphi A: AO and AH agglutinins
• Paratyphi B: BO and BH agglutinins

• Definitive criterion: 4-fold rise in titer in paired sera taken 10-14 days apart
• Presumptive criterion (non-endemic areas): Single O titer ≥ 1:160
• In endemic areas, cut-off titers must be higher (local baseline titers are elevated)

2. Typhidot Test

• Detects IgM and IgG against a specific 50 kDa outer membrane protein of S. Typhi
• Typhidot-M (modified) detects IgM only - more specific for acute infection; eliminates IgG that persists from past infection
• Results available in 3-4 hours
• Better performance than Widal in endemic areas
• Sensitivity ~70%, specificity ~80%

3. TUBEX Test

• Detects IgM antibodies against O9 antigen of S. Typhi
• Semi-quantitative colorimetric test
• Good specificity; does NOT cross-react with typhoid vaccination
• Results in 2-3 hours
• Useful for rapid diagnosis in resource-limited settings

4. Molecular Methods (PCR)

• Blood culture PCR / multiplex PCR panels
• Can identify S. Typhi vs S. Paratyphi A/B with high sensitivity
• Can detect organisms even after antibiotics have been started
• Not yet widely available in endemic regions but increasingly used in reference labs

5. Vi Antibody Test

• Detects antibody against the Vi capsular antigen of S. Typhi
• Vi agglutinins present in ~80% of chronic carriers
• Used to screen for chronic carrier state, not for acute diagnosis
• Elevated Vi titer in a patient without active fever = suspect chronic carrier

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D. Diagnostic Algorithm by Week

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E. Differential Diagnosis

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7. COMPLICATIONS

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A. Gastrointestinal Complications

Intestinal Perforation (Most Feared)

• Incidence: 1-3% of hospitalized cases
• Site: Terminal ileum, 20-30 cm proximal to ileocecal valve (site of Peyer's patches)
• Pathology: full-thickness necrosis of ulcerated Peyer's patch with bacterial spillage into peritoneum
• Clinical presentation:
  • Sudden worsening of abdominal pain
  • Abdomen becomes "board-like" (rigidity)
  • Absent bowel sounds
  • Rebound tenderness, guarding
  • Paradoxically, fever may temporarily drop
  • Signs of peritoneal sepsis / septic shock
• Investigations: Erect chest X-ray or abdominal X-ray shows free air under the diaphragm (pneumoperitoneum); CT abdomen is more sensitive
• Management:
  • Emergency laparotomy (primary repair of small perforations, or resection + anastomosis for large/multiple perforations)
  • IV broad-spectrum antibiotics covering Gram-negatives AND anaerobes (e.g., ceftriaxone + metronidazole)
  • ICU care, IV fluids, vasopressors if in shock
• Mortality: 10-32% even with prompt surgery

Intestinal Hemorrhage

• Incidence: 1-5%
• Mechanism: erosion of a mesenteric blood vessel at the base of an ulcerated Peyer's patch
• Clinical presentation: Melena (dark tarry stools) or bright red rectal bleeding; sudden fall in body temperature and fever; tachycardia; hypotension in massive hemorrhage
• Management:
  • IV fluids, blood transfusion (keep Hb >8 g/dL)
  • NPO, IV antibiotics continued
  • Conservative management initially (most stop spontaneously)
  • Surgery (bowel resection) for massive or uncontrolled hemorrhage
  • Endoscopy not typically feasible in acute typhoid

Hepatitis

• Elevated transaminases in up to 40%; jaundice in some
• Usually self-limiting; severe hepatic failure is rare

Cholecystitis

• Acute or chronic acalculous cholecystitis
• The gallbladder is the persistent reservoir in chronic carriers
• May require cholecystectomy in refractory carriers with gallstones

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B. Neurological Complications ("Typhoid Encephalopathy") — 1-10%

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C. Cardiovascular Complications

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D. Hematological Complications

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E. Respiratory Complications

• Pneumonia (bronchopneumonia): from hematogenous seeding or aspiration; occurs in ~1-3%
• Pleural effusion: uncommon
• Adult respiratory distress syndrome (ARDS): in severe sepsis

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F. Renal Complications

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G. Other Complications

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H. Relapse

• Occurs in approximately 10% of inadequately treated patients (and some fully treated ones)
• Onset: 1-3 weeks after apparent clinical recovery
• Usually milder than the primary illness
• Generally NOT due to antibiotic resistance - organisms remain sensitive
• Re-treatment with the same antibiotic is effective
• Second relapse is possible but rare
• Thought to occur due to persisting intracellular organisms reactivating from the reticuloendothelial system

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8. TREATMENT

A. Antimicrobial Resistance — Critical Context for Treatment Decisions

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B. Antibiotic Treatment Regimens

Uncomplicated Typhoid/Paratyphoid — Oral, Outpatient

Severe / Complicated Typhoid — IV, Inpatient

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Adjuvant Dexamethasone — For Severe Toxicity

• Typhoid shock (circulatory failure)
• Altered consciousness / encephalopathy
• Severe delirium

• Loading dose: 3 mg/kg IV over 30 minutes
• Maintenance: 1 mg/kg IV every 6 hours for 48 hours (8 doses total)
• Shown to significantly reduce mortality in severe disease with neurological involvement
• Do NOT use for uncomplicated disease - may prolong shedding and increase relapse risk

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C. Supportive Treatment

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D. Treatment of Specific Complications

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E. Treatment of Chronic Carriers

• Chloramphenicol is ineffective at clearing the carrier state
• Probenecid increases biliary concentration of beta-lactams
• Follow-up stool/urine cultures at 3-4 months and 12 months post-treatment

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9. PARATYPHOID A & B — COMPARISON TABLE

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10. CHRONIC CARRIER STATE

• Definition: Excretion of S. Typhi in stool or urine for more than 1 year after the primary infection
• Affects 1-4% of typhoid fever cases (Park's quotes 2-5%)
• Organisms persist in the gallbladder and biliary tract where bile concentration maintains them
• Higher risk: women, elderly, individuals with pre-existing gallbladder pathology
• Faecal carriers are more common than urinary carriers
• Chronic urinary carrier state is often associated with structural urinary tract abnormality
• Vi antibody positive in ~80% of chronic carriers (best screening test)
• Convalescent carriers excrete bacilli for 6-8 weeks; only ~4% still excrete at 3 months; ~3% at 1 year
• Famous historical case: "Typhoid Mary" (Mary Mallon) — an asymptomatic chronic cook-carrier responsible for more than 1,300 typhoid cases during her lifetime

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11. PROGNOSIS

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12. PREVENTION

Vaccination

• No vaccine protects against paratyphoid A or B
• WHO recommends TCV for routine childhood immunization in typhoid-endemic countries
• Vaccines are NOT 100% effective - food and water precautions remain essential for all travelers

Sanitation (Single Most Important Measure)

• Safe water supply and sewage treatment - "the weakest link in transmission is sanitation" (Park's)
• Hand hygiene before eating and after toilet use
• Safe food handling and cooking practices
• Pasteurization of dairy products
• Elimination of flies from food preparation areas

Control of Cases and Carriers

• Case isolation until 3 consecutive bacteriologically negative stool and urine samples (on separate days)
• Notification to public health authorities (typhoid is a notifiable disease)
• Disinfection of stools and urine: 5% cresol for 2 hours
• Soiled linen: 2% chlorine solution or steam sterilization
• Exclusion of carriers from food handling, catering, healthcare, and childcare
• Follow-up cultures at 3-4 months and 12 months post-treatment for all cases

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QUICK REFERENCE CARD

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