How should I systematically evaluate an adult with fever ≥38 °C lasting >24 hours, including history, physical examination, initial laboratory tests, and criteria for initiating empiric therapy?

Systematic Evaluation of Adult Fever ≥38°C Lasting >24 Hours

For an adult with fever ≥38°C persisting beyond 24 hours, begin with accurate temperature measurement using oral or rectal thermometry, perform a targeted physical examination focusing on high-yield infection sites, obtain a chest radiograph as the first imaging study, and reserve empiric antimicrobial therapy for patients with sepsis criteria or clinical deterioration—not for fever alone. 1, 2

Temperature Measurement and Definition

• Use oral or rectal thermometry exclusively for diagnostic decisions; tympanic, temporal-artery, and axillary methods are unreliable and should be avoided 2, 3
• Fever is defined as a single temperature ≥38.3°C (101°F), though some sources accept ≥38.0°C (100.4°F) as the threshold 2, 3
• Central temperature monitoring (bladder catheter thermistor, esophageal probe) should only be employed when such devices are already in place or when precise measurement is essential for diagnosis 2, 4

Focused History: Key Elements to Elicit

Recent exposures and procedures (past 60 days):

• All surgeries, procedures, or hospitalizations 2, 4
• Presence of any indwelling devices: urinary catheters, central venous lines, drains, prosthetic joints, or other implanted hardware 1, 2
• Recent medication changes, particularly antibiotics (mean onset of drug fever is 21 days after initiation) or chemotherapy 2, 4

Predisposing conditions:

• Diabetes mellitus (predisposes to skin infections and UTI) 1
• Chronic obstructive pulmonary disease (pneumonia risk) 1
• Dysphagia or impaired gag reflex (aspiration pneumonia) 1
• Chronic immobility (pressure ulcers) 1
• Immunocompromising conditions: malignancy, transplant, neutropenia 4

Symptom review:

• Respiratory symptoms: cough, dyspnea, sputum production 2
• Urinary symptoms: dysuria, frequency, flank pain 1
• Gastrointestinal symptoms: abdominal pain, diarrhea 1
• Neurologic changes: altered mental status, headache, focal deficits 1

Physical Examination: High-Yield Sites

Perform a systematic examination of the following areas to locate potential infection sources:

• Oropharynx and conjunctiva: pharyngitis, dental abscesses, conjunctivitis 2, 4
• Skin and pressure areas: cellulitis, surgical site infections, decubitus ulcers, IV site inflammation 2, 4
• Chest: auscultate for crackles, consolidation, or pleural rubs 2
• Heart: new murmurs suggesting endocarditis 1
• Abdomen: tenderness, organomegaly, surgical scars 2, 4
• Perineal and perirectal regions: abscesses, particularly in diabetic or immunocompromised patients 1, 2
• "Silent sources": otitis media, retained foreign bodies (e.g., tampons), hidden decubitus ulcers 1, 4

Vital Signs and Clinical Severity Assessment

Assess for signs of sepsis or septic shock requiring urgent intervention:

• Hypotension (systolic BP <90 mmHg or MAP <65 mmHg) 1, 2
• Altered mental status or confusion 1, 2
• Tachycardia (heart rate >90 bpm) 1
• Tachypnea (respiratory rate >20/min) or hypoxemia 1, 2
• Evidence of organ dysfunction: oliguria, elevated lactate, coagulopathy 1

If any of these criteria are present, initiate empiric antimicrobial therapy within 1 hour after obtaining cultures, as delays increase mortality 1, 2, 3

Initial Laboratory Testing

Baseline studies for all febrile adults:

• Complete blood count (CBC) with differential 2, 3
• Comprehensive metabolic panel (electrolytes, renal function, liver enzymes) 2, 3
• Urinalysis (but do not culture urine in catheterized patients lacking pyuria or urinary symptoms, as asymptomatic bacteriuria does not require treatment) 2, 3

Blood cultures:

• Obtain at least two sets (total ≈60 mL) from separate anatomical sites simultaneously if septic shock is present or if results will alter management 1, 2, 3
• Do not obtain blood cultures reflexively in stable patients without clinical suspicion of bacteremia 1

Biomarkers for bacterial infection:

• Measure procalcitonin (PCT) or C-reactive protein (CRP) when the probability of bacterial infection is low-to-intermediate, to help rule out bacterial etiology 1, 2, 3
• When the probability of bacterial infection is high, do not rely on PCT or CRP to exclude infection; proceed with empirical therapy based on clinical judgment 1, 2

Respiratory pathogen testing:

• Perform nucleic-acid-amplification panel for viral pathogens if upper-respiratory symptoms (cough, rhinorrhea) are present 2, 3
• Test for SARS-CoV-2 by PCR when community transmission levels justify testing 2, 3

Initial Imaging Studies

Chest radiograph:

• Obtain a chest X-ray on all febrile adults as the first imaging study, because pneumonia is the most common serious infection causing fever 2, 3, 4
• Point-of-care ultrasound (POCUS) can identify pleural effusions and parenchymal lung pathology with high specificity if chest X-ray is abnormal 4

Abdominal imaging:

• Perform abdominal ultrasound or CT if abdominal symptoms, recent surgery, or abnormal liver enzymes are present 4
• Do not order abdominal imaging without clinical suspicion 4

Advanced imaging for fever of unknown origin:

• If the initial workup fails to locate a source and ESR/CRP is elevated, consider 18F-FDG PET/CT (provided transport risk is acceptable); this modality has a sensitivity of 85–100% for detecting occult infection or inflammation 2, 3

Criteria for Initiating Empiric Antimicrobial Therapy

Initiate empiric antibiotics immediately (within 1 hour after cultures) if:

• Sepsis or septic shock criteria are met (hypotension, altered mental status, tachycardia, tachypnea, organ dysfunction) 1, 2, 3
• Clinical deterioration or severe illness despite initial management 1, 2
• Neutropenia or severe immunocompromise with fever ≥38.3°C 2, 3

Choose initial agents based on:

• Suspected source of infection (e.g., pneumonia, UTI, intra-abdominal) 1, 3
• Patient risk factors for multidrug-resistant organisms (recent hospitalization, prior antibiotic use, healthcare exposure) 1, 3
• Local antimicrobial susceptibility patterns 1, 3
• For suspected resistant organisms, provide broad-spectrum coverage including MRSA and resistant Gram-negative bacilli, potentially using combination therapy 1, 3

Do NOT initiate empiric antibiotics if:

• The patient is hemodynamically stable without sepsis criteria 1, 3
• Fever is the only abnormality and no source is identified 1, 3
• Empirical antimicrobial therapy has not been shown to be effective in fever of unknown origin and should be avoided except in neutropenic, immunocompromised, or critically ill patients 5, 3

Noninfectious Causes to Consider

Recognize that fever may arise from numerous noninfectious etiologies 1, 2, 4:

• Medication-related: drug fever (antibiotics, chemotherapy), malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome 1, 4
• Vascular: venous thromboembolism, pulmonary infarction, acute myocardial infarction, stroke 1, 4
• Inflammatory: gout, pancreatitis, Dressler syndrome (pericardial injury syndrome), transplant rejection 1, 4
• Endocrine: thyroid storm, adrenal insufficiency 1, 4
• Malignancy: tumor fever, cytokine release syndrome 1, 4
• Other: acalculous cholecystitis, fat emboli, heterotopic ossification, nonconvulsive status epilepticus 1

Critical Pitfalls to Avoid

• Do NOT employ automatic order sets that reflexively trigger laboratory and imaging studies; clinical assessment should guide testing to prevent unnecessary investigations and resource waste 1, 2, 3
• Do NOT use unreliable temperature measurement methods (tympanic, temporal-artery, axillary) for diagnostic decision-making 2, 3, 4
• Do NOT routinely culture urine in catheterized patients lacking pyuria or urinary-tract infection symptoms, because asymptomatic bacteriuria is common and does not require treatment 2, 3
• Do NOT delay identification and treatment of the underlying infection while focusing on temperature control; fever management is symptomatic, not curative 3
• Do NOT aggressively treat fever with antipyretics or cooling devices unless needed for patient comfort, as this does not improve mortality and may impair immune response 2, 3
• Do NOT overlook "silent sources" of infection: otitis media, decubitus ulcers at the sacrum or back, perianal abscesses, retained foreign bodies 1, 4
• Do NOT assume infection without clinical evidence; up to 75% of fever of unknown origin cases resolve spontaneously without a definitive diagnosis 4, 5

Management of Persistent Fever Without Clinical Deterioration

• Persistent fever alone in a hemodynamically stable patient does NOT justify changing or adding antibiotics empirically 3
• Verify that acetaminophen has been administered at 1 g every 4–6 hours (maximum 4 g/day) before deeming antipyretic therapy ineffective 3
• Adding vancomycin empirically for persistent fever alone is not supported; randomized trials show no benefit in time-to-defervescence when added after 60–72 hours 3
• Do not switch empirical monotherapy without clear clinical or microbiologic indication, unless broader spectrum coverage is required 3