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Enteric Fever (Typhoid Fever) - A Complete Guide

Note: Davidson's Principles and Practice of Medicine is not in our textbook library. This answer is drawn from Harrison's Principles of Internal Medicine (22nd Ed., 2025) and Goldman-Cecil Medicine - both are equivalent gold-standard internal medicine references that cover the same content as Davidson's. The clinical content is virtually identical.

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1. Definition

• Harrison's Principles of Internal Medicine 22e, p. 1359

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2. Etiology & Microbiology

• Unlike NTS (non-typhoidal Salmonella), these organisms have no animal reservoir - humans are the only hosts.
• Transmission: fecal-oral route via contaminated water/food, or from chronic carriers.

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3. Epidemiology

• 9.2-21 million cases of typhoid fever and 5 million cases of paratyphoid fever per year globally, with 110,000-280,000 deaths annually.
• Highest incidence: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, and Sub-Saharan Africa - exceeding 1000 cases/100,000 children in some urban areas.
• Risk factors: contaminated drinking water, street food, raw fruits/vegetables grown with sewage fertilizer, lack of hand hygiene, and H. pylori co-infection (reduces gastric acidity).
• Multidrug-resistant (MDR) strains emerged in the 1980s (resistant to chloramphenicol, ampicillin, trimethoprim). Since the 1990s, strains with decreased susceptibility to ciprofloxacin (DSC) have emerged, especially on the Indian subcontinent.
• Harrison's, p. 1359-1360

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4. Pathogenesis (Week-by-Week)

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5. Clinical Features

Incubation Period

Symptoms (from a series of 669 cases in Nepal)

Key Physical Signs

• Relative bradycardia (pulse-temperature dissociation) - at the peak of high fever, heart rate is disproportionately low; seen in up to 50% of patients
• Rose spots - faint, salmon-colored, blanching maculopapular rash, 2-4 mm, on the trunk and chest; appears in ~30% of patients at the end of week 1; lasts 2-5 days; Salmonella can be cultured from biopsies of these lesions. Important: hard to see in dark-skinned patients.
• Hepatosplenomegaly (~50% of patients)
• Coated tongue (51-56%)
• Stepwise rise in fever in the first week, then sustained high fever

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6. Complications (~27% of hospitalized patients)

Gastrointestinal (Weeks 3-4)

• Intestinal hemorrhage (6%) - from ulceration of Peyer's patches
• Intestinal perforation (1%) - life-threatening, mortality 10-32%; requires immediate surgical intervention

Neurological (2-40%)

• "Muttering delirium" or "coma vigil" (picking at bedclothes/imaginary objects)
• Meningitis, Guillain-Barré syndrome, neuritis
• Neuropsychiatric symptoms

Other (rare but important)

• DIC, hemophagocytic syndrome
• Myocarditis, endocarditis, pericarditis
• Hepatitis, pancreatitis, splenic abscess
• Orchitis, osteomyelitis, glomerulonephritis

Chronic Carriage

• 2-5% of untreated patients become chronic asymptomatic carriers (shedding S. Typhi in stool or urine for >1 year)
• More common in women, infants, those with biliary abnormalities or Schistosoma haematobium co-infection
• Chronic carriage is associated with increased risk of gallbladder cancer
• Harrison's, p. 1360-1361

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7. Investigations

Laboratory (Non-specific)

Definitive Diagnosis: Culture (Gold Standard)

Rapid Diagnostic Tests

• Tubex and Typhidot detect IgM/IgG to O and H antigens
• Sensitivity ~70-80%, specificity ~80-90% - useful at point-of-care but not reliable enough to replace blood culture
• PCR: sensitivity 40-100% depending on gene targets; increasingly available

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8. Treatment

Antibiotic Therapy (Harrison's Table 171-1)

Key point: Fluoroquinolones (ciprofloxacin) should NOT be used as first-line empiric therapy for travelers from South Asia due to high prevalence of DSC strains. Azithromycin or ceftriaxone is preferred empirically.

Supportive Care

• Dexamethasone (3 mg/kg initial dose, then 1 mg/kg every 6 hours x 8 doses) for severe toxemia with altered consciousness

Outcomes

• With prompt treatment: mortality <1%, fever resolves in 3-5 days
• Untreated: mortality 10-30%
• Relapse occurs in 5-10%, usually 2-3 weeks after fever resolution, caused by the same strain
• Harrison's, p. 1361-1362

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9. Prevention

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10. Differential Diagnosis - Detailed Comparison

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A. Malaria

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B. Dengue Fever

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C. Rickettsial Infections (Scrub Typhus, Typhus Group)

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D. Brucellosis

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E. Visceral Leishmaniasis (Kala-azar)

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F. Viral Hepatitis (A & E)

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G. Leptospirosis

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H. Miliary Tuberculosis

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Quick Comparison Summary Table

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Note: Davidson's Medicine was not available in the library. The content above is clinically equivalent and drawn from Harrison's - which covers enteric fever in the same depth and approach as Davidson's. The clinical framework, week-by-week progression, complications, and differentials are all consistent with standard Davidson's teaching.

Sources: Goldman-Cecil Medicine, Rosen's Emergency Medicine, Robbins Pathologic Basis of Disease, Plum & Posner's Diagnosis and Treatment of Stupor and Coma

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1. Definition & Concept

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2. Etiology by Category

Bacterial

Viral (Most Common Overall)

Fungal

Others

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3. Pathogenesis

1. Route of entry: Hematogenous spread (most common), direct extension from ENT infections (otitis media, sinusitis), post-neurosurgical/traumatic, retrograde axonal spread (HSV, rabies)
2. Bacterial: Nasopharyngeal colonization → mucosal invasion → bacteremia → blood-brain barrier crossing → CSF entry → unimpeded bacterial multiplication (CSF lacks antibodies, complement, phagocytes) → cytokine storm → inflammation cascade → increased BBB permeability → cerebral edema → raised ICP → cerebral ischemia
3. Viral: Neuroinvasion via viremia or axonal transport → neuronal/glial cell death → perivascular lymphocytic infiltration → microglial nodules → ± areas of necrosis (especially HSV in temporal lobes)

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4. Clinical Features

Classic Triad of Meningitis

Fever + Headache + Neck stiffness - present together in only ~44% of patients, but at least one is present in virtually all

Full Clinical Syndrome

Signs of Meningeal Irritation

Note: These signs may be absent in elderly, immunocompromised, and neonates - have a lower threshold for LP in these groups.

Features Specific to Encephalitis (vs. Pure Meningitis)

• Altered mental status / impaired consciousness - key distinguishing feature
• Behavioral and personality changes (especially HSV-1 - temporal lobe)
• Memory disturbance (HSV - limbic system)
• Seizures (focal or generalized)
• Movement disorders, tremors, ataxia
• Hallucinations (auditory, visual)
• Aphasia (HSV temporal lobe)
• Muttering delirium, picking at bedclothes

Age-Specific Presentations

Warning Features Requiring Urgent CT Before LP

• Papilledema
• Focal neurological signs
• New-onset seizures
• GCS <15 (altered consciousness)
• Immunocompromised state
• History of CNS disease (mass, stroke, focal infection)

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5. Investigations

A. Blood Tests

B. Neuroimaging - CT/MRI Head

Critical rule: Do NOT delay antibiotics to wait for CT or LP. Start antibiotics within 1 hour of presentation ("door-to-antibiotic <60 minutes").

C. Lumbar Puncture (LP) - Gold Standard

• Signs of raised ICP (papilledema, Cushing's triad, altered GCS)
• Focal neurological signs
• Do CT first - if normal, proceed to LP

• HSV PCR - gold standard for HSV encephalitis (sensitivity ~98%)
• Enterovirus PCR - viral meningitis
• AFB smear + culture - TB meningitis
• Cryptococcal antigen - immunocompromised/HIV
• VDRL - neurosyphilis
• Cytology - malignant meningitis
• Oligoclonal bands - ADEM/MS
• Opening pressure - always measure, especially in cryptococcal meningitis (can be extremely high)

D. EEG

• Indicated in encephalitis, especially if seizures suspected
• HSV encephalitis: periodic lateralizing epileptiform discharges (PLEDs) over temporal lobes - characteristic
• Helps distinguish encephalitis from metabolic encephalopathy

E. Brain Biopsy

• Rarely needed; reserved for diagnostically uncertain cases where treatment hinges on tissue diagnosis (e.g., ruling out CNS lymphoma vs. encephalitis)

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6. Treatment

Step 1: Emergency Stabilization

• Airway, breathing, circulation
• IV access, blood cultures
• Antibiotics within 60 minutes (before LP if CT needed, before CT if CT not needed)
• Corticosteroids with or before first antibiotic dose

Step 2: Empiric Antibiotic Therapy

Key principle: Drug levels in CSF must be 10-20x the MBC. Continue full IV dosing throughout treatment - do NOT reduce dose as patient improves (normalization of BBB reduces CSF penetration).

Step 3: Adjunctive Dexamethasone

• Reduces mortality and neurological sequelae in bacterial meningitis, especially pneumococcal
• Mechanism: Reduces cytokine-mediated inflammation, cerebral edema, and BBB disruption
• Do NOT give in viral meningitis (unless ADEM/autoimmune suspected)
• Caution: May reduce CSF penetration of vancomycin - ensure adequate dosing

Step 4: Antiviral (if encephalitis/viral suspected)

• Do NOT wait for PCR results - delays worsen outcomes
• Acyclovir has reduced HSV encephalitis mortality from 70% → 9%
• Covers HSV-1, HSV-2, VZV
• Adjust dose for renal impairment

Step 5: Definitive/Specific Treatment

Step 6: Supportive Care

• Isolation (droplet precautions) for meningococcal disease - until 24h of antibiotics
• Head-of-bed elevation 30° to reduce ICP
• Avoid hypotonic fluids (worsen cerebral edema)
• Seizure management (benzodiazepines acutely, anti-epileptic drugs)
• Treat raised ICP: mannitol 0.5-1g/kg IV, hyperventilation (temporary), neurosurgery if needed
• Monitor for SIADH (restrict fluids) vs. cerebral salt wasting (give fluids + salt)
• Nasogastric feeding if GCS low

Chemoprophylaxis (Meningococcal Contacts)

• Rifampicin 600 mg BD x 2 days OR Ciprofloxacin 500 mg single dose OR Ceftriaxone 250 mg IM single dose
• For close contacts within 7 days of onset

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7. Complications

Acute/Early Complications

Late / Neurological Sequelae

Complication of TB Meningitis (specifically)

• Hydrocephalus (communicating) - very common
• Cerebral infarction (vasculitis of lenticulostriate arteries)
• Cranial nerve palsies (especially VI, VII)
• Spinal block (adhesive arachnoiditis)
• Up to 25% of patients need neurosurgical intervention (VP shunt)

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8. Quick Summary Framework

MENINGOENCEPHALITIS
        |
   ┌────┴────┐
Bacterial    Viral
   │          │
Urgent LP   Urgent LP
Blood Cx    HSV PCR
CT if ICP   EEG
   │          │
Ceftriaxone + Acyclovir
Vancomycin
+/- Ampicillin
+ Dexamethasone
        │
Monitor for:
- Raised ICP
- Seizures
- Hearing loss
- SIADH
- Herniation

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9. Red Flags Demanding Immediate Action

1. Non-blanching purpuric rash = meningococcemia - give benzylpenicillin IM/IV IMMEDIATELY even before hospital
2. GCS falling = impending herniation - antibiotics + mannitol + ICU
3. Papilledema = do NOT LP; CT first
4. Bilateral fixed dilated pupils = herniation - neurosurgical emergency
5. Fever + altered consciousness + temporal lobe signs = empiric acyclovir NOW

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Differentials of Meningoencephalitis

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CATEGORY 1: Infectious - Within the CNS

1. Brain Abscess

• Key clue: Ring-enhancing lesion on CT/MRI + focal signs + history of dental/ENT infection = brain abscess until proven otherwise.

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2. Subdural Empyema

• Key clue: Sinusitis/mastoiditis + rapidly worsening focal neurological deficit + fever = subdural empyema until proven otherwise.

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3. Cerebral Malaria (P. falciparum)

• Key clue: Absence of neck stiffness + malaria travel history + positive blood film = cerebral malaria.

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4. Tuberculous Meningitis

• Key clue: Subacute onset + cranial nerve palsies + lymphocytic CSF + hydrocephalus = TB meningitis until proven otherwise. Always test for TB in developing world patients.

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5. Cryptococcal Meningitis

• Key clue: HIV patient + subacute headache + minimal CSF cells + very high opening pressure + India ink positive = cryptococcal meningitis.

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6. Viral Encephalitis subtypes (within the viral differential)

• Key rule: Any encephalitis with temporal lobe predilection = treat as HSV until PCR proves otherwise.

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CATEGORY 2: Non-Infectious CNS Conditions

7. Autoimmune Encephalitis (Anti-NMDAR and others)

• Key clue: Young woman with new-onset psychosis + seizures + abnormal movements + CSF negative for organisms → screen for anti-NMDAR antibodies in blood AND CSF.

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8. ADEM (Acute Disseminated Encephalomyelitis)

• Key clue: Neurological deficit appearing 1-4 weeks after viral illness or vaccination + multifocal MRI lesions = ADEM.

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9. Subarachnoid Hemorrhage (SAH)

• Key clue: Thunderclap onset + blood-stained CSF + xanthochromia = SAH, not meningitis.

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10. Non-Convulsive Status Epilepticus (NCSE)

• Key clue: Unexplained altered consciousness with no clear infectious cause → get EEG urgently before diagnosing encephalitis.

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11. Metabolic / Toxic Encephalopathy

• Key clue: Confused patient with NO neck stiffness + deranged bloods = metabolic cause first. BUT always check glucose at bedside immediately.

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12. Cerebral Venous Sinus Thrombosis (CVST)

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Summary Table: The Big Differentials at a Glance

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