What are the diagnostic criteria for typhoid fever in a patient with fever, headache, and abdominal pain, potentially with a history of travel to areas with poor sanitation?

Typhoid Fever Diagnostic Criteria

Confirmed typhoid fever requires isolation of Salmonella typhi from blood, stool, or other clinical specimens—serologic evidence alone is insufficient for diagnosis. 1

Laboratory Confirmation (Required for Definitive Diagnosis)

Blood culture is the gold standard and must be obtained in all suspected cases. 2, 3

• Draw 2-3 specimens of 20 mL each (adults) prior to antibiotics, as bacteremia levels are low (0.3 CFU/mL) 3
• Highest yield occurs within the first week of symptom onset (sensitivity 40-80%) 1, 3
• Bone marrow culture is more sensitive than blood culture, especially if antibiotics have already been given, though more invasive 3
• Stool and urine cultures become positive after the first week (stool sensitivity 35-65%, urine 0-58%) 1
• Culture-independent molecular diagnostics can be used from stool and blood when available 3

Clinical Case Definition

A clinically compatible case includes the following features 1:

• Sustained fever (present in 97-100% of cases, often high-grade) 2
• Headache 1, 2
• Malaise 1, 2
• Anorexia 1, 2
• Relative bradycardia 1
• Constipation or diarrhea 1
• Nonproductive cough 1

Important caveat: Many mild and atypical infections occur, and the classic "step-ladder" fever pattern is not reliably present in all cases. 1

Case Classification

• Confirmed case: A clinically compatible case that is laboratory confirmed (isolation of S. typhi) 1
• Probable case: A clinically compatible case that is epidemiologically linked to a confirmed case in an outbreak setting 1

Serologic Testing Limitations

The Widal test is NOT recommended for diagnosis due to lack of sensitivity and specificity. 1, 4

• Serologic evidence alone is not sufficient for diagnosis 1, 4
• False positives occur from cross-reactions with other Salmonella species, previous typhoid vaccination, prior infection, or other febrile illnesses 4
• False negatives occur from prior antibiotic treatment or immunosuppression 4
• In endemic areas, healthy individuals commonly have elevated background antibody titers, particularly in those over 10 years of age 5

Newer rapid serological tests (TyphiDot, TUBEX, Multi-Test Dip-S-Ticks) detecting IgM against specific antigens have shown mixed results 1:

• TyphiDot: 79% sensitivity, 89% specificity 6
• TUBEX: 78% sensitivity, 89% specificity 6
• These may serve as adjuncts but cannot replace culture confirmation 6, 7

Antibiotic Susceptibility Testing Pitfall

When testing isolates for antibiotic sensitivity, ciprofloxacin disc testing alone is unreliable. 1

• Only if the organism is also sensitive to nalidixic acid on disc testing should the isolate be considered sensitive to fluoroquinolones 1
• This is critical given increasing fluoroquinolone resistance, particularly in isolates from South and Southeast Asia 1, 3

Adjunctive Diagnostic Tools

Abdominal ultrasound can support diagnosis when serology is equivocal and cultures are negative, particularly in endemic areas 8:

• Splenomegaly (100% in culture-positive cases) 8
• Bowel wall thickening, particularly ileal and cecal (85%) 8
• Mesenteric lymphadenopathy (77%) 8
• Thickened gallbladder (62%) 8
• Hepatomegaly with normal parenchymal echotexture (31%) 8

Timeline Considerations

• Incubation period: 7-18 days (range 3-60 days) 1
• Onset: Insidious rather than abrupt 1
• Blood culture yield: Highest in first week 1, 3
• Stool/urine culture yield: Increases after first week 1
• Complications: Occur in 10-15% of patients, more likely if illness duration exceeds 2 weeks 1, 2

High-Risk Populations Requiring Lower Threshold for Testing

• Travelers returning from endemic areas, particularly South and Southeast Asia 1, 2
• Individuals visiting friends and relatives in endemic regions 1
• Immunocompromised individuals 2
• Those with chronic liver disease 2
• Malnourished children 2

Critical Diagnostic Pitfalls to Avoid

• Do not rely on Widal test alone—isolation of organism is required for confirmation 1, 4
• Do not report asymptomatic carriage as typhoid fever 1
• Do not delay blood culture collection if antibiotics are being considered—obtain cultures first 3
• Do not miss complications: intestinal perforation (typically third week), gastrointestinal bleeding, or encephalopathy, which occur in 10-15% of patients 1, 2
• Do not assume vaccination provides complete protection—it provides incomplete protection against typhoid and does not protect against paratyphoid 1