What is the sensitivity of Polymerase Chain Reaction (PCR) and Adenosine Deaminase (ADA) in Cerebrospinal Fluid (CSF)?

Sensitivity of PCR and ADA in CSF for Diagnosis of Tuberculous Meningitis

PCR has a sensitivity of 87-100% and specificity of 98-100% for detecting common meningeal pathogens in CSF, while ADA has a sensitivity of 79-93% and specificity of 91-97% depending on the cutoff value used. 1, 2

PCR Sensitivity and Specificity in CSF

• PCR for common meningeal pathogens shows excellent diagnostic performance:

  • Sensitivity: 87-100%
  • Specificity: 98-100% 1
  • Maintains high sensitivity even when cultures are negative due to prior antibiotic treatment

• For specific pathogens, PCR performance varies:

  • Herpes simplex virus: Sensitivity 96-98%, specificity 95-99% 2
  • Multiplex PCR for bacterial meningitis (N. meningitidis, H. influenzae, S. pneumoniae): Sensitivity 94%, specificity 96% 1
  • M. tuberculosis: Sensitivity 44.5-48%, specificity 92% 3, 4, 5

• PCR maintains diagnostic utility for up to 48 hours after antibiotic initiation, while cultures may become negative within 2-4 hours 1

ADA Sensitivity and Specificity in CSF

• ADA sensitivity and specificity are highly dependent on the cutoff value used:

  • At 4 U/L cutoff: Sensitivity >93%, specificity <80% 2
  • At 8 U/L cutoff: Sensitivity <59%, specificity >96% 2
  • At 10 U/L cutoff: Sensitivity 92.5%, specificity 97% 3, 4
  • At 6.65 U/L cutoff: Sensitivity 85.3%, specificity 84.3% 6

• Meta-analyses of ADA in CSF for tuberculous meningitis:

  • First meta-analysis (10 studies): Sensitivity 79%, specificity 91% using thresholds of 9-10 U/L 2
  • Second meta-analysis (13 studies): Showed sensitivity/specificity trade-off based on threshold 2

Comparative Performance for Tuberculous Meningitis

• For tuberculous meningitis specifically:

  • PCR for M. tuberculosis: Sensitivity 44.5-48%, specificity 92% 3, 4, 5
  • ADA at 10 U/L cutoff: Sensitivity 92.5%, specificity 97% 3, 4

• Direct comparison studies show ADA is more sensitive than PCR for tuberculous meningitis diagnosis 3, 4

Clinical Considerations and Limitations

• PCR limitations:

  • Sensitivity decreases significantly with low pathogen loads (e.g., cryptococcal meningitis) 1
  • False positives can occur, though infrequently 1
  • For Epstein-Barr virus, false positives may occur due to latently infected mononuclear cells 2

• ADA limitations:

  • Optimal cutoff values vary between studies and populations
  • ADA levels correlate with CSF protein, absolute lymphocyte count, and disease stage 3
  • Not specific for tuberculosis; can be elevated in other conditions

• The Infectious Diseases Society of America recommends ADA measurement in suspected TB meningitis (conditional recommendation, low-quality evidence) 2

For optimal diagnostic accuracy in suspected tuberculous meningitis, combining ADA (using appropriate cutoff values) with PCR provides complementary information, as ADA offers higher sensitivity while PCR provides good specificity.