How is typhoid fever diagnosed in a patient with fever, headache, and abdominal pain, who has recently traveled to an area where typhoid fever is endemic?

Diagnosis of Typhoid Fever

Typhoid fever diagnosis requires isolation of Salmonella typhi from blood, stool, or other clinical specimens, with blood culture being the gold standard and having the highest yield within the first week of symptoms. 1, 2

Diagnostic Algorithm

Step 1: Clinical Suspicion

• Consider typhoid fever in any patient with sustained fever, headache, malaise, anorexia, relative bradycardia, constipation or diarrhea, and nonproductive cough who has traveled to an endemic area (particularly South/Southeast Asia). 1, 2
• Fever is present in 97-100% of cases, often high-grade and sustained. 2
• The incubation period is 7-18 days (range 3-60 days), with most patients presenting within one month of leaving endemic areas. 1, 2
• Onset is typically insidious rather than abrupt, with gradual worsening over 3-7 days. 2, 3

Step 2: Initial Laboratory Testing

Obtain blood cultures immediately (two sets prior to any antibiotic therapy) as they have sensitivity of 40-80% and the highest yield within the first week of symptom onset. 1, 2

Additional initial investigations include: 1

• Complete blood count: Look for lymphopenia (common in typhoid) or thrombocytopenia
• Liver function tests and renal function: May show various patterns of derangement
• Stool and urine cultures: Become positive after the first week (stool culture sensitivity 35-65%, urine culture 0-58%) 1

Step 3: Additional Diagnostic Considerations

• Bone marrow culture has higher sensitivity than blood culture but is more invasive and typically reserved for cases where blood cultures are negative despite high clinical suspicion. 1
• Exclude malaria first in all patients who have visited tropical countries within 1 year—perform three thick films/rapid diagnostic tests over 72 hours. 1

Tests to AVOID or Use with Extreme Caution

The Widal Test is NOT Recommended

The Widal test lacks sensitivity and specificity and should not be used for diagnosis. 1, 4

Key limitations: 4, 5

• Serologic evidence alone is not sufficient for diagnosis per CDC guidelines
• False positives occur due to previous typhoid vaccination, prior infection, cross-reactions with other Salmonella species, or other febrile illnesses
• False negatives occur with prior antibiotic treatment or immunosuppression
• Elevated antibody titers are detected in high proportions of healthy subjects in endemic areas

Rapid Diagnostic Tests (RDTs)

Newer rapid serological tests (Typhidot, TUBEX, Test-It Typhoid) have shown mixed results with moderate diagnostic accuracy: 1, 6, 7

• TUBEX: Average sensitivity 78%, specificity 87%
• Typhidot variants: Average sensitivity 78%, specificity 77% (when indeterminate results reported or not applicable)
• Test-It Typhoid: Average sensitivity 69%, specificity 90%

These tests may be useful when blood culture facilities are unavailable, but isolation of the organism remains required for confirmation. 1, 6

Critical Diagnostic Pitfalls

• Do not dismiss vague complaints of "feeling unwell"—malaise is a legitimate and common presenting symptom. 3
• Do not attribute sustained symptoms beyond 3-5 days solely to viral illness in travelers from endemic areas. 3
• Do not miss complications: Watch for signs of intestinal perforation (typically third week if untreated), gastrointestinal bleeding, or encephalopathy, which occur in 10-15% of patients. 1, 2
• Absence of fever at presentation does not rule out typhoid if there is a history of fever. 1
• The classic "step-ladder" fever pattern is not reliably present in all cases. 1

When to Initiate Empiric Treatment

Start empiric antibiotics after culture collection in patients with: 2

• Clinical features of sepsis or severe illness with documented fever ≥38.5°C in travelers from endemic areas
• Signs of septic shock or encephalopathy
• Strong clinical suspicion with unstable condition

Use intravenous ceftriaxone as first-line empiric therapy due to increasing fluoroquinolone resistance (>70% of isolates imported into the UK are fluoroquinolone-resistant). 1, 2

Antibiotic Susceptibility Testing Caveat

When testing isolates, ciprofloxacin disc testing is unreliable—only consider the organism fluoroquinolone-sensitive if it is also sensitive to nalidixic acid on disc testing. 1