Initial Workup of High-Grade Fever with Chills (5 Days, No Localization)
Begin with chest radiograph, at least two sets of blood cultures (60 mL total blood), complete blood count with differential, comprehensive metabolic panel including liver function tests, urinalysis with culture, and if any central venous catheter is present, simultaneous central and peripheral blood cultures for differential time to positivity 1.
Core Diagnostic Approach
The systematic workup should proceed algorithmically based on clinical context and initial findings:
Immediate Laboratory and Imaging Studies
Blood cultures: Collect at least two sets (ideally 60 mL total) drawn one after the other from different sites. This is critical as pyogenic infections are the most common cause of fever with chills 1, 2. If a central venous catheter is present, sample at least two lumens simultaneously with peripheral draws to calculate differential time to positivity 1.
Chest radiograph: This is a best-practice statement recommendation for all febrile patients, as pneumonia is the most common infection causing fever in this setting 1. Even without respiratory symptoms, perform this routinely given the high prevalence and the low positive predictive value requiring a low threshold for imaging.
Complete blood count with differential: Look specifically for neutrophilic leukocytosis (suggests bacterial infection), lymphocytosis (viral), or atypical patterns like marked leukocytosis with hyperferritinemia (consider autoinflammatory conditions like adult-onset Still's disease if infectious workup negative) 3, 4.
Comprehensive metabolic panel with liver function tests: Elevated transaminases, alkaline phosphatase, or bilirubin would trigger abdominal imaging even without abdominal symptoms 1.
Urinalysis and urine culture: Urinary tract infection is a common source; look for dysuria, suprapubic tenderness, or positive culture 5.
Temperature Monitoring Considerations
Use oral or rectal temperatures rather than less reliable methods (axillary, tympanic, temporal artery, or chemical dot thermometers) 1. Central monitoring (bladder catheter thermistors, esophageal) is preferred only when these devices are already in place.
Conditional Second-Tier Investigations
If Initial Workup Is Negative
CT imaging: If recent thoracic, abdominal, or pelvic surgery occurred, perform CT of the operative area when fever persists and initial workup is unrevealing 1. For non-surgical patients with abdominal symptoms or abnormal liver tests, proceed to formal abdominal ultrasound 1.
Do NOT routinely perform abdominal ultrasound if there are no abdominal signs, symptoms, liver function abnormalities, or recent abdominal surgery 1. This is a common pitfall—avoid shotgun imaging without clinical indication.
Advanced Imaging for Persistent Fever
If diagnostic tests fail to establish etiology after comprehensive initial workup, consider 18F-FDG PET/CT (sensitivity 85-100%) if transport risk is acceptable 1. This is particularly useful after 3+ weeks of fever meeting fever of unknown origin criteria 6.
Critical Pitfalls to Avoid
Do not assume atelectasis causes fever—this has not been demonstrated despite common belief 5.
Do not use rapid molecular blood tests without concomitant blood cultures—they should supplement, not replace, traditional cultures 1.
Do not routinely use antipyretics unless the patient specifically values comfort from temperature reduction 1. Fever itself is not harmful in most cases and may impair diagnostic assessment.
Do not delay blood cultures for antibiotic administration in a patient with 5 days of fever and chills—this suggests possible bacteremia requiring urgent cultures before empiric therapy.
Special Considerations for This 5-Day Duration
At 5 days, this does not yet meet fever of unknown origin criteria (requires >3 weeks) 6, but the lack of localization after this duration warrants aggressive initial workup. The presence of chills strongly suggests bacteremia or pyogenic infection 2, making blood cultures and chest radiograph the highest yield initial tests. If the patient appears toxic or has compromised vital functions, hospitalization is mandatory 2.