Diagnosis of Typhoid Fever
Blood culture is the gold standard for diagnosing typhoid fever and must be obtained before starting antibiotics, with bone marrow culture reserved for cases where antibiotics have already been given or blood cultures remain negative despite high clinical suspicion. 1
Primary Diagnostic Test
- Obtain 2-3 blood cultures of 20 mL each in adults before any antimicrobial administration to maximize detection, as the median magnitude of bacteremia in enteric fever is low at 0.3 colony-forming units/mL 1, 2
- Blood culture sensitivity ranges from 40-80%, with highest yield during the first week of illness 3, 2
- Two sets should be taken prior to any antibiotic therapy, with sensitivity up to 80% in typhoid 3
When Blood Cultures Are Negative or Unavailable
- Bone marrow culture has superior sensitivity (35-65% vs blood culture) and is particularly valuable if antimicrobial agents have been administered 3, 1, 2
- Cultures of stool, duodenal fluid, and urine may be beneficial to detect enteric fever, though these are weaker recommendations 3, 1
Essential Supporting Laboratory Tests
- Complete blood count: Look specifically for lymphopenia (common in typhoid) and thrombocytopenia 3, 2
- Comprehensive metabolic panel: Obtain baseline urea, electrolytes, and liver function tests, as hepatic involvement occurs frequently 2
- Malaria testing is mandatory in all febrile travelers from tropical areas using both thick/thin smears and rapid diagnostic test to exclude malaria 3, 2
Critical Clinical Context Required
- Document detailed travel history: Geographic locations visited, dates of travel, dates of symptom onset, and risk activities undertaken 3
- Most tropical infections become symptomatic within 21 days of exposure, with typhoid having a typical incubation period of 7-18 days (range 3-60 days) 3, 4
- Fever is present in 97-100% of cases, often high-grade and sustained, with associated headache, malaise, anorexia, and relative bradycardia 4
Tests to AVOID
- Serologic tests including the Widal test should NOT be used to diagnose enteric fever due to poor performance characteristics 3, 1
- The Widal test has low sensitivity (52-71%), low specificity (53-88%), and very poor positive predictive value (5.7-76%) 5, 6, 7
- Serologic evidence alone is not sufficient for diagnosis—isolation of Salmonella typhi from clinical specimens is required for confirmation 1
Molecular Testing Considerations
- Nucleic acid amplification tests (NAAT) lack sensitivity for detection of S. Typhi in blood but may be useful for rapid detection in research settings 1
- Panel-based multiplex molecular diagnostics detect DNA and not necessarily viable organisms, so clinical context must be considered when interpreting results 1
Common Pitfalls to Avoid
- Never start antibiotics before obtaining blood cultures, as this dramatically reduces diagnostic yield 1, 2
- Do not rely on single blood culture—obtain multiple large-volume specimens to maximize sensitivity 1, 2
- Do not miss complications such as intestinal perforation (typically occurring in the third week if untreated), gastrointestinal bleeding, or encephalopathy 4, 2
- Perform serial neurologic examinations regularly to detect encephalopathy, which develops in 10-15% of patients 2
Public Health Requirements
- Typhoid fever is a nationally notifiable disease and must be reported immediately to local/state health departments 2
- All specimens testing positive by culture-independent methods should be cultured in clinical or public health laboratories to ensure outbreak detection and enable antimicrobial susceptibility testing 1, 2
- Isolate submission is required for surveillance and outbreak investigation, particularly important as >70% of isolates from Asia are fluoroquinolone-resistant 2