What is the differential diagnosis of typhoid fever?

Differential Diagnosis of Typhoid Fever

The differential diagnosis of typhoid fever must prioritize malaria exclusion first, followed by dengue fever, tuberculosis, and brucellosis, with the diagnostic approach guided by travel history, fever pattern, and specific laboratory findings including blood cultures before antibiotics. 1, 2

Priority #1: Malaria - Must Be Excluded First

Malaria should always be ruled out first in any patient with fever returning from tropical areas within the last year, as it represents a potentially fatal febrile illness that requires immediate diagnosis 1, 2. The diagnostic approach includes:

• Three thick blood films/rapid diagnostic tests (RDTs) over 72 hours are required to confidently exclude malaria 1
• Thick films read by experts have sensitivity equivalent to RDTs, but blood films are necessary for speciation and parasite count 1
• Thrombocytopenia can be seen in both malaria and typhoid, making this a key overlapping feature 1

Other Critical Infectious Diseases to Consider

Dengue Fever

Dengue is endemic in the same Southeast Asian and South Asian regions as typhoid and presents with remarkably similar symptoms 2. Key differentiating features:

• High fever, headache, and malaise overlap significantly with typhoid 2
• Thrombocytopenia and lymphopenia are common in both dengue and typhoid 1
• PCR testing is necessary for definitive dengue diagnosis when suspected 2

Tuberculosis (Particularly Miliary TB)

Miliary tuberculosis causes prolonged fever with subacute or chronic onset and should be strongly considered, especially in immunocompromised patients 2. This is particularly important when:

• Fever persists beyond the typical acute presentation window
• Constitutional symptoms are prominent
• Patient has risk factors for TB exposure

Brucellosis

Brucellosis presents with prolonged fever and subacute/chronic onset, requiring serologic testing for diagnosis 2. Consider when:

• Fever pattern is undulating or prolonged
• Patient has exposure to unpasteurized dairy or livestock
• Geographic exposure includes Mediterranean, Middle East, or Latin America

Diagnostic Laboratory Approach

Blood Cultures - The Gold Standard

Obtain 2-3 blood culture specimens (20 mL each in adults) BEFORE initiating any antibiotics 2, 3. This is critical because:

• Blood cultures have up to 80% sensitivity in typhoid 1
• Highest yield occurs in the first week of symptoms 4
• Pre-antibiotic cultures are essential for definitive diagnosis 2

Complete Blood Count Findings

Key hematologic patterns help differentiate between conditions 1:

• Lymphopenia: Common in viral infections (dengue, HIV) AND typhoid 1
• Thrombocytopenia: Seen in malaria, dengue, acute HIV, typhoid, and severe sepsis 1
• Eosinophilia (>0.45 × 10⁹/L): Suggests parasitic or fungal causes, NOT typical of typhoid 1
• Leukopenia: Present in approximately one-third of typhoid cases 5

Additional Essential Tests

• Stool cultures for Salmonella, Shigella, Campylobacter, and Yersinia if diarrhea is present 2
• Serologic tests for brucellosis and dengue guided by clinical presentation and epidemiologic history 2
• Urinalysis: Proteinuria and hematuria suggest leptospirosis rather than typhoid 1
• Liver function tests: Hepatocellular and cholestatic patterns can occur in typhoid, though acute liver failure is rare 6

Geographic and Epidemiologic Clues

Travel history to South and Southeast Asia (particularly India) is the highest risk factor, with incidence exceeding 100 cases per 100,000 person-years in these regions 4, 7. Important considerations:

• Incubation period is 7-18 days (range 3-60 days) 4
• Most tropical infections become symptomatic within 21 days of exposure 1
• In developed countries like the US, typhoid is primarily seen in returning travelers 4, 5

Clinical Presentation Patterns That Aid Differentiation

Classic Typhoid Features

• Sustained high-grade fever (present in 97-100% of cases) with insidious onset over 3-7 days 4, 3
• Relative bradycardia (fever with paradoxical bradycardia noted in 12/21 patients in one series) 5
• Gastrointestinal symptoms: constipation OR diarrhea, abdominal pain 4, 3
• Nonproductive cough 4, 3

Features NOT Typical of Typhoid

Calf pain and tenderness are specifically documented as features of Rocky Mountain Spotted Fever, NOT typhoid fever 3. When evaluating fever with calf pain, consider tickborne rickettsial diseases instead 3.

Common Pitfalls to Avoid

• The "step-ladder" fever pattern is NOT reliably present in all typhoid cases 4
• The Widal test alone is insufficient for diagnosis and should not be relied upon (positive in only 7/11 cases in one study) 4, 5
• Do not miss complications: intestinal perforation (typically third week if untreated), gastrointestinal bleeding, or encephalopathy 4
• Absence of fever at presentation does not rule out typhoid if there is a documented fever history 4

When to Initiate Empiric Antibiotics

Initiate empiric antibiotics after culture collection in patients with 4:

• Clinical features of sepsis or severe illness with documented fever ≥38.5°C in travelers from endemic areas
• Signs of septic shock or encephalopathy
• Suspected intestinal perforation or gastrointestinal bleeding

Empiric therapy options include fluoroquinolones (ciprofloxacin) or azithromycin depending on local resistance patterns, or third-generation cephalosporins (ceftriaxone) for severe cases 4. Note that multidrug-resistant isolates are increasingly common, particularly from South Asia 7, 6.