What blood tests, other than culture, can help differentiate between bacterial and viral infections in a general adult population?

Blood Tests to Differentiate Bacterial from Viral Infections

Use procalcitonin (PCT) as your primary biomarker: levels <0.25 ng/mL effectively rule out bacterial infection, while levels >0.5 ng/mL strongly indicate bacterial infection, with superior accuracy compared to traditional markers like CRP or white blood cell counts alone. 1

Primary Diagnostic Approach

Procalcitonin Testing

• PCT <0.25 ng/mL has high negative predictive value for ruling out bacterial infections and antibiotics may be safely withheld 1
• PCT >0.5 ng/mL with neutrophil predominance strongly suggests bacterial infection requiring antimicrobial therapy 1
• Serial PCT measurements are more valuable than single measurements, particularly in critically ill patients 1
• PCT outperforms CRP and routine laboratory parameters as a sole discriminator 1, 2

C-Reactive Protein (CRP)

• Traditional acute phase reactants like CRP should not be used as sole discriminators due to wide overlap between bacterial and viral infections and lack of reliable cut-off points 1, 3
• CRP >50 mg/L has 98.5% sensitivity and 75% specificity for identifying probable or definite sepsis 4
• CRP of 260 mg/L is markedly elevated and highly specific for bacterial infection 4
• Estimated CRP velocity (eCRPv) - calculated as admission CRP divided by hours since symptom onset - improves diagnostic accuracy: eCRPv >4 mg/L/h is highly indicative of bacterial infection, particularly when absolute CRP is 100-150 mg/L 5

Complete Blood Count with Differential

• Absolute band count ≥1,500 cells/mm³ is the most diagnostically powerful marker with a likelihood ratio of 14.5 for bacterial infection 4
• Neutrophil percentage >90% carries a likelihood ratio of 7.5 for bacterial infection 4
• Left shift (≥16% band neutrophils) has a likelihood ratio of 4.7 for bacterial infection, even with normal total WBC 4
• WBC ≥14,000 cells/mm³ has a likelihood ratio of 3.7 for bacterial infection 4
• Obtain manual differential count to assess for left shift and absolute band count, as automated differentials may miss these critical findings 4

Advanced Biomarker Panels

Multi-Protein Host-Response Assays

• The MeMed BV assay (measuring tumor necrosis factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and CRP) distinguishes bacterial from viral infections with 93.8% sensitivity and 89.8% specificity in febrile children 2
• This assay significantly outperforms CRP alone (sensitivity 88.2%, specificity 73.2%) and procalcitonin alone (sensitivity 63.1%, specificity 82.3%) 2, 6
• The assay produces equivocal results in approximately 11.7% of cases 2

Host mRNA Expression Panels

• A 29-messenger RNA host-response classifier (IMX-BVN-2) from whole blood showed area under the curve of 0.90 for bacterial infections and 0.83 for viral infections 7
• Complement receptor expression on neutrophils, particularly CR1 (CD35), can differentiate bacterial from viral infections with 98% sensitivity and 97% specificity when combined with standard laboratory data 8

Molecular Pathogen Detection

Multiplex PCR Testing

• Multiplex PCR for respiratory pathogens identifies viral etiology and reduces antibiotic use by 22-32% when a viral pathogen is detected 9, 1, 3
• Rapid nucleic acid amplification tests (NAATs) have higher sensitivity than antigen detection tests with turnaround times suitable for emergency department decision-making 9
• Key to clinical utility is short turnaround time providing point-of-care information that meaningfully impacts antimicrobial prescribing 9

Blood Cultures

• Blood cultures should be obtained immediately before antibiotic administration when bacterial infection is suspected 1, 4
• Positive in only 10% of bacterial infections but remain critical for pathogen identification and antimicrobial stewardship 1, 3

Site-Specific Testing

Cerebrospinal Fluid Analysis

• CSF neutrophilic predominance with CSF:plasma glucose ratio <0.5 indicates bacterial meningitis, while lymphocytic predominance with normal glucose strongly suggests viral meningitis 1, 3
• CSF lactate <2 mmol/L effectively rules out bacterial meningitis 3
• CSF PCR for HSV-1, HSV-2, VZV, and enteroviruses should be performed in all suspected encephalitis cases 9
• Intrathecal HSV-specific IgG antibodies detected 10-14 days after illness onset can establish diagnosis when early CSF was not tested by PCR 9
• CSF IgM detection for flaviviruses indicates intrathecal antiviral immune response 9

Integrated Diagnostic Algorithm

Initial Assessment (Within 1 Hour)

• Obtain CBC with manual differential, PCT, and CRP simultaneously 1, 4
• Assess clinical trajectory: duration of symptoms, fever pattern (>3 days suggests bacterial), and progression versus improvement 1, 3
• Look for "double-sickening" pattern where symptoms worsen after initial improvement, indicating bacterial superinfection 1, 3

Interpretation Strategy

• If PCT <0.25 ng/mL AND no left shift AND symptoms improving: bacterial infection unlikely, withhold antibiotics 1
• If PCT >0.5 ng/mL OR absolute band count ≥1,500 cells/mm³ OR neutrophils >90%: bacterial infection likely, initiate antibiotics 1, 4
• If intermediate values (PCT 0.25-0.5 ng/mL, CRP 100-150 mg/L): calculate eCRPv; if >4 mg/L/h, treat as bacterial 5
• Consider multiplex PCR for respiratory symptoms to identify viral pathogens and guide antibiotic discontinuation 9, 1

Common Pitfalls to Avoid

• Do not rely on purulent secretions alone - both bacterial and viral infections produce purulent discharge 3
• Do not use CRP or WBC count as sole discriminators without considering PCT and clinical trajectory 1, 3
• In older adults or immunocompromised patients, left shift has particular diagnostic importance due to atypical presentations 4
• Intrathecal immune responses may be delayed or absent when antiviral therapy is started early in encephalitis 9
• Serial measurements are more valuable than single measurements for monitoring treatment response 1, 4