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

Hospital Workup for Fever of Unknown Origin and Altered Mental Status

When a patient presents with both fever of unknown origin and altered mental status, this is a medical emergency requiring immediate empiric antimicrobial therapy for presumed meningoencephalitis while simultaneously pursuing urgent diagnostic evaluation—do not delay treatment for testing. 1

Immediate Actions (Within 1 Hour)

Initiate empiric antimicrobial therapy immediately with ceftriaxone 2g IV plus vancomycin 15-20 mg/kg IV to cover S. pneumoniae (including resistant strains) and N. meningitidis. 1 Add ampicillin 2g IV every 4 hours if the patient is >50 years old, immunocompromised, or has risk factors for Listeria monocytogenes. 1

Document specific clinical features including:

• Presence or absence of headache and neck stiffness 1
• Type and distribution of any rash (petechial rash with meningitis suggests N. meningitidis in 92% of cases) 1
• Seizure activity 1
• Signs of shock (hypotension, prolonged capillary refill time) 1

Diagnostic Criteria for Encephalitis

The altered mental status component meets the major criterion for encephalitis if it has lasted ≥24 hours with no alternative cause identified. 2 For probable or confirmed encephalitis, the patient must have ≥3 of the following minor criteria:

• Documented fever ≥38°C within 72 hours before or after presentation 2
• Generalized or partial seizures not fully attributable to a preexisting disorder 2
• New onset focal neurologic findings 2
• CSF WBC count ≥5/mm³ 2
• Abnormal brain parenchyma on neuroimaging suggestive of encephalitis 2
• Abnormal EEG consistent with encephalitis 2

Essential Diagnostic Studies (Do Not Delay Treatment)

Immediate Laboratory Testing:

Blood work (obtain before antibiotics if possible, but do not delay treatment):

• CBC with differential to assess for leukopenia, thrombocytopenia, or lymphopenia 1
• Metabolic panel to evaluate for hyponatremia and renal dysfunction 1
• At least 3 sets of blood cultures 3
• Glucose level (hypoglycemia is the most common metabolic cause of seizures and altered mental status) 2
• Inflammatory markers (ESR, CRP) 3, 4

Peripheral blood smear if any travel history exists, as malaria must be diagnosed immediately and is a medical emergency. 5 Treat as malaria until proven otherwise if travel to endemic areas occurred. 5

Lumbar Puncture:

Perform urgently but do not delay antibiotics if LP cannot be done immediately. 1 The LP should be done after antibiotics are started if there are contraindications or delays. 1

CSF analysis should include:

• Cell count with differential 2
• Glucose and protein 2
• Gram stain and bacterial culture 1
• Consider viral PCR panel (HSV, VZV, enteroviruses) 2

Neuroimaging:

Obtain CT or MRI of the brain to look for:

• Abnormalities of brain parenchyma suggestive of encephalitis 2
• Focal lesions or mass effect 1
• Signs of increased intracranial pressure before LP 1

Critical Differential Diagnoses to Prioritize

Meningococcal Meningitis/Sepsis

Monitor frequently as patients can deteriorate rapidly even if initially appearing well. 1 High-risk features for fatal outcome include rapidly progressing rash, coma, hypotension and shock, lactate >4 mmol/L, low/normal WBC count, low platelets with coagulopathy, and absence of meningitis (sepsis alone). 1

Encephalitis (Viral, Autoimmune, or Other)

West Nile virus should be considered in endemic areas, particularly during mosquito season. 6 HSV encephalitis requires specific antiviral therapy with acyclovir. 2

Rickettsial Diseases (Rocky Mountain Spotted Fever, Ehrlichiosis)

If tick exposure history exists with thrombocytopenia/leukopenia, consider empiric doxycycline 100mg PO/IV twice daily. 1, 5 Early RMSF presentations lack the characteristic rash during the first 2-4 days. 1

Malaria

If travel to endemic areas within the past 2-10 days to several months, assess for severe malaria criteria including altered mental status, parasitemia >5%, severe anemia, renal impairment, hypoglycemia, and metabolic acidosis. 5 Start IV artesunate immediately if severe criteria present. 5

Special Population Considerations

Elderly Patients (>50 years):

Elderly patients are more likely to have altered consciousness and less likely to have neck stiffness or fever. 1 Always add ampicillin for elderly patients due to higher risk for Listeria and pneumococcal disease. 1

Immunocompromised Patients:

May not mount typical inflammatory response; CSF findings can be minimal. 1 Consider broader differential including fungal infections (cryptococcus, histoplasmosis). 1 Add ampicillin to empiric regimen. 1

Advanced Diagnostic Modalities (If Initial Workup Unrevealing)

If the patient stabilizes but diagnosis remains unclear after initial evaluation:

• [18F]FDG PET/CT has 84-86% sensitivity and 56% diagnostic yield for FUO, and should be performed within 3 days of initiating oral glucocorticoid therapy to avoid false negatives. 3
• Temporal artery biopsy in patients >55 years old 7
• Tissue biopsy (liver, lymph node, bone marrow) based on clinical indications has relatively high diagnostic yield 4, 7

Critical Pitfalls to Avoid

Do not withhold empiric antibiotics in patients with altered mental status and fever while awaiting diagnostic studies—mortality increases with delay. 1

Do not use high-dose steroids empirically, as they increase hospital-acquired infection risk, hyperglycemia, GI bleeding, and delirium without improving mortality, and mask inflammatory findings on subsequent imaging. 3

Avoid empiric antibiotics for stable FUO without altered mental status, as they obscure diagnosis and may be harmful if malignancy is present. 3, 4 However, the presence of altered mental status changes this calculus entirely—treat immediately. 1

Do not rely on axillary, tympanic, or temporal artery thermometers for diagnostic purposes; use central, oral, or rectal temperature measurement. 3