What is the differential diagnosis for a patient with suspected typhoid fever?

Differential Diagnosis for Suspected Typhoid Fever

When evaluating a patient with suspected typhoid fever, malaria must be ruled out first in any patient with fever returning from tropical areas within the last year, as it represents a major cause of potentially fatal febrile illness. 1

Priority Infections to Exclude Immediately

Malaria (First Priority)

• Perform thick blood smears three times within 72 hours to rule out malaria in all febrile patients with travel history to endemic areas 1
• Malaria and typhoid share overlapping clinical features including fever, headache, abdominal pain, and can both present with leukopenia, thrombocytopenia, and altered mental status 2
• Both diseases can progress to septic shock and encephalopathy, making differentiation clinically challenging 2

Dengue Fever

• Common in Southeast Asia and South Asia (the same regions where typhoid is endemic) 1
• Presents with high fever, headache, malaise, thrombocytopenia, and leukopenia—features that overlap significantly with typhoid 1
• Requires PCR testing for definitive diagnosis if clinical suspicion is high 1

Bacterial Infections in the Differential

Acute Bacterial Causes

• Obtain 2-3 blood cultures before antibiotic administration in all suspected cases, as blood culture is the gold standard for typhoid diagnosis 1, 3
• If diarrhea is present, perform stool cultures for Salmonella, Shigella, Campylobacter, and Yersinia 4, 1
• Consider other Salmonella infections (non-typhoidal) which can cause similar gastrointestinal symptoms but typically have shorter duration 4

Chronic/Subacute Bacterial Infections

• Tuberculosis (particularly miliary TB) should be considered in patients with prolonged fever and subacute onset, especially in immunocompromised hosts 4, 1
• Brucellosis can cause prolonged fever with subacute or chronic onset and requires serologic testing for diagnosis 4, 1
• Subacute bacterial endocarditis may present with sustained fever and constitutional symptoms 4

Other Infectious Causes to Consider

Based on Clinical Context

• Visceral leishmaniasis in patients from endemic areas presenting with chronic fever, splenomegaly, pancytopenia, and weight loss 4
• Acute schistosomiasis (Katayama fever) can present with fever, abdominal pain, and hepatosplenomegaly in travelers 4
• Rickettsial diseases (typhus) should be considered with fever, headache, and tick exposure history 4
• Viral hepatitis can cause fever, abdominal pain, and elevated liver enzymes 4

Respiratory Considerations

• Influenza, parainfluenza, respiratory syncytial virus, and adenovirus can cause fever and constitutional symptoms 4
• Mycoplasma pneumonia may present with fever and systemic symptoms, diagnosed with mycoplasma-specific IgM 4

Non-Infectious Causes

Hematologic/Oncologic

• Lymphoma and leukemia can present with prolonged fever, weight loss, and cytopenias 4
• Hemophagocytic lymphohistiocytic syndrome may mimic infectious presentations 4

Autoimmune

• Rheumatoid arthritis with Felty syndrome can cause fever, splenomegaly, and leukopenia 4
• Other autoimmune processes should be considered in patients with prolonged fever of unknown origin 4

Critical Diagnostic Approach

Initial Laboratory Workup

• Complete blood count: Look for leukopenia (present in some cases), lymphopenia, thrombocytopenia, and anemia 1, 5, 6
• Blood cultures (2-3 sets) before antibiotics—highest yield in first week of symptoms (sensitivity 40-80%) 1, 3
• Liver function tests: Elevated transaminases, alkaline phosphatase may be present 7
• Do NOT rely on Widal test alone—it lacks sensitivity and specificity and is positive in only 7/18 cases initially 3, 5

Timing Considerations

• Blood culture yield is highest in the first week of illness 3, 8
• Stool and urine cultures become positive after the first week (stool sensitivity 35-65%) 3
• Bone marrow culture is more sensitive than blood culture, especially if antibiotics have already been given 3

High-Risk Populations Requiring Lower Threshold for Testing

• Travelers returning from South and Southeast Asia (highest incidence >100 cases per 100,000 person-years) 1, 8
• Individuals visiting friends and relatives in endemic regions 3
• Immunocompromised patients (HIV/AIDS, transplant recipients) 1, 3
• Patients with chronic liver disease 3
• Malnourished children 3

Key Clinical Pitfalls to Avoid

• Do not assume absence of "step-ladder" fever pattern rules out typhoid—this classic pattern is not reliably present in all cases 8
• Do not miss complications: intestinal perforation (typically third week), gastrointestinal bleeding, encephalopathy, or septic shock 3, 8, 9
• Do not delay blood culture collection if antibiotics are being considered 3
• Relative bradycardia is present in only a minority of cases (6/24 in one series), so its absence does not exclude typhoid 5
• Average duration of fever before diagnosis can be 14 days (range up to 30 days), so prolonged fever should heighten suspicion 5