Novel Diagnostic Methods to Identify External Ventricular Drain Associated Infections

In the literature, the reported incidence ranges between 1-35% of inserted drains. This disparity results from the lack of an international consensus on a definition for EVDIs and the use of various diagnostic criteria across studies. In a neurointensive care setting, clinical symptoms are often difficult to evaluate due to underlying illness. Cerebrospinal fluid (CSF) bacterial culture is the current golden standard of EVDI diagnostics. However, CSF bacterial cultures often take several days to finalize and prior use of antibiotics may further prolong culture incubation time or cause false negative cultures. It is seldom possible to delay treatment until the bacterial cultures have finalized. Additionally, due to the etiology of these infections, contamination and true positives can be difficult to distinguish based on the cultured bacteria alone. Thus, early identification of EVDIs are based on indirect signs of bacterial infection, namely CSF analysis of glucose, lactate, protein, leukocytes, and erythrocytes. In the neurocritically ill, CSF parameters are frequently confounded by intraventricular hemorrhage (IVH). Leukocytes and erythrocytes in particular may vary greatly depending on the IVH volume.

To adjust for IVH, the ratio of leukocytes and erythrocytes (LE ratio) in CSF is commonly used and is one of the main metrics in identifying EVDIs. The LE ratio is based on the assumption that erythrocytes and leukocytes are homogeneously distributed in the CSF. This assumption has previously not been questioned. However, it is clear from computed tomography (CT) scans that blood sediments in the ventricles, suggesting that a homogeneous distribution is unlikely. The LE ratio fails to account for the fact that the blood causes an aseptic inflammation in itself, resulting in immigration of leukocytes. Additionally, leukocytes, in particular granulocytes, may exhibit upwards floatation, or antisedimentation, a property shown to be exacerbated in critically ill patients. Thus, leukocytes may sediment at a slower rate than erythrocytes which may further skew the intraventricular CSF/blood distribution towards heterogeneity.

Due to the specific pathogens, patient characteristics, and confounding factors, early identification of EVDIs have proven difficult and no CSF parameter, by itself or in aggregate, have yet been shown to reliably predict or identify EVDIs. As such, algorithms based on routinely analyzed CSF parameters and clinical symptoms are ambiguous and diagnosis is often based on "expert-opinion". This results in an excessive use of broad spectrum antibiotics and a large variation in clinical practice, with up to 10-20 patients being treated for every true infection. Additionally, the main metric in EVDI diagnostics, the LE ratio, is based on the uncertain assumption that cells are homogeneously distributed in the CSF. If, and how, this affects routinely analyzed CSF parameters has yet to be studied. With the questionable precision of current indirect methods to identify EVDIs in mind, there is a need for more rapid and accurate tools for direct microbiological detection and identification in the diagnostics of EVDI.

The use of emerging bacterial DNA sequencing techniques in infectious diseases medicine increasing. Unfortunately, these techniques for CSF with primers covering the specific bacteria found in EVDIs have not yet been verified. Moreover, due to the lack of established around the clock work flows surrounding these methods, results from these techniques are not yet readily available within the time-frame needed to decide whether to instigate treatment. However, regular PCR methods have been shown to identify bacteria in a large portion of clinically suspected severe sepsis patients exhibiting negative blood cultures. Interestingly, this group had the highest mortality suggesting that the positive bacterial findings were not just due to the use of an oversensitive technique. Bacterial DNA sequencing techniques may have the potential to exhibit a higher sensitivity compared to conventional bacterial cultures within a smaller time frame.

16s ribosomal ribonucleic acid (16s rRNA) is a component of the prokaryotic ribosomal 30s subunit and is present in all prokaryotic lifeforms. The use of 16s rRNA sequencing have been shown to reliably identify bacteria in normally sterile body fluids, such as CSF, compared to bacterial cultures. 16s rRNA also have the advantage of being able to identify non viable bacteria, thus potentially exhibiting a greater sensitivity in patients who have been subjected to antibiotic treatment prior to sampling, making it a promising target for bacterial DNA sequencing. However, 16s rRNA sequencing have not been studied extensively for EVDIs.