What is the cause of elevated white blood cell (WBC) count and altered mental status with no identifiable source of infection?

From the Guidelines

A high white blood cell count with altered mental status and no obvious infection source requires prompt empiric broad-spectrum antibiotic therapy while continuing to search for the infection. I recommend starting with vancomycin plus a carbapenem (meropenem 1g IV q8h or imipenem-cilastatin 500mg IV q6h) or cefepime 2g IV q8h plus metronidazole 500mg IV q8h, as suggested by the most recent guidelines 1. Obtain blood cultures (at least two sets from different sites), urine culture, chest X-ray, and consider lumbar puncture to evaluate for meningitis if no contraindications exist, as recommended by the ESCMID guideline 1.

Key Considerations

• Complete neurological assessment, metabolic panel, liver function tests, and ammonia levels are essential to rule out metabolic causes of altered mentation.
• Consider CT imaging of chest, abdomen, and pelvis to identify occult infection sources like abscesses.
• This aggressive approach is necessary because sepsis with encephalopathy can rapidly progress to septic shock and has high mortality, as highlighted in the study by Soares et al 1.
• The elevated white count indicates immune system activation, while altered mental status suggests either direct CNS infection or septic encephalopathy from systemic inflammation.
• Maintain adequate hydration, monitor vital signs closely, and reassess antibiotic coverage once culture results return, typically within 48-72 hours.

Diagnostic Approach

• The diagnosis of encephalitis requires one of the following: pathologic confirmation of brain inflammation, defined pathologic, microbiologic, or serologic evidence of acute infection, or laboratory evidence of an autoimmune condition strongly associated with encephalitis, as stated in the consensus statement of the international encephalitis consortium 1.
• CSF analysis is crucial in the diagnosis of bacterial meningitis, and the CSF leucocyte count is the best diagnostic parameter for differentiating bacterial meningitis from other diagnoses, as shown in the study by the ESCMID guideline 1.
• Neuroimaging plays a crucial role in the evaluation of patients with suspected encephalitis, and MRI is the radiologic modality of choice, as recommended by the international encephalitis consortium 1.

From the FDA Drug Label

Cryptococcal meningitis: In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B (0. 3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3

The patient's altered mentation and high white count suggest a possible diagnosis of cryptococcal meningitis. However, the source of infection is unknown.

• Abnormal mental status is a predictor of death in patients with cryptococcal meningitis.
• A cerebrospinal fluid white blood cell count is necessary to further evaluate the patient's condition. Given the information from the study 2, it is crucial to determine the source of infection to provide appropriate treatment.

From the Research

Altered Mentation and High White Blood Cell Count

• A high white blood cell count can be caused by various factors, including infections, inflammatory conditions, and malignant diseases 3
• In cases where the source of infection is unknown, empirical antibiotic therapy may be initiated, with meropenem being a suitable option for serious bacterial infections 4
• Meropenem has a broad spectrum of activity against Gram-positive and Gram-negative pathogens, including extended-spectrum beta-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae 4

Diagnostic Approach

• A repeat complete blood count with peripheral smear may provide helpful information, such as types and maturity of white blood cells, uniformity of white blood cells, and toxic granulations 3
• The leukocyte differential may show eosinophilia in parasitic or allergic conditions, or it may reveal lymphocytosis in childhood viral illnesses 3
• Symptoms suggestive of a hematologic malignancy include fever, weight loss, bruising, or fatigue, and if malignancy cannot be excluded, referral to a hematologist/oncologist is indicated 3

Treatment Considerations

• Meropenem is well tolerated and has the advantage of being suitable for administration as an intravenous bolus or infusion 4
• Therapeutic drug monitoring (TDM) of meropenem can be beneficial in guiding therapy, especially in critically ill patients and those with impaired renal function 5
• The combination of vancomycin with piperacillin/tazobactam significantly increases the risk of acute kidney injury compared with other broad-spectrum antibiotic combinations, including meropenem 6