In a 65-year-old woman with diabetes mellitus and hypertension who has had a ten-day fever, neutrophilic leukocytosis, markedly elevated C-reactive protein, mildly elevated procalcitonin, a normal chest X-ray but right‑lung crepitations and modest pyuria without urinary symptoms, could this be seronegative typhoid?

Seronegative Typhoid: Unlikely Primary Diagnosis in This Clinical Context

This presentation is highly atypical for typhoid fever and "seronegative typhoid" is not a recognized clinical entity—the term refers to negative serologic tests (Widal, Typhidot, Tubex), not a distinct disease variant. The clinical picture instead suggests a bacterial pneumonia or urinary tract infection requiring immediate empirical antibiotic therapy while pursuing definitive microbiologic diagnosis.

Why Typhoid Fever is Unlikely Here

Clinical Features Inconsistent with Enteric Fever

• Neutrophilic leukocytosis directly contradicts typhoid fever, which characteristically presents with leukopenia (found in 33% of cases) or normal white counts, not elevated neutrophils 1, 2, 3

• Enteric fever manifests as a bacteremic systemic illness with fever, headache, malaise, and abdominal pain—diarrhea is actually uncommon 4. This patient's presentation with respiratory findings (crepitations) and pyuria points away from typhoid 4

• The typical typhoid patient presents after 7-8 days of fever with relative bradycardia (paradoxical bradycardia with high fever in 57% of cases), not the acute presentation with tachycardia expected in bacterial pneumonia 2

Understanding "Seronegative" Results

• Serologic tests (Widal, Typhidot, Tubex) have poor sensitivity early in disease (58-67% even after day 5 of illness), so negative serology does not rule out typhoid if clinical suspicion is high 5, 6

• Blood cultures remain the gold standard for diagnosing typhoid fever (not serology), with 2-3 specimens needed before antibiotic administration 1, 4

• The Widal test at 1:160 titer has only 61% sensitivity in culture-confirmed cases, meaning 39% of true typhoid cases are "seronegative" by this test 3

What This Clinical Picture Actually Suggests

Most Likely Diagnoses

Community-acquired pneumonia with possible urinary tract infection:

• Right lung crepitations with elevated inflammatory markers (CRP markedly elevated, procalcitonin mildly elevated) strongly suggest bacterial pneumonia 7

• Procalcitonin elevation of 0.5 ng/mL or higher occurs within 2-3 hours of bacterial infection onset, with levels 0.6-2.0 ng/mL indicating systemic inflammatory response and 2-10 ng/mL suggesting severe sepsis 7

• Pyuria without urinary symptoms can represent asymptomatic bacteriuria or early pyelonephritis, particularly in diabetic patients 7

• Neutrophilic leukocytosis with elevated CRP (>50 mg/L has 98.5% sensitivity for bacterial sepsis) supports bacterial rather than typhoid etiology 7

Critical Immediate Actions Required

Obtain blood cultures (2-3 sets) immediately before antibiotics, as this remains the definitive diagnostic test if typhoid is truly considered 1, 4

Obtain sputum or deep tracheal aspirate for bacterial culture and Gram stain to identify the pneumonia pathogen 7

Replace urinary catheter (if present) and culture urine from the new catheter given pyuria, as catheter colonization can confound interpretation 7

Initiate empirical broad-spectrum antibiotics immediately (within 2 hours) covering community-acquired pneumonia pathogens, given the patient's age, comorbidities (diabetes, hypertension), and signs of systemic infection 7, 8

If Typhoid Must Still Be Considered

Epidemiologic Requirements

Recent travel to endemic areas (South Asia, Southeast Asia, Latin America, Sub-Saharan Africa) within the past 60 days is essentially mandatory for considering typhoid in developed countries 1, 2

• Mexico and El Salvador represent common countries of origin for typhoid cases presenting in the US 2

• Without travel history or exposure to endemic areas, typhoid probability approaches zero 1

Diagnostic Approach If Travel History Present

Blood cultures (not serology) are the only reliable diagnostic test, with sensitivity highest when obtained before antibiotics and during the first week of fever 1, 4, 5

Stool cultures should be obtained if diarrhea develops, though they are less sensitive than blood cultures early in disease 1

Chest imaging (CT preferred over plain radiograph) should characterize the pulmonary findings, as typhoid can rarely cause pulmonary complications, though this is uncommon 4

Critical Pitfalls to Avoid

Do not delay empirical antibiotics for pneumonia/sepsis while awaiting typhoid serology or cultures, as bacterial pneumonia in a diabetic patient can rapidly progress to septic shock 7, 8

Do not rely on negative Widal or other serologic tests to exclude typhoid if clinical suspicion is genuinely high based on travel history—only blood cultures can definitively exclude the diagnosis 5, 6, 3

Do not attribute neutrophilic leukocytosis to typhoid fever, as this finding essentially rules out the diagnosis 1, 2, 3

Do not overlook the possibility of tuberculosis if fever persists despite appropriate antibiotics, particularly given the pulmonary findings and diabetes (immunocompromised state) 7, 1