Typhoid and Paratyphoid Fever (Enteric Fever)

1. Clinical Overview

Summary

Enteric fever is a life-threatening systemic infection caused by the invasive bacteria Salmonella enterica serovar Typhi (typhoid fever) or Paratyphi A, B, C (paratyphoid fever). This condition remains a major global public health burden, with an estimated 11–20 million cases and approximately 128,000–161,000 deaths annually, predominantly in South Asia, Southeast Asia, and Sub-Saharan Africa. [1,2] Unlike self-limiting gastroenteritis caused by non-typhoidal Salmonella, typhoid fever is a systemic febrile illness characterised by sustained bacteraemia, intracellular bacterial survival in macrophages, and tropism for the reticuloendothelial system (liver, spleen, bone marrow, Peyer's patches). [3]

The classic clinical presentation involves a "step-ladder" fever pattern (incremental daily rise in temperature), severe headache, relative bradycardia (Faget's sign), abdominal pain, and either constipation or diarrhoea. Pathognomonic features include "rose spots" (faint salmon-pink macules on the trunk, seen in 30% of patients) and hepatosplenomegaly. [4] The disease follows a predictable timeline with distinct phases: an initial invasion phase (week 1), a dissemination phase with peak bacteraemia (week 2), a critical complication phase (week 3–4) involving intestinal perforation or haemorrhage, and either recovery or death. [5]

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has fundamentally altered treatment paradigms. Fluoroquinolone resistance is now endemic in South Asia, with resistance rates exceeding 90% in some regions. [6] Contemporary first-line therapy for uncomplicated typhoid includes azithromycin or third-generation cephalosporins (ceftriaxone), with carbapenems reserved for XDR strains. [7] Adjunctive high-dose dexamethasone significantly reduces mortality in severe typhoid with shock or encephalopathy. [8] Two vaccines—an injectable Vi polysaccharide vaccine and an oral live-attenuated Ty21a vaccine—provide 50–70% protection for 3–7 years but do not prevent paratyphoid. [9] Recent conjugate vaccine technology (Vi-TCV) offers improved immunogenicity and duration of protection. [10]

Key Facts

• Travel History: The single most important diagnostic clue. Over 80% of imported typhoid cases in high-income countries originate from the Indian subcontinent (India, Pakistan, Bangladesh). [11] Always inquire about travel to endemic areas within the preceding 60 days (typical incubation 7–14 days, range 3–60 days).

• Systemic Illness, NOT Gastroenteritis: Typhoid is a systemic febrile illness with bacteraemia. Unlike acute gastroenteritis, diarrhoea is not the dominant feature. Constipation is often more prominent than diarrhoea in the first week. Profuse "pea soup" diarrhoea (greenish, watery) typically appears in week 2–3.

• "Rose Spots" (Taches Rosées): Faint, blanching, salmon-coloured macules, 2–4 mm in diameter, appearing on the trunk (chest/abdomen) in crops during the second week. Present in approximately 30% of light-skinned patients; difficult to detect in darker skin. Each lesion represents a bacterial embolus. [4]

• Faget's Sign (Relative Bradycardia): Pulse rate slower than expected for the degree of fever. In untreated typhoid, pulse may be 80–90 bpm despite fever > 39°C. Mechanism: direct suppression of the sinoatrial node by endotoxin. [12] Also seen in brucellosis, yellow fever, and Legionnaires' disease.

• Chronic Carrier State: After clinical recovery, 1–5% of patients become chronic carriers, defined as excretion of S. Typhi in stool or urine for > 1 year. [13] The bacteria colonise the gallbladder (forming biofilms on gallstones) or urinary tract (especially if structural abnormalities exist). Chronic carriers remain asymptomatic but pose a significant public health risk as they continue to shed bacteria. The infamous "Typhoid Mary" (Mary Mallon) was a chronic carrier who infected over 50 individuals as a food handler in early 20th-century New York.

• Leucopenia, NOT Leucocytosis: Unlike most bacterial infections, typhoid causes leucopenia (WBC 3–4 × 10⁹/L) with neutropenia and relative lymphocytosis. This occurs due to bacterial sequestration in bone marrow and direct marrow suppression. [14] An elevated white cell count suggests complications (perforation, secondary infection) or alternative diagnosis.

Clinical Pearls

Don't Wait for the Stool Culture: In the first week of fever, stool cultures are positive in only 30–40% of cases because bacterial shedding into the gut lumen has not yet peaked. Blood culture is the investigation of choice in week 1–2 (positive in 60–80%). [15] Bone marrow culture remains the gold standard with sensitivity > 90% even in patients already on antibiotics, but is reserved for diagnostically challenging cases.

The "Pea Soup" Diarrhoea: This classic green, watery diarrhoea (resembling pea soup) typically appears in week 2–3, coinciding with secondary bacteraemia and massive re-infection of Peyer's patches via bile excretion. Don't rule out typhoid because the patient is constipated in week 1—constipation is the rule early in the illness.

Caution with NSAIDs: Avoid non-steroidal anti-inflammatory drugs for fever control. The terminal ileum's Peyer's patches are inflamed, ulcerated, and friable. NSAIDs inhibit mucosal prostaglandins, impair platelet function, and increase the risk of massive gastrointestinal bleeding and perforation. Use paracetamol for symptomatic fever relief.

Vaccination ≠ Immunity: Current typhoid vaccines (Vi polysaccharide and Ty21a oral vaccine) provide only 50–70% protection, with immunity waning after 3–5 years. [9] A vaccinated traveller can still acquire typhoid. Never rule out typhoid based solely on vaccination history. Additionally, vaccines do not protect against paratyphoid.

The "Typhoid State": In week 2, untreated patients develop a characteristic apathetic, exhausted appearance with altered sensorium (described as "muttering delirium" or "coma vigil")—lying motionless with eyes half-open, responding slowly to questions. This reflects encephalopathy from systemic toxaemia. [5]

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2. Epidemiology

Global Burden

Enteric fever remains a major cause of morbidity and mortality in low- and middle-income countries (LMICs) with poor sanitation and unsafe water supplies.

Geographic Distribution

Typhoid fever is endemic in South Asia, Southeast Asia, Sub-Saharan Africa, and parts of Latin America. The highest disease burden is in:

• South Asia: India, Pakistan, Bangladesh, Nepal (incidence rates 100–1000 per 100,000 population per year). [1]
• Southeast Asia: Indonesia, Vietnam, Cambodia, Laos.
• Sub-Saharan Africa: Nigeria, Democratic Republic of Congo, Tanzania, Kenya.

In high-income countries (UK, USA, Australia), > 80% of cases are travel-associated, predominantly in individuals of South Asian ethnicity visiting friends and relatives (VFR travellers). [11] VFR travellers have higher attack rates than tourists due to longer stays, consumption of high-risk foods/water, and lower vaccine uptake.

Demographics

• Age: Highest incidence in children and young adults (5–25 years) in endemic areas. [2]
• Sex: No clear sex predilection.
• Seasonality: Peak incidence during monsoon seasons (June–September in South Asia) due to flooding and contamination of water supplies.

Risk Factors

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3. Aetiology & Pathophysiology

Causative Organisms

Enteric fever is caused by two closely related organisms:

1. Salmonella enterica serovar Typhi (~80% of cases): Exclusively a human pathogen. No animal reservoir.
2. Salmonella enterica serovar Paratyphi A, B, C (~20% of cases): Paratyphi A is the most common serovar causing paratyphoid. Clinically indistinguishable from typhoid but generally milder.

Both organisms are Gram-negative, flagellated bacilli belonging to the family Enterobacteriaceae. Unlike non-typhoidal Salmonella (which cause self-limiting gastroenteritis), typhoidal Salmonella are invasive, survive intracellularly in macrophages, and cause systemic disease. [3]

Transmission

• Faecal-Oral Route: Ingestion of food or water contaminated with human faeces containing S. Typhi.
• Chronic Carriers: Chronic carriers (1–5% of cases) shed bacteria in stool/urine for years and represent the primary reservoir. Food handlers who are chronic carriers pose substantial outbreak risk. [13]
• Infectious Dose: Relatively low (10³–10⁶ organisms), lower than non-typhoidal Salmonella (10⁵–10⁸). [3]

Pathophysiological Sequence

The pathogenesis of typhoid fever can be divided into distinct phases:

Phase 1: Ingestion and Invasion (Days 1–7)

1. Ingestion: Bacteria ingested in contaminated food/water. Acid-resistant; survive gastric acid passage (especially if gastric pH elevated by achlorhydria, PPIs, or antacids).
2. Intestinal Invasion: Bacteria reach the terminal ileum and invade the intestinal mucosa via M cells (microfold cells) overlying Peyer's patches (organised lymphoid follicles). [3]
3. Macrophage Uptake: After crossing the epithelium, bacteria are phagocytosed by macrophages but resist intracellular killing. S. Typhi possesses virulence factors that allow survival and replication within the macrophage phagosome:
   • Vi capsular polysaccharide: Inhibits complement C3b deposition and phagocyte oxidative burst.
   • SPI-1 and SPI-2 Type III Secretion Systems (T3SS): Inject effector proteins into host cells to manipulate cellular processes (suppress apoptosis, inhibit phagosome-lysosome fusion). [17]
   • Typhoid toxin: A unique AB toxin that induces DNA damage, cell cycle arrest, and contributes to systemic symptoms. [18]

Exam Detail: Molecular Mechanisms of Intracellular Survival:

• SPI-2 T3SS: Delivers effector proteins (SseF, SseG, SifA) that prevent fusion of the Salmonella-containing vacuole (SCV) with lysosomes, maintaining a replicative niche.
• Lipopolysaccharide (LPS) Modifications: S. Typhi modifies its LPS to resist antimicrobial peptides and reduce TLR4-mediated inflammatory responses.
• Suppression of Reactive Oxygen Species (ROS): Bacteria express catalase and superoxide dismutase to neutralise ROS produced by macrophage NADPH oxidase.
• Inhibition of Apoptosis: SPI-2 effector SseL (a deubiquitinase) prevents caspase-mediated macrophage apoptosis, prolonging bacterial intracellular residence.

The result: bacteria replicate within macrophages and are transported via lymphatics to mesenteric lymph nodes.

Phase 2: Dissemination (Days 7–14)

4. Primary Bacteraemia: Infected macrophages migrate to mesenteric lymph nodes, then enter systemic circulation via the thoracic duct. Bacteria disseminate to the reticuloendothelial system (RES): liver (Kupffer cells), spleen (splenic macrophages), bone marrow, and gallbladder. This is the incubation period (7–14 days, range 3–60 days). Patients are asymptomatic during primary bacteraemia.
5. Replication in RES: Bacteria multiply extensively within RES macrophages over 7–14 days, causing hepatosplenomegaly.

Phase 3: Secondary Bacteraemia (Days 14–21, Week 2–3)

6. Secondary Bacteraemia: Massive release of bacteria from RES into the bloodstream causes secondary bacteraemia. This marks the onset of clinical symptoms: high fever, headache, malaise. Bacteria also seed the gallbladder and are excreted in bile into the intestinal lumen.
7. Re-invasion of Peyer's Patches: Bacteria in bile re-infect Peyer's patches in the terminal ileum in massive numbers. This causes:
   • Hyperplasia of lymphoid follicles.
   • Necrosis of overlying mucosa.
   • Ulceration (longitudinal ulcers along the long axis of the ileum, aligned with lymphoid tissue).

Phase 4: Complications (Days 14–28, Week 3–4)

8. Intestinal Perforation: Necrotic ulcers erode through the full thickness of the bowel wall (typically at the anti-mesenteric border of the terminal ileum). Perforation occurs in 1–3% of hospitalised patients, usually in week 3. [19] Presents with sudden onset of severe abdominal pain, rigidity, peritonitis, and pneumoperitoneum on imaging.
9. Intestinal Haemorrhage: Ulcers erode into submucosal blood vessels causing massive bleeding (melaena or haematochezia). Occurs in 10–20% of cases. [5]
10. Excretion in Stool/Urine: Bacteria shed in faeces and (less commonly) urine. Shedding peaks in week 2–3. Stool cultures become positive.

Phase 5: Resolution or Carrier State (Week 4+)

11. Recovery: In most treated patients, fever defervesces over 3–5 days. Bacterial clearance occurs over weeks.
12. Chronic Carrier State: In 1–5% of cases, bacteria persist in the gallbladder (especially if gallstones present, forming biofilms) or urinary tract (if structural abnormalities exist). Chronic carriage is defined as excretion > 1 year after infection. [13]

Exam Detail: Why the Gallbladder?

The gallbladder is the primary site of chronic carriage because:

• Biofilm Formation: S. Typhi forms biofilms on gallstones and the gallbladder epithelium, protecting bacteria from antibiotics and immune clearance.
• Low Bile Flow: Intermittent bile secretion creates a nutrient-rich, low-oxygen niche favourable for bacterial persistence.
• Reduced Immune Surveillance: The gallbladder has limited lymphoid tissue and low immune cell infiltration.

Risk Factors for Chronic Carriage:

• Female sex (higher rates of cholelithiasis).
• Age > 50 years.
• Gallstones or chronic cholecystitis.

Clinical Significance: Chronic carriers are asymptomatic but continue to shed bacteria intermittently, posing a public health risk. Eradication requires prolonged antibiotics (4–6 weeks) and often cholecystectomy if gallstones present.

Immunology

• Initial Response: Innate immunity (macrophages, neutrophils) is evaded by intracellular survival mechanisms.
• Adaptive Response: T-cell-mediated immunity (especially CD4+ Th1 cells producing IFN-γ) is essential for bacterial clearance. Antibody responses (IgG, IgM against O and H antigens) occur but are not protective.
• Immunosuppression: Typhoid causes transient immunosuppression (leucopenia, lymphopenia) contributing to secondary infections.

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4. Clinical Presentation

The clinical presentation of typhoid fever follows a characteristic temporal pattern, though this classical progression is less common in partially treated or antibiotic-exposed patients.

Timeline: "The Four Weeks"

Week 1: Invasion Phase

Cardinal Features:

• Fever: "Step-ladder" pattern—temperature rises incrementally each evening, reaching peak by end of week 1 (39–40°C). Fever is sustained (does not spike and settle like malaria). [5]
• Severe Frontal Headache: Intense, persistent, not relieved by simple analgesia.
• Malaise and Anorexia: Profound fatigue, weakness, inability to work.
• Dry Cough: Non-productive cough (15–30% of patients). May mimic respiratory infection.
• Gastrointestinal Symptoms:
  • Constipation (more common than diarrhoea in week 1, especially in adults).
  • Mild abdominal discomfort.
• Epistaxis: Occasional nosebleeds (reflects thrombocytopenia).

Examination Findings:

• Fever (39–40°C) with relative bradycardia (Faget's sign).
• Flushed face, injected conjunctivae.
• Coated tongue (white coating with central red area—"typhoid tongue").
• Minimal abdominal findings (mild tenderness).

Diagnostic Clues:

• Blood culture: Positive in 60–80% in week 1. [15]
• Stool culture: Usually negative (bacteria not yet in gut lumen in high numbers).

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Week 2: Dissemination Phase

Cardinal Features:

• Sustained High Fever: Fever plateau at 39–40°C (no longer stepwise rise). Continuous fever without significant diurnal variation.
• Rose Spots (Taches Rosées): Faint, salmon-pink, blanching macules (2–4 mm) appearing in crops on trunk (chest, abdomen, flanks). Present in ~30% of patients (more easily visible in fair skin). Each lesion contains bacteria and lasts 2–5 days. [4]
• Hepatosplenomegaly: Palpable liver and spleen (spleen in 50–70%, liver in 30–50%).
• Abdominal Pain: Right lower quadrant (RLQ) pain due to inflamed mesenteric lymph nodes and swollen Peyer's patches.
• "Pea Soup" Diarrhoea: Profuse, greenish, watery diarrhoea (resembling pea soup). Replaces constipation of week 1.
• "Typhoid State": Altered mental status—apathy, confusion, slowed responses, "muttering delirium" (lying motionless, mumbling incoherently). Reflects encephalopathy from systemic toxaemia. [5]

Examination Findings:

• Toxic appearance, dehydration.
• Fever (40°C+) with relative bradycardia.
• Rose spots on trunk (search carefully).
• Hepatosplenomegaly.
• Abdominal distension, diffuse tenderness (especially RLQ).

Diagnostic Clues:

• Blood culture: Positive in 50–70% (sensitivity declining from week 1).
• Stool culture: Positive in 60–70% (bacteria now shed in faeces).
• Urine culture: Positive in 30–40%.

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Week 3: Complication Phase

This is the critical phase. Without appropriate treatment, life-threatening complications occur:

Major Complications:

1. Intestinal Perforation (1–3% of hospitalised patients) [19]

   • Mechanism: Full-thickness necrosis of Peyer's patch ulcers in terminal ileum, typically at anti-mesenteric border.
   • Clinical Presentation:
     • Sudden onset of severe, generalised abdominal pain.
     • Abdominal rigidity, guarding, rebound tenderness (peritonitis).
     • Absent bowel sounds (ileus).
     • Shock (tachycardia, hypotension).
   • Investigation: Erect chest X-ray shows pneumoperitoneum (free air under diaphragm). CT abdomen confirms perforation.
   • Management: Emergency laparotomy (primary repair vs. resection + ileostomy). High mortality (10–30% even with surgery). [19]

2. Intestinal Haemorrhage (10–20% of cases) [5]

   • Mechanism: Ulcer erosion into submucosal vessels.
   • Clinical Presentation:
     • Sudden drop in haemoglobin.
     • Melaena (black, tarry stools) or haematochezia (fresh blood per rectum).
     • Hypovolaemic shock in severe cases.
   • Management: Resuscitation (IV fluids, blood transfusion), supportive care. Surgery reserved for massive bleeding unresponsive to conservative measures.

3. Encephalopathy ("Typhoid Encephalopathy")

   • Clinical Presentation: Progressive alteration in consciousness, delirium, stupor, coma, seizures (rare). Mortality 10–40% if untreated. [8]
   • Mechanism: Direct bacterial invasion of CNS, cerebral oedema, or metabolic derangement (hyponatraemia, hypoglycaemia).
   • Management: High-dose dexamethasone reduces mortality (see Management section). [8]

4. Myocarditis

   • Rare but life-threatening. Presents with arrhythmias, heart failure, cardiogenic shock.

5. Cholecystitis and Hepatitis

   • "Salmonella hepatitis": elevated transaminases (2–5× upper limit of normal), jaundice (uncommon).

6. Relapse

   • Occurs in 5–10% of patients 1–3 weeks after fever resolution. Usually milder than initial illness. Caused by inadequate bacterial clearance. [5]

Examination Findings:

• Signs of perforation: rigid abdomen, absent bowel sounds, shock.
• Signs of bleeding: pallor, tachycardia, hypotension, melaena on PR exam.
• Signs of encephalopathy: reduced GCS, confusion, seizures.

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Week 4: Recovery or Death

• Recovery: Gradual defervescence of fever over 3–5 days with appropriate antibiotic therapy. Fatigue, weakness, and weight loss persist for weeks.
• Relapse: 5–10% experience return of fever 1–3 weeks post-treatment (usually milder). [5]
• Chronic Carriage: 1–5% become chronic carriers (asymptomatic shedding > 1 year). [13]
• Death: Untreated mortality 10–20%; treated mortality less than 1%. [7]

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Atypical Presentations

• Children: Often milder, with diarrhoea more prominent than constipation.
• Elderly: Presentation may be subtle (low-grade fever, confusion) with higher complication rates.
• HIV/Immunocompromised: Increased severity, bacteraemia may be prolonged, higher relapse rates.
• Partially Treated: Prior antibiotic exposure (common in returning travellers who took empirical antibiotics abroad) may obscure classical features, delay diagnosis, and reduce culture yield.

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5. Clinical Examination

General Inspection

• Appearance: "Typhoid facies"—toxic, exhausted, apathetic, lying still with eyes half-open.
• Conscious Level: Alert in week 1, progressing to confusion/delirium ("typhoid state") in week 2, possible stupor/coma in severe cases.
• Hydration Status: Dry mucous membranes, reduced skin turgor (diarrhoea, poor oral intake).

Vital Signs

• Temperature: 39–40°C (sustained fever).
• Pulse: Relative bradycardia (Faget's sign)—pulse 70–90 bpm despite high fever. (Expected pulse for 40°C: ~120 bpm).
• Blood Pressure: Normal initially; hypotension if shock/dehydration.
• Respiratory Rate: Normal unless complications (pneumonia, shock).

Skin

• Rose Spots: Search carefully on trunk (chest, abdomen, flanks). Faint, salmon-pink, blanching macules, 2–4 mm diameter, appearing in crops during week 2. Difficult to see in dark skin. Present in ~30% of cases. [4]

Head and Neck

• Tongue: Coated white with red edges ("typhoid tongue").
• Conjunctivae: Injected (red), pallor if anaemic.

Cardiovascular

• Pulse: Relative bradycardia.
• Heart Sounds: Usually normal. Listen for signs of myocarditis (arrhythmia, gallop rhythm) in severe cases.

Respiratory

• Chest Examination: Usually clear. Crackles if secondary pneumonia.

Abdominal

• Inspection: Distended abdomen (ileus).
• Palpation:
  • "Right Lower Quadrant Tenderness: Inflamed Peyer's patches, mesenteric adenitis."
  • "Hepatomegaly: Liver edge palpable 2–4 cm below costal margin (tender)."
  • "Splenomegaly: Spleen palpable in 50–70% (soft, tender)."
• Percussion: Tympanic (distended bowel loops). If perforated: loss of liver dullness (free air).
• Auscultation: Reduced or absent bowel sounds (ileus). Absent in perforation.

Neurological

• Conscious Level: GCS 15 initially; may drop to 12–14 ("typhoid state") or less than 8 (coma) if encephalopathy.
• Focal Neurology: Usually absent (encephalopathy is diffuse).
• Meningism: Neck stiffness may occur (rare "typhoid meningitis").

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6. Differential Diagnosis

Typhoid fever is a "great mimicker" and must be distinguished from other causes of prolonged fever in returning travellers or residents of endemic areas.

Red Flags for Alternative Diagnoses

• Cyclical Fever: Think malaria (not sustained fever of typhoid).
• Lymphadenopathy: Uncommon in typhoid; suggests EBV, TB, HIV.
• Jaundice: May occur in typhoid (hepatitis) but prominent jaundice suggests viral hepatitis, leptospirosis, or malaria.
• Leucocytosis: Typhoid causes leucopenia. Leucocytosis suggests pyogenic infection or perforation.

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7. Investigations

Microbiological Diagnosis

The gold standard for diagnosis is culture isolation of S. Typhi or S. Paratyphi from a normally sterile site.

1. Blood Culture

• Timing: Most sensitive in week 1–2 (positive in 60–80%). [15]
• Technique: Collect 10–20 mL blood (adults) into blood culture bottles (higher volume increases yield). Take samples before antibiotics if possible.
• Sensitivity Decline: Sensitivity drops in week 3–4 and after antibiotic therapy.
• Disadvantage: Takes 2–5 days for growth; doesn't help with acute diagnosis.

2. Stool Culture

• Timing: Becomes positive in week 2–3 (positive in 60–70%) as bacteria shed in bile.
• Sensitivity: Lower than blood culture in acute phase, but useful for:
  • Diagnosis after week 2.
  • Identifying chronic carriers (persistent positive stool cultures > 3 months post-infection).
• Multiple Samples: Submit 3 samples on consecutive days to increase yield.

3. Urine Culture

• Timing: Positive in week 2–3 (30–40% sensitivity).
• Useful for: Identifying urinary tract carriage (rare).

4. Bone Marrow Culture (Gold Standard)

• Sensitivity: > 90% even in patients on antibiotics for several days. [15]
• Indications:
  • Negative blood/stool cultures in highly suspected cases.
  • Patients already on antibiotics.
• Disadvantages: Invasive, painful, not routinely performed.
• Technique: Aspirate 1–2 mL marrow from iliac crest; inoculate directly into culture medium.

5. Serology: Widal Test (Largely Obsolete)

The Widal test detects antibodies against S. Typhi O (somatic) and H (flagellar) antigens.

Why NOT Recommended:

• Low Sensitivity/Specificity: Cross-reacts with other Salmonella species, malaria, dengue, chronic liver disease.
• False Positives: Prior typhoid infection, prior vaccination (Vi, Ty21a), endemic-area residents have baseline antibodies.
• False Negatives: Early infection (antibodies not yet detectable), immunosuppression.
• Requires Paired Sera: Single titre meaningless; need 4-fold rise between acute and convalescent samples (impractical).

Verdict: The Widal test has no role in modern clinical practice. [20] Do not use.

6. Newer Diagnostic Tests

• Typhidot: Detects IgM and IgG against S. Typhi outer membrane protein (OMP). Moderate sensitivity (60–80%). Useful in resource-limited settings. [20]
• PCR-based Tests: Real-time PCR for S. Typhi DNA in blood. High specificity, rapid (hours). Not widely available.

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Haematology

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Biochemistry

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Imaging

Chest X-Ray

• Indications: Suspected perforation.
• Findings:
  • Pneumoperitoneum (free air under diaphragm) if perforated.
  • "Erect CXR: Crescentic lucency below right hemidiaphragm."

Abdominal Ultrasound

• Findings:
  • Hepatosplenomegaly (diffuse organ enlargement).
  • Gallbladder wall thickening (acalculous cholecystitis).
  • Mesenteric lymphadenopathy.
  • Ascites (if perforated).

CT Abdomen/Pelvis

• Indications: Suspected perforation or intra-abdominal complication.
• Findings:
  • Free air (pneumoperitoneum).
  • Free fluid (peritonitis).
  • Bowel wall thickening (terminal ileum).
  • Abscess formation.

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Diagnostic Algorithm

Suspected Typhoid (Fever + Travel/Endemic Area)
                     ↓
    ┌────────────────┴────────────────┐
    │ BEFORE ANTIBIOTICS:             │
    │ - Blood Culture (10–20 mL)      │
    │ - Stool Culture                 │
    │ - FBC, LFTs, U&E, CRP           │
    └────────────────┬────────────────┘
                     ↓
        ┌────────────┴────────────┐
   Positive Culture          Negative Culture
   (CONFIRMED)               (Suspected Clinically)
        ↓                          ↓
   Start Treatment       Consider:
   (see Management)      - Repeat cultures
                         - Bone marrow culture
                         - Serology (Typhidot)
                         - PCR (if available)
                         - Empirical treatment

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8. Management

Management of typhoid fever involves antimicrobial therapy, supportive care, monitoring for complications, and public health measures. The choice of antibiotic is dictated by local resistance patterns.

General Principles

1. Hospitalisation Criteria:

   • Severe disease (shock, encephalopathy, dehydration).
   • Complications (perforation, bleeding).
   • Inability to tolerate oral intake.
   • Diagnostic uncertainty.
   • Vulnerable populations (children, elderly, pregnant, immunocompromised).

2. Isolation and Hygiene:

   • Enteric precautions: Single room, strict hand hygiene, safe disposal of faeces/urine.
   • Patients are infectious during illness and for weeks after (shedding in stool/urine).
   • Food handlers, healthcare workers, and childcare workers must have 3 consecutive negative stool cultures (1 week apart) before returning to work.

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Antimicrobial Therapy

The emergence of antimicrobial resistance (AMR) has fundamentally altered typhoid treatment. Fluoroquinolone resistance is now endemic in South Asia (> 90% of isolates in India, Pakistan, Bangladesh). [6] Extensively drug-resistant (XDR) typhoid (resistant to chloramphenicol, ampicillin, co-trimoxazole, fluoroquinolones, AND third-generation cephalosporins) has emerged in Pakistan since 2016. [7]

Definitions of Resistance

First-Line Antibiotics (Uncomplicated Typhoid)

Second-Line Antibiotics

Third-Line Antibiotics (XDR Typhoid)

Exam Detail: Historical Antibiotics (No Longer Recommended):

1. Chloramphenicol:

   • Historical Significance: First effective antibiotic for typhoid (1948). Reduced mortality from 20% to 2–5%. [5]
   • Dose: 50–75 mg/kg/day PO/IV QID for 14 days.
   • Why Obsolete: High relapse rate (15–20%), bone marrow toxicity (aplastic anaemia), widespread resistance.

2. Ampicillin/Amoxicillin:

   • Dose: 100 mg/kg/day QID for 14 days.
   • Why Obsolete: Widespread resistance (MDR strains).

3. Co-trimoxazole:

   • Dose: 960mg BD for 14 days.
   • Why Obsolete: Widespread resistance (MDR strains).

Key Message: Chloramphenicol, ampicillin, and co-trimoxazole are no longer first-line due to resistance and toxicity. Mention historical context in exams but recommend azithromycin/ceftriaxone.

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Adjunctive Corticosteroid Therapy

High-dose dexamethasone significantly reduces mortality in severe typhoid with shock or altered mental status. [8]

Mechanism: Reduces cytokine-mediated inflammatory damage, cerebral oedema, and vascular collapse.

Important: Steroids should only be used in severe disease (shock, GCS less than 12). Do not use in uncomplicated typhoid.

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Supportive Care

1. Fluid Resuscitation:

   • IV crystalloids (0.9% saline, Hartmann's) for dehydration, shock.
   • Oral rehydration solution (ORS) if tolerating oral intake.

2. Antipyretics:

   • Paracetamol (1g PO/IV QDS) for fever relief.
   • Avoid NSAIDs (ibuprofen, aspirin) due to risk of GI bleeding/perforation.

3. Nutrition:

   • Soft, low-residue diet to reduce bowel trauma.
   • NG feeding if unable to tolerate oral intake.

4. Monitoring:

   • Daily FBC (watch for anaemia, thrombocytopenia).
   • Daily abdominal examination (watch for perforation signs).
   • Stool charts (monitor for bleeding).

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Management of Complications

1. Intestinal Perforation

• Recognition: Sudden severe abdominal pain, rigidity, peritonitis.
• Investigation: Erect CXR (pneumoperitoneum), CT abdomen (confirm site, extent).
• Management:
  • "Resuscitation: IV fluids, broad-spectrum antibiotics (add anaerobic cover: metronidazole)."
  • "Surgery: Emergency laparotomy."
    • Primary Repair: Simple closure of perforation if small, single, minimal contamination.
    • Resection + Ileostomy: If multiple perforations, necrotic bowel, or gross contamination. [19]
  • "Post-operative: ICU care, complete 14-day antibiotic course."
• Mortality: 10–30% even with surgical intervention. [19]

2. Intestinal Haemorrhage

• Recognition: Melaena, haematochezia, drop in Hb, shock.
• Management:
  • "Resuscitation: IV fluids, blood transfusion (target Hb > 7 g/dL)."
  • "Conservative: Most bleeds stop spontaneously."
  • "Surgery: Reserved for massive bleeding (> 4 units transfused, haemodynamic instability despite resuscitation). Laparotomy + oversewing of bleeding ulcer or resection."
• Avoid: NSAIDs, antiplatelet agents.

3. Encephalopathy

• Management:
  • High-dose dexamethasone (as above). [8]
  • "Airway protection: Intubation if GCS less than 8."
  • "Seizures: Benzodiazepines (lorazepam, diazepam), antiepileptics (phenytoin) if refractory."
  • "Cerebral oedema: Elevate head of bed 30°, consider mannitol if raised ICP."

4. Relapse

• Definition: Return of fever and symptoms 1–3 weeks after treatment.
• Incidence: 5–10% (higher with short-course therapy). [5]
• Management: Repeat full course of antibiotics (same agent or switch based on susceptibility).

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Chronic Carrier Eradication

Indications: Chronic carriage (positive stool cultures > 1 year post-infection), especially food handlers, healthcare workers.

Post-Treatment: Verify clearance with 3 consecutive negative stool cultures (1 week apart, starting 1 month after antibiotics stopped).

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Treatment Algorithm

           CONFIRMED/SUSPECTED TYPHOID
                      ↓
        ┌─────────────┴─────────────┐
     MILD                       SEVERE
  (Ambulatory,                (Shock, Encephalopathy,
   Oral Intake OK)            Complications, Dehydration)
        ↓                             ↓
   AZITHROMYCIN                  CEFTRIAXONE IV
   1g PO once,                   2g OD for 10–14 days
   then 500mg OD                      +
   for 7 days                    DEXAMETHASONE
        ↓                        (if shock/GCS less than 12)
   Outpatient                    3mg/kg IV stat,
   monitoring                    then 1mg/kg Q6H × 48h
        ↓                             ↓
   Fever defervesces          Switch to PO when
   in 3–5 days                afebrile/tolerating
        ↓                             ↓
   Complete course            Complete 14-day course

If XDR Suspected (Travel to Pakistan):

• Start Meropenem 1g IV TDS or High-dose Azithromycin pending susceptibility results.

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Special Populations

Pregnancy

• Preferred: Ceftriaxone 2g IV OD (Category B).
• Avoid: Fluoroquinolones (teratogenic, arthropathy in fetus). Chloramphenicol (grey baby syndrome).
• Azithromycin: Category B (safe).

Children

• Preferred: Azithromycin 20mg/kg OD or Ceftriaxone 50–75mg/kg OD.
• Avoid: Fluoroquinolones (risk of arthropathy, tendinopathy in growing children).

Renal/Hepatic Impairment

• Ceftriaxone: Dose reduction not required (dual renal + biliary excretion).
• Azithromycin: Caution in severe hepatic impairment.

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9. Prevention and Vaccination

Primary Prevention

The cornerstone of prevention is safe water, sanitation, and hygiene (WASH).

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Vaccination

Two vaccines are available for typhoid fever. Neither prevents paratyphoid fever.

1. Vi Polysaccharide Vaccine (Injectable)

• Formulation: Purified Vi capsular polysaccharide antigen of S. Typhi.
• Route: Intramuscular (single dose).
• Efficacy: 50–70% protection. [9]
• Duration: 3 years (requires booster every 3 years if ongoing risk).
• Age: Approved for ≥2 years.
• Advantages: Single dose, well-tolerated, can be co-administered with other vaccines.
• Disadvantages: Does not induce mucosal immunity, short duration, not effective in children less than 2 years.

2. Ty21a Oral Vaccine (Live-Attenuated)

• Formulation: Live-attenuated S. Typhi strain Ty21a.
• Route: Oral capsules (3–4 doses, alternate days).
• Efficacy: 50–70% protection. [9]
• Duration: 5–7 years.
• Age: Approved for ≥6 years.
• Advantages: Longer duration, induces mucosal immunity.
• Disadvantages:
  • Requires 3–4 doses (compliance issue).
  • Must be taken on empty stomach (1 hour before meals).
  • Avoid concurrent antibiotics (kills live bacteria).
  • Contraindicated in immunocompromised (live vaccine).

3. Vi-TCV (Typhoid Conjugate Vaccine) – New Generation

• Formulation: Vi polysaccharide conjugated to tetanus toxoid (enhances immunogenicity).
• Route: Intramuscular (single dose).
• Efficacy: 80–85% protection (superior to Vi polysaccharide). [10]
• Duration: > 5 years (possibly longer).
• Age: Approved for ≥6 months.
• Advantages:
  • Single dose.
  • Effective in infants/young children (induces T-cell-dependent immunity).
  • Longer duration of protection.
  • WHO-prequalified (2018). [10]
• Availability: Increasingly used in endemic countries (mass vaccination campaigns).

Vaccine Recommendations

Key Message: Vaccines reduce risk by 50–70% but do not guarantee protection. Travellers must still adhere to food/water precautions. [9]

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Public Health Measures

1. Case Reporting: Typhoid is a notifiable disease in most countries. Report to public health authorities.
2. Contact Tracing: Identify source (chronic carrier, contaminated food/water).
3. Carrier Screening: Food handlers, healthcare workers in outbreak settings.
4. Environmental Sanitation: Improve water treatment, sewage systems in endemic areas.

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10. Prognosis and Outcomes

Natural History (Untreated)

• Mortality: 10–20% (death from complications: perforation, bleeding, encephalopathy, shock). [5]
• Recovery: 30–40% of untreated patients recover spontaneously (relies on host immunity).
• Chronic Carriage: 1–5% become chronic carriers. [13]

With Appropriate Treatment

Factors Associated with Poor Prognosis

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11. Key Guidelines and Evidence

Major Guidelines

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Landmark Studies

1. Hoffman et al. (1984): Dexamethasone in Severe Typhoid [8]

• Study Design: Randomised controlled trial (RCT), Jakarta, Indonesia.
• Population: 38 patients with severe typhoid and shock or coma.
• Intervention: Chloramphenicol + High-dose dexamethasone (3mg/kg stat, then 1mg/kg Q6H × 48h) vs. Chloramphenicol alone.
• Results: Mortality 56% (control) vs. 10% (dexamethasone) (p less than 0.01).
• Impact: Established high-dose corticosteroids as standard of care for severe typhoid with shock/encephalopathy.

2. Parry et al. (2013): Fluoroquinolone Resistance in Asia [6]

• Study Design: Prospective surveillance, Vietnam and Nepal.
• Findings: Fluoroquinolone resistance rates > 90% in South Asia due to mutations in gyrA and parC genes (quinolone resistance-determining regions).
• Impact: Shifted treatment guidelines away from empirical fluoroquinolones to azithromycin/ceftriaxone.

3. Klemm et al. (2018): XDR Typhoid Outbreak in Pakistan [7]

• Study Design: Outbreak investigation, Hyderabad, Pakistan.
• Findings: Extensively drug-resistant (XDR) S. Typhi H58 clone resistant to chloramphenicol, ampicillin, co-trimoxazole, fluoroquinolones, AND ceftriaxone. Only susceptible to azithromycin and carbapenems.
• Impact: Highlighted global threat of XDR typhoid. Led to emergency vaccination campaigns with Vi-TCV in Pakistan.

4. Mohan et al. (2015): Vi-TCV Efficacy [10]

• Study Design: Phase 3 RCT, Nepal.
• Population: Children aged 9 months to 16 years.
• Intervention: Single-dose Vi-TCV vs. control.
• Results: Vaccine efficacy 80–85% over 2 years.
• Impact: Supported WHO prequalification of Vi-TCV (2018) and mass vaccination campaigns.

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12. Examination Focus

Common Exam Scenarios (MRCP, FRACP, USMLE)

1. Returning Traveller with Fever (Classic Presentation)

Stem: "A 28-year-old man presents with 10 days of fever after returning from Pakistan. He reports progressive fever worsening each evening, severe headache, and constipation. Examination reveals temperature 40°C, pulse 85 bpm, palpable spleen, and faint pink macules on his trunk. Blood tests show WBC 3.2 × 10⁹/L. What is the most likely diagnosis?"

Answer: Typhoid fever.

Key Clues:

• Travel to endemic area (Pakistan).
• "Step-ladder" fever (worsening each evening).
• Relative bradycardia (pulse 85 with temp 40°C).
• Rose spots (pink macules on trunk).
• Leucopenia (WBC 3.2).
• Splenomegaly.

Next Step: Blood culture, stool culture, empirical azithromycin or ceftriaxone (depending on severity).

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2. Acute Abdomen in Week 3 (Perforation)

Stem: "A 35-year-old woman with typhoid fever (diagnosed 2 weeks ago, on azithromycin) suddenly develops severe generalised abdominal pain and rigidity. Vital signs: BP 90/60, HR 120, temp 38.5°C. Abdomen is rigid with absent bowel sounds. What is the most likely complication?"

Answer: Intestinal perforation (perforated ileum).

Key Clues:

• Week 3 of typhoid (complication phase).
• Sudden severe abdominal pain, rigidity (peritonitis).
• Shock (hypotension, tachycardia).
• Absent bowel sounds (ileus).

Next Step: Erect CXR (pneumoperitoneum), IV resuscitation, broad-spectrum antibiotics (add metronidazole), emergency laparotomy.

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3. Leucopenia as Diagnostic Clue

Stem: "Which of the following infections typically causes leucopenia? (A) Pneumococcal pneumonia, (B) Typhoid fever, (C) Staphylococcal sepsis, (D) Cholecystitis."

Answer: (B) Typhoid fever.

Rationale: Typhoid causes leucopenia (WBC 3–4 × 10⁹/L) due to bone marrow suppression and bacterial sequestration. Most bacterial infections cause leucocytosis.

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4. Widal Test Interpretation

Stem: "A patient with fever and recent travel to India has a Widal test showing O antigen titre 1:160. What is the correct interpretation?"

Answer: The test is non-specific and should not guide treatment. Blood culture is required.

Rationale: Widal test has low sensitivity/specificity, high false-positive rate (cross-reaction, prior vaccination, endemic-area residence). It has no role in modern diagnosis. [20]

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Viva Questions and Model Answers

Q1: "What is typhoid fever and how does it differ from gastroenteritis?"

Model Answer: "Typhoid fever is a systemic infection caused by Salmonella enterica serovar Typhi, an invasive intracellular bacterium. Unlike gastroenteritis caused by non-typhoidal Salmonella, which is self-limiting and localised to the gut, typhoid fever involves sustained bacteraemia, dissemination to the reticuloendothelial system, and systemic manifestations including high fever, hepatosplenomegaly, and potentially life-threatening complications such as intestinal perforation. The key difference is that typhoid is a systemic febrile illness, not primarily a diarrhoeal disease."

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Q2: "Describe the pathophysiology of intestinal perforation in typhoid fever."

Model Answer: "Perforation occurs in week 3–4 due to the pathophysiological sequence of typhoid. After initial invasion of Peyer's patches in the terminal ileum via M cells, bacteria disseminate to the liver, spleen, and bone marrow. During secondary bacteraemia, bacteria are excreted in bile and re-infect the Peyer's patches in massive numbers. This causes hyperplasia, necrosis, and ulceration of the overlying mucosa. The ulcers are longitudinal, aligned with the long axis of the ileum, and located at the anti-mesenteric border. Full-thickness necrosis of these ulcers leads to perforation into the peritoneal cavity, causing peritonitis and pneumoperitoneum. The risk is highest in the third week, occurring in 1–3% of hospitalised patients, with mortality of 10–30% despite surgical intervention." [19]

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Q3: "Why is the Widal test no longer recommended?"

Model Answer: "The Widal test detects antibodies against S. Typhi O and H antigens but has poor sensitivity and specificity. False positives occur due to cross-reaction with other Salmonella species, malaria, dengue, prior typhoid vaccination, and baseline antibodies in endemic-area residents. False negatives occur in early infection (antibodies not yet detectable) and immunocompromised patients. Additionally, interpretation requires paired sera (acute and convalescent) showing a 4-fold rise in titre, which is impractical. Blood culture remains the gold standard for diagnosis. The Widal test has no role in modern clinical practice." [20]

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Q4: "What is the role of corticosteroids in typhoid fever?"

Model Answer: "High-dose dexamethasone is indicated for severe typhoid with shock or altered mental status (GCS less than 12). The landmark Jakarta Protocol study by Hoffman et al. (1984) demonstrated that dexamethasone (3mg/kg IV stat, then 1mg/kg Q6H for 48 hours) reduced mortality from 56% to 10% in patients with severe typhoid and coma or shock. The mechanism is reduction of cytokine-mediated inflammatory damage, cerebral oedema, and vascular collapse. Importantly, steroids should not be used in uncomplicated typhoid as they may prolong bacterial clearance." [8]

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Q5: "What is the current first-line antibiotic for typhoid fever, and why?"

Model Answer: "The current first-line antibiotic depends on disease severity and local resistance patterns. For uncomplicated typhoid, azithromycin (1g PO once, then 500mg OD for 7 days) is the drug of choice. For severe typhoid requiring hospitalisation, ceftriaxone (2g IV OD for 10–14 days) is preferred. This shift from fluoroquinolones occurred due to widespread fluoroquinolone resistance in South Asia, now exceeding 90%. Empirical ciprofloxacin should be avoided unless susceptibility is confirmed. For extensively drug-resistant (XDR) typhoid (resistant to ceftriaxone), carbapenems such as meropenem are required." [6,7]

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Common Exam Mistakes

❌ Mistake 1: Diagnosing typhoid based on Widal test alone.

• Correction: Widal test has no role in modern diagnosis. Use blood culture.

❌ Mistake 2: Empirically prescribing ciprofloxacin for returning traveller from South Asia.

• Correction: Fluoroquinolone resistance > 90% in South Asia. Use azithromycin or ceftriaxone.

❌ Mistake 3: Expecting diarrhoea in week 1.

• Correction: Constipation is more common than diarrhoea in week 1. "Pea soup" diarrhoea appears in week 2–3.

❌ Mistake 4: Missing relative bradycardia (Faget's sign).

• Correction: Pulse should be ~120 bpm for temp 40°C; if 80–90 bpm, think typhoid, brucellosis, or Legionnaires'.

❌ Mistake 5: Using NSAIDs for fever control.

• Correction: NSAIDs increase risk of GI perforation/bleeding. Use paracetamol only.

❌ Mistake 6: Assuming vaccination = immunity.

• Correction: Vaccines provide only 50–70% protection. Vaccinated travellers can still get typhoid.

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13. Patient and Layperson Explanation

What is Typhoid Fever?

Typhoid fever is a serious infection caused by a bacterium called Salmonella Typhi. It is caught by eating food or drinking water that has been contaminated with the faeces (poo) of someone who has the infection. It is common in countries with poor sanitation, especially in South Asia (India, Pakistan, Bangladesh), Southeast Asia, and parts of Africa.

Is it Just a Stomach Bug?

No. Although typhoid starts in the gut, it spreads through your bloodstream to your liver, spleen, and bone marrow. This causes weeks of high fever, severe headaches, and can make you very ill. Unlike a stomach bug (which causes diarrhoea and vomiting for a few days), typhoid is a whole-body infection that lasts for weeks if not treated.

What Are the Symptoms?

In the first week, you develop a fever that gets worse each day (like climbing a ladder). You feel exhausted, have a severe headache, and may be constipated (not diarrhoea—that comes later).

In the second week, the fever stays very high (40°C). You may develop faint pink spots on your chest and abdomen (called "rose spots"). Your liver and spleen enlarge, and you may have "pea soup" diarrhoea (greenish, watery poo). You may feel confused or very sleepy.

In the third week, serious complications can occur, including a hole in the bowel (perforation) causing severe belly pain, or bleeding inside the gut causing black, tarry poo.

How is it Diagnosed?

Doctors take a blood sample to grow the bacteria in a laboratory (called a "blood culture"). This is the best test in the first week. Later, they may test your poo or urine.

An old test called the "Widal test" is not reliable and should not be used.

How is it Treated?

Typhoid is treated with antibiotics (tablets or injections). The most common antibiotics used are:

• Azithromycin (tablets for 7 days) if you're not too sick.
• Ceftriaxone (injection for 10–14 days) if you're very sick.

You usually feel better within 3–5 days of starting antibiotics, but you must finish the full course to stop the infection coming back.

If you're very sick (confused, low blood pressure), doctors may also give you steroids to reduce swelling in the brain.

Can it Be Prevented?

Yes! The best way to prevent typhoid is to:

• Drink safe water: Only drink bottled, boiled, or filtered water. Avoid ice.
• Eat safe food: "Boil it, cook it, peel it, or forget it." Avoid raw vegetables, salads, street food, and unpasteurised dairy.
• Get vaccinated: There are two vaccines available (an injection or tablets). They reduce your risk by 50–70%, but they don't guarantee protection. You still need to be careful with food and water.

Am I Contagious?

Yes. The bacteria are in your poo and (sometimes) your urine. You must:

• Wash your hands thoroughly with soap and water after using the toilet and before eating.
• Not prepare food for others until you've been tested and cleared (3 negative poo tests).

Some people (1 in 20) become "chronic carriers"—they feel well but continue to spread the bacteria for years. This is treated with long-term antibiotics and sometimes surgery to remove the gallbladder (where the bacteria hide).

What if I've Travelled to India or Pakistan?

If you develop a fever within 2 months of returning from South Asia, Southeast Asia, or Africa, see a doctor immediately and tell them where you've travelled. Typhoid is curable with antibiotics, but it can be life-threatening if not treated promptly.

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14. References

Primary Sources

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2. Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive Salmonella infections. Clin Microbiol Rev. 2015;28(4):901-937. doi:10.1128/CMR.00002-15

3. Dougan G, Baker S. Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever. Annu Rev Microbiol. 2014;68:317-336. doi:10.1146/annurev-micro-091313-103739

4. Cunha BA. The diagnostic and prognostic significance of relative bradycardia. Clin Microbiol Infect. 2000;6(12):633-634. doi:10.1046/j.1469-0691.2000.00185.x

5. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med. 2002;347(22):1770-1782. doi:10.1056/NEJMra020201

6. Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and nontyphoidal salmonellae. Curr Opin Infect Dis. 2008;21(5):531-538. doi:10.1097/QCO.0b013e32830f453a

7. Klemm EJ, Shakoor S, Page AJ, et al. Emergence of an extensively drug-resistant Salmonella enterica serovar Typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins. mBio. 2018;9(1):e00105-18. doi:10.1128/mBio.00105-18

8. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984;310(2):82-88. doi:10.1056/NEJM198401123100202

9. Anwar E, Goldberg E, Fraser A, Acosta CJ, Paul M, Leibovici L. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014;(1):CD001261. doi:10.1002/14651858.CD001261.pub3

10. Mohan VK, Varanasi V, Singh A, et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicentric, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis. 2015;61(3):393-402. doi:10.1093/cid/civ295

11. Steinberg EB, Bishop R, Haber P, et al. Typhoid fever in travelers: who should be targeted for prevention? Clin Infect Dis. 2004;39(2):186-191. doi:10.1086/421940

12. Woodward TE. The fever pattern as a diagnostic aid. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. New York: Raven Press; 1991:215-235.

13. Gunn JS, Marshall JM, Baker S, Dongol S, Charles RC, Ryan ET. Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol. 2014;22(11):648-655. doi:10.1016/j.tim.2014.06.007

14. Butler T, Ho M, Acharya G, Tiwari M, Gallati H. Interleukin-6, gamma interferon, and tumor necrosis factor receptors in typhoid fever related to outcome of antimicrobial therapy. Antimicrob Agents Chemother. 1993;37(11):2418-2421. doi:10.1128/AAC.37.11.2418

15. Gilman RH, Terminel M, Levine MM, Hernandez-Mendoza P, Hornick RB. Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever. Lancet. 1975;1(7918):1211-1213. doi:10.1016/s0140-6736(75)92194-7

16. Maskey AP, Day JN, Phung QT, et al. Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal. Clin Infect Dis. 2006;42(9):1247-1253. doi:10.1086/503033

17. Spanò S, Galán JE. A Rab32-dependent pathway contributes to Salmonella typhi host restriction. Science. 2012;338(6109):960-963. doi:10.1126/science.1229224

18. Song J, Gao X, Galán JE. Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin. Nature. 2013;499(7458):350-354. doi:10.1038/nature12377

19. Bitar R, Tarpley J. Intestinal perforation in typhoid fever: a historical and state-of-the-art review. Rev Infect Dis. 1985;7(2):257-271. doi:10.1093/clinids/7.2.257

20. Olopoenia LA, King AL. Widal agglutination test—100 years later: still plagued by controversy. Postgrad Med J. 2000;76(892):80-84. doi:10.1136/pmj.76.892.80

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference only. Clinical decisions must account for individual patient circumstances, local guidelines, and antimicrobial susceptibility patterns. Always consult appropriate specialists and infectious disease guidance for complex cases. This content is designed for postgraduate medical education (MRCP, FRACP, USMLE) and professional development.