Infection Can Lead to False Negatives for Cerebrospinal Fluid β-2 Transferrin

Researchers have found that the presence of Streptococcus pneumoniae in cerebrospinal fluid (CSF) can lead to false-negative β-2 transferrin (β2TRNSF) test results and misdiagnosis that may detrimentally affect healthcare decisions for patients.

Free passage of bacterial flora from the nasal cavity and paranasal sinuses through a CSF fistula into the cranium may pose increased risk for meningitis and encephalitis. Thus, early diagnosis and treatment of CSF leakage could decrease the risk of a lethal infection. Although β2TRNSF is a highly reliable marker for diagnosing cases of CSF leakage (even in CSF contaminated with blood or other secretions)—it has not been examined in the presence of central nervous system bacterial infection.


In a prospective analysis, a team led by Nir Hirshoren, MD, at the Hebrew University School of Medicine–Hadassah Medical Center (Jerusalem, Israel) examined β2TRNSFdetection in artificially contaminated CSF as a research model. Sterile (tested for sterility) CSF was drawn from 9 prospectively-recruited neurosurgical patients. CSF samples were contaminated in vitro by controlled spiking with bacteria, chosen for ability to cause meningeal neurosurgical-related infections: Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus (MSSA), Staphylococcus epidermidis, or Pseudomonas aeruginosa.

β2TRNSF analysis was performed using qualitative immunoblotting electrophoresis and quantitative enzyme-linked immunosorbent assay (ELISA). Two time points were examined, following immediate inoculation (t0 ) and following an overnight incubation (t18 ), over various bacterial-load concentrations. In this study, only S. pneumoniae was observed to significantly affect β2TRNSF detection. At both the t0 and t18 time points following S. pneumoniae inoculation, β2TRNSF was not detected when immunoblotting electrophoresis was used; quantitative analysis using ELISA demonstrated significant β2TRNSF concentration decrease.

A secondary objective of the study was to explore whether the disappearance of β2TRNSF in the assays is due to a passive or active mechanism. The researchers suspected that in some cases of bacterial infections, β2TRNSF might be adsorbed, degraded, or consumed by bacteria. CSF inoculated with S. pneumoniae was also examined in the presence of the non-cell-wall antibiotic ciprofloxacin, which led to the same results. Since β2TRNSF detection decreased also with inactivated (i.e. + ciprofloxacin) S. pneumoniae, a passive process was suggested, possibly due to adsorption via distinctive features of the S. pneumoniae cell wall not present in the other species examined.

The authors note that although the study was limited by a small sample number (n=9), potential bias was largely overcome by exploring different bacterial loads, examining diverse clinical bacterial species, and using two reliable assays. Further investigation in the clinical setting is needed, however the results indicate that, in the presence of a S. pneumoniae cerebral nervous system infection, using a β2TRNSF test for CFS leak detection may be deceiving and should be interpreted cautiously.

The authors further caution that the importance of β2TRNSF assays is limited to borderline, clinical-uncertainty cases. In other cases, a β2TRNSF negative result may not change a clinical decision regardless of CSF S. pneumoniae presence, and appropriate imaging modalities and surgery may be warranted anyway.

The study was reported by Korem M. et al. in the journal Laryngoscope, September 29, 2014, online ahead of print.

Related Links:
Hebrew University School of Medicine – Hadassah Medical Center
Hebrew University Hadassah Medical School