What is the diagnostic approach for typhoid fever?

Diagnostic Approach for Typhoid Fever

Blood culture is the gold standard for diagnosing typhoid fever and should be obtained immediately in all patients with suspected enteric fever, ideally collecting 2-3 specimens of 20 mL each in adults before starting antibiotics. 1, 2, 3

Clinical Presentation to Recognize

• Fever pattern: Sustained high-grade fever with insidious onset over 3-7 days, present in 97-100% of cases 2, 4
• Key symptoms: Malaise, headache, myalgia, and notably diarrhea is uncommon in enteric fever (which distinguishes it from other infectious diarrheas) 1
• Timing: Suspect typhoid in patients with fever lasting 3-30 days, particularly with travel history to endemic areas 5
• Complications: Abdominal pain and peritonitis typically occur in the third week if untreated, signaling potential intestinal perforation 1

Diagnostic Algorithm

First-Line Testing (Obtain Before Antibiotics)

Blood Culture 1, 2, 3

• Collect 2-3 blood cultures of 20 mL each in adults (larger volumes needed because bacteremia is low at 0.3 CFU/mL) 2, 3
• Highest yield in the first week of symptoms (sensitivity 40-80%) 2, 3
• Sensitivity approximately 50% compared to bone marrow culture 3
• This is the reference standard despite modest sensitivity 4

Second-Line Testing (When Blood Culture Negative or Antibiotics Already Given)

Bone marrow culture 1, 2, 3

• More sensitive than blood culture, especially if antibiotics have already been administered 1, 2, 3
• Should be reserved for cases where blood cultures remain negative despite high clinical suspicion 3
• In adults, 1 mL bone marrow culture gives similar results to 15 mL blood culture 6

Adjunctive Cultures (Weak Evidence, But May Help)

• Stool culture: May be beneficial as adjunct; culturing 2g rather than 1g increases isolation rate by 10.5% 1, 3, 6
• Duodenal fluid and urine cultures: May provide additional diagnostic yield 1, 2, 3
• Direct plating of blood buffy coat: Can be used where resources are scarce, with 50% sensitivity compared to standard blood culture 6

Molecular Testing (Emerging Role)

• PCR targeting flagellin gene: Shows superior sensitivity (58.2%) compared to blood culture (14.5%) in problematic cases with ambiguous clinical pictures 5
• Nucleic acid amplification tests (NAAT): Lack sensitivity for detection in blood but may be useful for rapid detection in research settings 3
• Panel-based multiplex molecular diagnostics: Can be used from stool and blood when available, but detect DNA not necessarily viable organisms 2, 3
• Critical caveat: All specimens testing positive by culture-independent methods should be cultured in clinical or public health laboratories for antimicrobial susceptibility testing and outbreak detection 3

Tests to AVOID

Serologic tests (including Widal test) should NOT be used 1, 3

• Poor performance characteristics with high false-positive rates (52.7% positive in suspected cases vs 45% in healthy controls) 3, 5
• Sensitivity only 61-64% with specificity 76-100% depending on operator 7
• Displays significant interoperator variability 7
• The IDSA gives this a strong recommendation with moderate evidence 1

Laboratory Findings (Supportive But Non-Specific)

Complete blood count 8

• Leukopenia with relative lymphocytosis (suggests enteric fever over viral fever) 8
• Monocyte predominance (suggests intracellular pathogen like Salmonella) 8
• Thrombocytopenia may be present 8
• CBC alone is insufficient for diagnosis due to non-specific nature 8

Common Pitfalls to Avoid

• Don't wait for culture results to treat severe cases: Start IV ceftriaxone immediately after obtaining cultures in patients with sepsis, fever ≥38.5°C from endemic areas, or encephalopathy 2
• Don't use small blood volumes: The low magnitude of bacteremia (0.3 CFU/mL) requires 20 mL per culture bottle 2, 3
• Don't rely on serology: Despite widespread use in endemic areas, serologic tests have unacceptable false-positive rates 1, 3, 5
• Don't forget public health reporting: Isolate submission is required for surveillance and outbreak investigation 3

Special Considerations by Clinical Context

If antibiotics already given: Bone marrow culture becomes the preferred specimen 1, 2, 3

In resource-limited settings: Direct buffy coat plating can provide 50% sensitivity when standard culture is unavailable 6, and PCR may offer superior diagnostic yield 5

For children <3 months: Third-generation cephalosporin is recommended empirically while awaiting culture results 2