What is the cause of persistent high-grade fever with altered sensorium, normal CBC, impaired renal function, and normal LFTs and MRI brain, with pending blood culture results?

Differential Diagnosis: Persistent High-Grade Fever with Altered Sensorium and Acute Kidney Injury

The most likely causes in this clinical scenario are tickborne rickettsial diseases (particularly ehrlichiosis), bacterial sepsis with encephalopathy, or acute encephalitis—all requiring immediate empiric antimicrobial therapy while awaiting blood culture results. 1, 2

Immediate Diagnostic Priorities

Start empiric broad-spectrum antibiotics immediately (within 1 hour) after blood cultures are obtained, given the presence of altered sensorium and acute kidney injury (creatinine 2.3), which indicate organ dysfunction and potential sepsis. 2

Most Likely Infectious Etiologies

Tickborne Rickettsial Disease (Ehrlichiosis/Anaplasmosis):

• This presentation closely mirrors ehrlichiosis: high fever, altered sensorium (occurs in up to 20% of cases), elevated creatinine, and normal CBC initially 1
• Thrombocytopenia and transaminitis typically develop but may be absent early 1
• Normal MRI brain is characteristic—neuroimaging is usually normal or nonspecific in ehrlichiosis despite CNS involvement 1
• CSF may show lymphocytic pleocytosis in 50% of cases, but can be completely normal 1
• Critical point: Doxycycline must be started empirically if any suspicion exists, as delays worsen outcomes significantly 1

Bacterial Sepsis with Encephalopathy:

• Altered sensorium with fever and acute kidney injury strongly suggests septic encephalopathy 1, 2
• Normal CBC does not exclude serious bacterial infection, particularly in elderly patients or those with renal dysfunction 3
• Patients with end-stage renal disease often have altered fever responses and blunted inflammatory markers 3
• Empiric broad-spectrum coverage (anti-pseudomonal beta-lactam or carbapenem) is mandatory while awaiting cultures 2

Viral or Autoimmune Encephalitis:

• Altered mental status with fever can occur without CSF pleocytosis, particularly in immunocompromised states 1, 4
• Normal MRI does not exclude encephalitis—9% of HSV encephalitis cases present without fever, and imaging can be initially normal 4
• Empiric acyclovir should be added immediately given altered sensorium, as treatment delays significantly worsen outcomes 4

Recommended Empiric Treatment Regimen

Initiate triple therapy immediately:

• Doxycycline 100 mg IV/PO twice daily for rickettsial coverage 1
• Ceftriaxone 2g IV daily or anti-pseudomonal carbapenem for bacterial sepsis 2
• Acyclovir 10 mg/kg IV every 8 hours (adjusted for renal function) for possible viral encephalitis 4

Rationale for Empiric Triple Coverage

The combination addresses the three most life-threatening possibilities simultaneously while awaiting definitive diagnosis 1, 2, 4. This approach is supported by the case series showing that delayed treatment of any of these conditions significantly increases mortality 1, 2.

Additional Urgent Investigations Needed

Obtain immediately:

• Repeat lumbar puncture if not yet done—CSF cell count, protein, glucose, Gram stain, bacterial culture, HSV PCR, and consider rickettsial PCR if available 1
• Procalcitonin level—values >2 ng/mL suggest severe sepsis, >10 ng/mL indicates septic shock 1
• Peripheral blood smear—look for morulae (intracellular inclusions) suggestive of ehrlichiosis, though absence does not exclude diagnosis 1
• Rickettsial serology (acute and convalescent titers for Ehrlichia and Anaplasma) 1
• Skin examination for eschar or rash—particularly on lower extremities, scalp, and hidden areas 1, 5

Critical Clinical Pearls and Pitfalls

Do not wait for blood culture results before starting antibiotics—each hour of delay in septic patients increases mortality by 10% 2

Normal CBC does not exclude serious infection:

• Ehrlichiosis often presents with normal or only mildly elevated WBC initially 1
• Thrombocytopenia and transaminitis may develop later in the disease course 1
• Patients with renal dysfunction have altered inflammatory responses 3

Normal MRI brain does not exclude CNS infection:

• Ehrlichiosis typically has normal neuroimaging despite altered sensorium 1
• Early HSV encephalitis may have normal initial MRI 4
• Consider repeat imaging in 48-72 hours if clinical suspicion remains high 1

Normal or acellular CSF does not exclude encephalitis:

• Immunocompromised patients may have absent CSF pleocytosis despite severe CNS infection 1, 4
• Early viral encephalitis can present with normal CSF parameters 1

Geographic and Exposure Considerations

If rural exposure or endemic area:

• Scrub typhus presents identically: high fever, altered sensorium, renal dysfunction, with or without eschar 5
• Leptospirosis causes fever, renal failure, and altered mental status 5
• Both require doxycycline empirically 5

Travel history is essential:

• Recent travel to endemic areas mandates consideration of malaria, dengue, enteric fever, and rickettsial diseases 2
• Initiate empiric treatment for life-threatening tropical infections if clinical instability present 2

Monitoring and Supportive Care

Immediate interventions:

• Fluid resuscitation with 250-500 mL crystalloid boluses if hypotensive 2
• Serial lactate measurements every 2-4 hours 2
• Strict intake/output monitoring given acute kidney injury 2
• Continuous pulse oximetry and vital sign monitoring 2

Renal function considerations:

• Adjust acyclovir dosing for creatinine 2.3 (typically 5-10 mg/kg every 12-24 hours) 4
• Monitor for further deterioration—may require renal replacement therapy 1
• Renal dysfunction is an independent mortality risk factor in rickettsial disease 5

Expected Clinical Course

If ehrlichiosis/rickettsial disease:

• Defervescence typically occurs within 24-72 hours of doxycycline initiation 1
• Mental status normalizes over 3-5 days 1
• Convalescent serology (3-4 weeks later) confirms diagnosis retrospectively 1

If bacterial sepsis:

• Clinical improvement expected within 48-72 hours if appropriate antibiotic coverage 2
• Persistent fever beyond 72 hours mandates re-evaluation and imaging for occult abscess 1

Red flags requiring ICU transfer:

• Worsening mental status or seizures 2
• Hemodynamic instability despite fluid resuscitation 2
• Respiratory failure or oxygen saturation <92% 2
• Progressive renal failure requiring dialysis 5