Enteric Fever

1. Introduction and Definition

Enteric fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi) and Salmonella enterica serovar Paratyphi A, B, or C (S. Paratyphi). While S. Typhi causes the majority of cases (approximately 90%), S. Paratyphi contributes to the remaining burden, though the clinical presentation is often indistinguishable. The disease is characterized by fever, abdominal pain, and multisystem involvement resulting from bacteremia and colonization of the reticuloendothelial system.

2. Epidemiology

• Global Burden: Enteric fever remains a major public health problem in resource-limited settings with poor sanitation and water supply. It is endemic in the Indian subcontinent, Southeast Asia, and parts of Africa.
• Pediatric Prevalence: In endemic areas, the incidence is highest in children and adolescents (5–15 years), though recent data indicates a significant burden in children under 5 years of age.
• Transmission: The mode of transmission is fecal-oral, typically through the ingestion of food or water contaminated with human feces containing the bacteria. Humans are the only natural reservoir for S. Typhi.
• Carriers: Chronic carriers (excreting bacilli for >1 year) act as crucial reservoirs for infection spread. This state is less common in children than adults.

3. Etiopathogenesis

The pathogenesis involves a complex interaction between the pathogen and the host immune system.

1. Ingestion: The infectious dose varies (${10}^3$ to ${10}^6$ organisms). Factors decreasing gastric acidity (antacids, proton pump inhibitors, age <1 year) reduce the inoculum required for infection.
2. Invasion: Bacteria survive the gastric acid, reach the small intestine, and penetrate the mucosa, primarily through M cells overlying the Peyer's patches in the ileum.
3. Primary Bacteremia (Transient): Bacteria are transported to the mesenteric lymph nodes, entering the thoracic duct and bloodstream.
4. Reticuloendothelial System (RES) Multiplication: The bacteria are rapidly cleared from the blood by macrophages and sequestered in the RES organs (liver, spleen, bone marrow, gallbladder). Here, they survive and multiply intracellularly (facultative intracellular pathogens) during the incubation period (7–14 days).
5. Secondary Bacteremia: Bacteria spill back into the bloodstream from the RES, marking the onset of clinical symptoms (fever).
6. Organ Seeding: The gallbladder is heavily infected via the biliary tract. Bacteria are re-excreted into the intestine in bile, re-infecting Peyer's patches, which may lead to necrosis, ulceration, hemorrhage, or perforation.

4. Clinical Manifestations

The clinical presentation varies by age. The classic "step-ladder" fever pattern described in older literature is now less common due to early antibiotic use.

4.1. General Features

• Incubation Period: Typically 7–14 days (range 3–60 days).
• Onset: Usually insidious with malaise, anorexia, dull frontal headache, and myalgia.
• Fever: The hallmark sign. It rises in a stepwise fashion in the first week, becoming sustained/continuous (high grade 39°C–40°C) by the second week.
• Gastrointestinal:
  • Older Children/Adults: Constipation is classic.
  • Young Children/Infants: Diarrhea is more common.
  • Abdominal pain, tenderness, and distension are frequent.
• Physical Findings:
  • Coated Tongue: Central white fur with red margins.
  • Hepatosplenomegaly: Soft, tender splenomegaly is palpable by the end of the first week.
  • Rose Spots: Blanching, erythematous maculopapular lesions (2–4 mm) on the trunk/chest. They appear around day 7–10, fade in 2–3 days, and are harder to see in dark-skinned patients.
  • Relative Bradycardia: Pulse-temperature dissociation (Faget's sign) is less common in children than adults.

4.2. Neonatal and Infant Typhoid

• Can be severe with rapid onset.
• Presentations include high fever, vomiting, diarrhea, distension, jaundice, and failure to thrive.
• Vertical transmission from an infected mother can occur, leading to neonatal sepsis.

5. Complications

Complications usually occur in the 2nd or 3rd week of untreated illness.

5.1. Intestinal Complications

• Intestinal Hemorrhage: Occurs in 1–10% of cases due to erosion of necrotic Peyer’s patches. Manifests as melena or hematochezia.
• Intestinal Perforation: A serious surgical emergency occurring in 0.5–3% of cases, typically in the terminal ileum. It presents with sudden abdominal pain, tachycardia, guarding, rigidity, and obliteration of liver dullness.

5.2. Systemic/Extraintestinal Complications

• Neurologic (Typhoid Encephalopathy): Occurs in 10–15% of cases. Manifests as delirium ("muttering delirium"), stupor, obtundation, coma, or shock. This defines Severe Enteric Fever.
• Cardiovascular: Toxic myocarditis, shock.
• Hepatobiliary: Hepatitis (Typhoid hepatitis), cholecystitis (rare in children).
• Hematologic: Hemophagocytic lymphohistiocytosis (HLH), disseminated intravascular coagulation (DIC).
• Others: Pneumonia, osteomyelitis (especially in Sickle Cell Disease), meningitis, arthritis.

6. Diagnosis

6.1. Microbiological Diagnosis (Gold Standard)

• Blood Culture: The mainstay of diagnosis. Sensitivity is highest in the 1st week (90%) and declines thereafter (50% by 3rd week). Automated systems (BACTEC) improve yield. Adequate blood volume is crucial.
• Bone Marrow Culture: The most sensitive test (>90%). It remains positive even after antibiotic therapy has started and in late stages. It is invasive and reserved for difficult cases.
• Stool Culture: Positive from the 2nd or 3rd week. Lower sensitivity than blood culture but useful for detecting carriers.

6.2. Serology (Widal Test)

• Detects agglutinating antibodies against O (somatic) and H (flagellar) antigens.
• Limitations: Low sensitivity/specificity, cross-reactivity with other Salmonella and malaria, and anamnestic reactions in endemic areas.
• Interpretation: A four-fold rise in titer in paired sera (10–14 days apart) is diagnostic. A single high titer (e.g., O >1:160 and H >1:160) in an endemic setting is only suggestive, not confirmatory.

6.3. Newer Rapid Tests

• Typhidot (detects IgM/IgG) and Tubex have been developed but lack superior sensitivity/specificity compared to culture and are not recommended as replacements for culture.

6.4. Nonspecific Laboratory Findings

• CBC: Leukopenia (or normal WBC) with eosinopenia (absence of eosinophils) is characteristic. Thrombocytopenia may occur.
• Liver Enzymes: Mild elevation of transaminases (SGOT > SGPT) is common.

7. Differential Diagnosis

Enteric fever mimics many febrile illnesses:

• Malaria: Differentiated by fever pattern, rigors, splenomegaly, and peripheral smear.
• Dengue: Acute onset, retro-orbital pain, significant thrombocytopenia/leukopenia.
• Rickettsial Diseases (Scrub Typhus): Presence of eschar, rapid response to doxycycline.
• Tuberculosis: Chronic course, respiratory signs.
• Brucellosis: Animal contact history, joint symptoms.

8. Management

8.1. Supportive Care

• Antipyretics (Paracetamol) for fever control.
• Adequate hydration and nutrition.
• Monitoring for "danger signs" (abdominal distension, bleeding, altered sensorium).

8.2. Antimicrobial Therapy

Antibiotic choice is guided by local susceptibility patterns, specifically the prevalence of Multi-Drug Resistant (MDR) and Fluoroquinolone-resistant strains.

A. Uncomplicated Enteric Fever (Outpatient)

• First Line: Cefixime (20 mg/kg/day PO divided BD for 14 days) OR Azithromycin (10–20 mg/kg/day PO once daily for 5–7 days).
  • Note: Azithromycin is highly effective for intracellular clearance and reduces relapse rates.
• Alternative: Amoxicillin or Trimethoprim-Sulfamethoxazole (only if sensitivity is proven, as resistance is common).

B. Severe/Complicated Enteric Fever (Inpatient)

• First Line: IV Ceftriaxone (75–100 mg/kg/day IV OD or BD for 10–14 days).
• For MDR/XDR Strains: If there is no response to Ceftriaxone or if Extensively Drug-Resistant (XDR) S. Typhi (resistant to ceftriaxone) is suspected (e.g., Pakistan outbreak strains):
  • Meropenem (Carbapenem).
  • Aztreonam.

C. Role of Fluoroquinolones (Ciprofloxacin/Ofloxacin)

• Historically the drug of choice, but widely prevalent resistance (Nalidixic acid-resistant S. Typhi - NARST) and high MICs for ciprofloxacin have reduced their clinical efficacy in many parts of India and Asia. They are generally avoided as empiric therapy in children unless sensitivity is confirmed.

8.3. Adjunctive Corticosteroid Therapy

• Indication: Strictly indicated for Severe Enteric Fever characterized by delirium, obtundation, stupor, coma, or shock.
• Regimen: Dexamethasone 3 mg/kg IV (initial dose), followed by 1 mg/kg IV every 6 hours for 48 hours.
• Benefit: Significantly reduces mortality in severe cases (from ~50% to 10%).

8.4. Management of Carriers

• Antibiotics must concentrate in the bile.
• High-dose Amoxicillin or Ciprofloxacin for 4–6 weeks. Cholecystectomy may be required for carriers with gallstones who fail medical therapy.

9. Prevention

9.1. Sanitation and Hygiene

Improvement in water supply, sewage disposal, and food hygiene is the ultimate preventive strategy.

9.2. Vaccination

Vaccination is recommended for children in endemic areas and travelers.

1. Typhoid Conjugate Vaccine (TCV):
   • Type: Vi polysaccharide conjugated to Tetanus Toxoid.
   • Schedule: Single dose from 6 months of age (typically 9-12 months).
   • Efficacy: High efficacy (>85%) and longer duration of protection. It is the preferred vaccine currently recommended by IAP and WHO.
2. Vi Polysaccharide Vaccine:
   • Age: >2 years.
   • Dose: Single IM dose, requires boosters every 3 years.
   • Efficacy: 60–70%.
3. Ty21a (Oral Live Attenuated):
   • Age: >5 years or >6 years (capsule form).
   • Schedule: 3–4 doses on alternate days.
   • Efficacy: Modest, requires boosters.