Early Diagnosis of Sepsis Using Serum Biomarkers

Terence Chan; Frank Gu

Disclosures

Expert Rev Mol Diagn. 2011;11(5):487-496. 

In This Article

Expert Commentary

The main challenge facing future biomarker research, and in reviewing biomarker studies, is the lack of standard operating protocols for each specific biomarker. There is high variability in study designs, including small sample sizes,[16,21,27,34,37–40,43–46,48,62,73] heterogeneous population types,[27,33,34,46] population type specificity[21,37,39,45,46,62] and high variation in assay equipment. Several studies also suffer from poor presentation and/or application of statistical analysis of data,[4,16,21,27,33,34,37,38,40,41,43–45,48,53,62] which may lead to improper interpretation of results by the readers. Many studies are single-centre studies involving small sample sizes, which may result in incorrect representation of the general population, but this restriction is a result of the high costs of running studies in the clinical setting and incorporating multiple centres. However, other issues pertaining to study design require the establishment of standardization among biomarker research studies.[17,22,58] Efforts have already been made to establish reporting and analysis standards, such as Standards for Reporting of Diagnostic Accuracy[81,82] and Grading of Recommendations Assessment, Development and Evaluation,[83,84] and the research community should endeavour to adopt these standards on a global scale for all future studies.

Although CRP and PCT are both commonly studied biomarkers for sepsis and infection, some studies suggest neither can be used in singular capacities. CRP shows a 12–24 h delay in elevated levels to infection,[15,58] so it may not be a sensitive marker during initial measurement.[72] Serum PCT levels can naturally rise 3–24 h after exercise.[58] In newborn infants, PCT also naturally increases to 2–3 ng/ml at 24 h after birth, returning to normal levels at 48–72 h after birth.[54] A few noninfectious diseases and conditions can also cause abnormally elevated levels of CRP[4,14,42,77] or PCT.[17,25,58] In addition, some studies report CRP[27,28,34,40,43,46,72,80] and PCT[9,15,24,27,33] to be less diagnostically relevant than other potential biomarkers of sepsis. The current research suggests that a singular 'ideal' biomarker of perfect diagnostic relevance and accuracy does not yet exist.[14] However, the many studies reporting the usefulness of CRP, PCT and other molecules as biomarkers of sepsis cannot be ignored. To overcome this issue, multiple biomarkers must be used in combination to provide definitive diagnostic test results.

A possible strategy is described in Figure 1. Many of the studies reviewed have also demonstrated the use and/or need of measuring multiple markers in combination,[4,17,25,27,29,33,41,45,53,63,70] generally reporting improved DA values. POCT kit developers are also calling for the development of multiplex assays for various diseases,[85–88] emphasizing the need and benefits of multiplex POCT kits.

Figure 1.

A possible strategy for diagnosing the type of infectious cause of sepsis. CRP: C-reactive protein; IP-10: IFN-γ-inducible protein-10; PCT: Procalcitonin; SAA: Serum amyloid A.

The past decade in diagnostics has seen a growing interest in POCT kits due to the benefits they offer in the areas of personal care and medicine, which are elucidated in-depth in other review papers.[85,87] POCT kits share many of the same advantages of existing rapid and automated molecular-based tests; mainly that they offer fast diagnostic results, ideally within several minutes to under an hour. POCT kits also offer several advantages over existing rapid tests including: requiring no expertise or specialized training to operate;[85,86] providing easily interpretable diagnostic results;[85] being extremely portable and self-contained;[85,87] and requiring no technical manipulations of the samples.[85] These features are especially useful in rural and low income communities. Comparatively, the existing rapid tests, such as ELISA, PCR and FISH, require specialized laboratory equipment and highly trained technicians, both of which are not commonly available in rural and low resource areas. POCT kits have the power to perform similarly to laboratory diagnostic methods. Mtapuri-Zinyowera et al. reported that their POCT used for early diagnosis of HIV patients produced comparable results to the flow cytometers commonly used in laboratory settings.[89]

For the purposes of this article, only biomarkers directly quantifiable from the serum were extensively examined, as POCT kits typically operate with minimal sample manipulation. Further study of POCT kits for sepsis, specifically able to distinguish between bacterial, fungal and viral infectious causes, would provide substantial benefit in patient care, compared with already available diagnostic assays. There are two main benefits: firstly, knowing the type of infectious causes of sepsis would prevent broad antimicrobial use, thereby reducing occurrences of drug toxicity and drug-resistant microbes, and ultimately resulting in greater patient comfort; secondly, identifying the type of infectious cause would allow earlier use of specialized cultures and diagnostic tests specific to bacteria, fungi or viruses, leading to diagnostic results of greater sensitivity.

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