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Oakley et al.

The search identified a total of 36 studies, of which 6 met inclusion criteria and were relevant to the diagnosis of CSF rhinorrhea with glucose testing. These are all cross sectional studies with level 3 evidence. Chan et al. 13 tested the use of glucose test strips by comparing their diagnostic sensitivity and specificity in 15 CSF rhinorrhea and otor rhea patients. They found that the test strips were nonspe cific (0% specificity) and poorly sensitive (80%) compared to beta-2 transferrin, which was considered the gold stan dard in this study. Warnecke et al. 14 retrospectively exam ined results in 19 patients tested with glucose test strips and found a sensitivity of 1.0, a specificity of 0.45, a positive predictive value of 0.57, and a negative predictive value of 1.0 when compared to the beta-2 transferrin results. A number of studies have shown glucose in otherwise normal patient nasal secretions. These studies started com ing out as early as the 1960s. Philips et al. 15 assessed the glucose content in the air way secretions of 19 healthy volunteers, 20 patients with acute viral rhinitis, 24 patients with diabetes mellitus, and 60 ventilated intensive care unit (ICU) patients. They found that glucose was undetectable in all healthy patients, was detected in 50% of acute viral rhinitis patients, 90% of di abetes mellitus patients, and in the endotracheal secretions of 52%of ICU patients. The conclusion from this study was that, although glucose is not detected in normal human air way secretions, it is detectable in settings of acute airway inflammation or hyperglycemia, both of which are com monly found in acute skull-base trauma patients. Along this same line, Wood et al. 16 evaluated if airway glucose detection could be elicited in 30 healthy volunteers, and at what blood glucose threshold. Subjects with normal glu cose tolerance were made hyperglycemic with either a 20% dextrose intravenous (IV) or 75 g per os (PO) glucose load. They found that glucose was detectable in nasal secretions at blood glucose levels of 121 to 175 mg/dL (6.7 to 9.7 mmol/L) and changes occurred within 10 minutes of blood glucose changes. Given these findings, one could argue that nasal discharge in patients at risk of CSF leak could be considered likely to contain CSF if the sample contained no blood, the patient was normoglycemic, and there were no signs of viral res piratory infection. However, because these criteria could be difficult to meet, particularly in the setting of a trau matic or iatrogenic leak or otherwise acutely ill patient, and false positives could lead to unnecessary interventions, those adopting this practice should do so with extreme cau tion. Overall, the findings of the studies mentioned in this section do not support the use of glucose testing to diagnose CSF rhinorrhea (Supporting material 3). 13–18 Aggregate grade of evidence: C (Level 3: 6 studies); Benefit: Noninvasive, quick test; Harm: High potential for misdiagnosis due to low speci ficity and sensitivity, with subsequent unnecessary inter ventions due to false positives; Cost: Low;

Benefits-harm assessment: Potential harm outweighs bene fits; Value judgments: None; Recommendation level: Recommendation against; Intervention: Avoiding glucose testing in diagnosing a CSF leak. Beta-2 transferrin Beta-2 transferrin is a glycoprotein that is present in CSF, but is not detected in nasal secretions or surrounding tissue, allowing it to be used as a marker for CSF leak. A total of 9 studies were identified relating to CSF rhinorrhea confirma tion with the use of beta-2 transferrin assay. Various testing methods were described in these studies, including isoelec tric focusing, immunofixation, and sodium dodecyl sul fate polyacrylamide gel electrophoresis (SDS-PAGE) with immunoblotting. Regardless of the testing method used, the sensitivity ranged from 87% to 100% 14, 19–24 and the specificity from 71% to 100%. 14, 19, 20, 22, 25 Of the 9 included studies, 1 is a case-control study and 8 are cross-sectional studies. In the Warnecke et al. 14 study, 205 patients with suspected CSF rhinorrhea or otorrhea had samples tested for beta-2 transferrin. Thirty-five were positive, of which 34 were verified to be true positives by clinical history, RNC, and intraoperative visualization. They reported a beta-2 transferrin sensitivity and speci ficity of 97% and 99%, with positive and negative pre dictive values of 97% and 99%, and therefore recom mended it be the primary screening method for possible CSF rhinorrhea. The primary objective of 4 of the identified studies was reporting the accuracy of a specific beta-2 transferrin testing method in comparison to established methods rather than highlighting the role of beta-2 transferrin in the diagnos tic algorithm for CSF rhinorrhea. 19, 20, 22, 23 However, the CSF samples used for these studies are from the same skull base CSF leak patient population, so they retain their valid ity. Two of these studies, McCudden et al. 22 and Gorogh et al. 20 compared the beta-2 transferrin testing accuracy be tween CSF leak samples and non-CSF samples from healthy donors. These studies had the largest subject numbers (63 and 241) of this group. Similarly, the primary objective of the Zapalac et al. 24 and Marshall et al. 21 studies were to demonstrate simplified algorithms for the diagnosis and management of CSF leaks, of which beta-2 transferrin was a part. Marshall et al. 21 reported that in 30 CSF leak patients, 18 were tested for beta-2 transferrin and all were positive. This was confirmed with intraoperative visualization and either IF or HRCT. Zapalac et al. 24 performed a retrospective chart review of diagnosis and management of CSF leak patients. Forty four underwent beta-2 transferrin testing and demonstrated 98% sensitivity. In addition to the reported accuracy of beta-2 transferrin testing, the cost of the test according to CMS is $37.90, compared to approximately $700 for RNC, an 18-fold

International Forum of Allergy & Rhinology, Vol. 6, No. 1, January 2016

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