Hospital Workup for Fever of Unknown Origin and Altered Mental Status

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The American College of Physicians recommends initiating empiric antimicrobial therapy immediately with ceftriaxone 2g IV plus vancomycin 15-20 mg/kg IV to cover S. pneumoniae and N. meningitidis in patients with fever of unknown origin and altered mental status 1
The Infectious Diseases Society of America suggests adding ampicillin 2g IV every 4 hours if the patient is >50 years old, immunocompromised, or has risk factors for Listeria monocytogenes 1
Documenting specific clinical features, including presence or absence of headache and neck stiffness, is crucial in patients with fever of unknown origin and altered mental status 1
The presence of a petechial rash with meningitis suggests N. meningitidis in 92% of cases, according to the Centers for Disease Control and Prevention 1

The altered mental status component meets the major criterion for encephalitis if it has lasted ≥24 hours with no alternative cause identified, as defined by the International Encephalitis Consortium 2
For probable or confirmed encephalitis, the patient must have ≥3 of the following minor criteria: documented fever ≥38°C, generalized or partial seizures, new onset focal neurologic findings, CSF WBC count ≥5/mm³, abnormal brain parenchyma on neuroimaging, or abnormal EEG, according to the International Encephalitis Consortium 2

Blood work, including CBC with differential, metabolic panel, and at least 3 sets of blood cultures, should be obtained before antibiotics if possible, but treatment should not be delayed, as recommended by the American College of Emergency Physicians 1
A peripheral blood smear should be performed if any travel history exists, as malaria must be diagnosed immediately and is a medical emergency, according to the World Health Organization 5
CSF analysis, including cell count with differential, glucose and protein, Gram stain and bacterial culture, and viral PCR panel, is essential in patients with fever of unknown origin and altered mental status, as recommended by the Infectious Diseases Society of America 2

Meningococcal meningitis/sepsis should be considered in patients with fever of unknown origin and altered mental status, and 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, according to the Centers for Disease Control and Prevention 1
Encephalitis, including viral, autoimmune, or other causes, should be considered in patients with fever of unknown origin and altered mental status, and HSV encephalitis requires specific antiviral therapy with acyclovir, as recommended by the Infectious Diseases Society of America 2

Elderly patients (>50 years) are more likely to have altered consciousness and less likely to have neck stiffness or fever, and should always receive ampicillin due to higher risk for Listeria and pneumococcal disease, according to the American Geriatrics Society 1
Immunocompromised patients may not mount typical inflammatory response, and CSF findings can be minimal, according to the Infectious Diseases Society of America 1

[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, as recommended by the Society of Nuclear Medicine and Molecular Imaging 3

Withholding empiric antibiotics in patients with altered mental status and fever while awaiting diagnostic studies increases mortality, according to the American College of Emergency Physicians 1
Using high-dose steroids empirically increases hospital-acquired infection risk, hyperglycemia, GI bleeding, and delirium without improving mortality, and masks inflammatory findings on subsequent imaging, as warned by the Infectious Diseases Society of America 3