What is the appropriate inpatient workup for a patient presenting with fever of unknown origin (FUO) and altered mental status (AMS)?

Inpatient Workup for Fever of Unknown Origin and Altered Mental Status

Immediately initiate empiric antimicrobial therapy with ceftriaxone 2g IV plus vancomycin 15-20 mg/kg IV, and add ampicillin 2g IV every 4 hours if the patient is >50 years old, immunocompromised, or has risk factors for Listeria monocytogenes, before completing the diagnostic workup. 1

Immediate Actions and Empiric Treatment

• Start antibiotics immediately after obtaining blood cultures, as withholding empiric antibiotics while awaiting diagnostic studies increases mortality in patients with altered mental status and fever 1
• Ceftriaxone 2g IV plus vancomycin 15-20 mg/kg IV covers S. pneumoniae and N. meningitidis, the most common bacterial causes of meningitis 1
• Add ampicillin 2g IV every 4 hours for patients >50 years, immunocompromised, or with Listeria risk factors, as elderly patients are more likely to have altered consciousness and less likely to have neck stiffness or fever 1
• Document specific clinical features including presence or absence of headache, neck stiffness, and petechial rash, as petechial rash with meningitis suggests N. meningitidis in 92% of cases 1

Essential Diagnostic Criteria Assessment

The combination of fever and altered mental status requires evaluation for encephalitis:

• Major criterion: Altered mental status lasting ≥24 hours with no alternative cause identified 2, 1
• Minor criteria (≥3 required for probable/confirmed encephalitis): documented fever ≥38°C within 72 hours, generalized or partial seizures not fully attributable to preexisting disorder, new focal neurologic findings, CSF WBC count ≥5/mm³, abnormal brain parenchyma on neuroimaging, or abnormal EEG consistent with encephalitis 2, 1

Initial Laboratory Workup

Obtain before antibiotics if possible, but do not delay treatment:

• At least 2 sets (ideally 3 sets) of blood cultures from different anatomical sites, totaling at least 60 mL of blood 2, 1, 3
• If central venous catheter present, obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity 2, 3
• CBC with differential, comprehensive metabolic panel including liver function tests 1, 3
• Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate 3
• Peripheral blood smear if any travel history exists, as malaria is a medical emergency requiring immediate diagnosis 1

Cerebrospinal Fluid Analysis

Lumbar puncture is essential unless contraindicated:

• Perform imaging study (non-contrast CT) before lumbar puncture if focal neurologic findings suggest disease above foramen magnum, to exclude mass lesions or obstructive hydrocephalus 2
• If bacterial meningitis suspected and lumbar puncture delayed for imaging, start empirical antibiotics after blood cultures obtained 2
• CSF studies must include: cell count with differential, glucose and protein, Gram stain and bacterial culture, and viral PCR panel 2, 1
• In patients with intracranial devices, obtain CSF from the reservoir; if CSF flow to subarachnoid space is obstructed, also obtain CSF from lumbar space 2
• For patients with ventriculostomies who develop stupor or meningitis signs, remove catheter and culture the tip 2

Initial Imaging Studies

• Chest radiograph is mandatory for all patients with fever of unknown origin, as pneumonia is the most common infection in ICU patients who develop fever 2, 3
• Non-contrast head CT before lumbar puncture if focal neurologic findings present 2
• Brain MRI with contrast if encephalitis suspected and initial workup unrevealing 1

Surgical Patients Specific Workup

• For patients with recent thoracic, abdominal, or pelvic surgery, perform CT of the operative area in collaboration with surgical service if etiology not identified by initial workup 2, 3
• Perform formal diagnostic ultrasound of abdomen for patients with abdominal symptoms, abnormal liver tests (elevated transaminases, alkaline phosphatase, or bilirubin), or recent abdominal surgery 2, 3
• Avoid routine abdominal ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities 2, 3

Advanced Imaging When Initial Workup Unrevealing

• 18F-FDG PET/CT has 84-86% sensitivity and 56% diagnostic yield for fever of unknown origin 1, 3
• Should be performed within 3 days of initiating oral glucocorticoid therapy to avoid false negatives 1, 3
• Consider for critically ill patients with fever when other diagnostic tests have failed to establish etiology, if transport risk is acceptable 2, 3

Critical Differential Diagnoses to Consider

Meningococcal meningitis/sepsis:

• High-risk features for fatal outcome include rapidly progressing rash, coma, hypotension/shock, lactate >4 mmol/L, low/normal WBC count, low platelets with coagulopathy, and absence of meningitis 1

Encephalitis (viral, autoimmune, or other):

• HSV encephalitis requires specific antiviral therapy with acyclovir 1
• Immunocompromised patients may not mount typical inflammatory response, and CSF findings can be minimal 1

Other infectious causes:

• Consider plague in patients from endemic areas (southwestern United States) 4
• Evaluate for malaria in patients with travel history 1

Non-infectious causes:

• CPPD deposition disease can present with fever and altered mental status in elderly patients; examine joints carefully 5

Special Population Considerations

Elderly patients (>50 years):

• More likely to have altered consciousness and less likely to have neck stiffness or fever 1
• Always receive ampicillin due to higher risk for Listeria and pneumococcal disease 1

Immunocompromised patients:

• May not mount typical inflammatory response 1
• CSF findings can be minimal 1
• Consider broader differential including opportunistic infections 1

Critical Pitfalls to Avoid

• Never withhold empiric antibiotics while awaiting diagnostic studies in patients with altered mental status and fever, as this increases mortality 1
• Avoid high-dose steroids empirically without specific indication, as they increase hospital-acquired infection risk, hyperglycemia, GI bleeding, and delirium without improving mortality, and mask inflammatory findings on subsequent imaging 1, 3
• Do not use rapid molecular tests on blood as replacement for blood cultures; they should only be used concomitantly with conventional blood cultures 2, 3
• Avoid empirical antibiotic therapy in non-neutropenic, non-critically ill patients with fever of unknown origin alone (without altered mental status), as most cases resolve spontaneously 3, 6
• Do not systematically remove central venous catheters in clinically stable patients unless microbiological evidence of catheter-related infection exists 3

Prognosis and Follow-up

• Up to 75% of fever of unknown origin cases resolve spontaneously without definitive diagnosis 3, 6
• Negative 18F-FDG PET/CT can predict favorable prognosis through spontaneous remission of fever 3
• Daily surveillance required for neutropenic patients under antibiotics to evaluate response, adverse effects, and emergence of secondary infections 3