Early Diagnosis of Sepsis Using Serum Biomarkers

Terence Chan; Frank Gu

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

Five-year View

Recent advances in molecular biology and biochemistry will lead to the discovery of new biomarkers for sepsis. The bottleneck challenge in the diagnosis of sepsis is determining the diagnostic relevancy of biomarkers with absolute certainty. The keys to verifying their diagnostic relevancies are standardization in study methodology and use of assays with better detection limits. Assays capable of lower functional detection limits should be readily available for these purposes within the next 5 years as several are already in development, while new technologies will allow improvements to existing ones. The ongoing development of POCT kits for other diseases may also be beneficial for sepsis biomarker research. Designs from these kits can be applied towards developing a sepsis diagnostic kit that may ultimately provide greater accuracy and faster results over current assays. The standardization of study methodology is a complicated task and may not occur within the next 5 years. Researchers should seize the opportunity at current annual conferences on sepsis and biomarker research to achieve some consensus on methodology standards.

In parallel, general consensus in the scientific community regarding the diagnostic relevancies of the current sepsis biomarkers needs to be established within the next few years. Consequently, the direction of research will need to evolve from single-centre to multicentre studies to reduce the limitation of generalization of small data sets. Sepsis often presents alongside other conditions; due to this complexity, a single 'golden' biomarker may not exist, thus research should shift more focus on to assessing the combined diagnostic capabilities of multiple biomarkers.

Complementary research paths also exist and should be explored. Firstly, as sepsis results from systemic infection, the most diagnostically relevant sepsis biomarkers should be studied for their potential towards early diagnosis of general infections. Results from these studies can be applied to the development of POCT kits designed to monitor sudden homeostatic imbalances, indicating that the body is diseased before symptoms are presented. Secondly, some research should be devoted to designing and testing a rigorous, multiplex POCT kit for sepsis within the next 5 years, which would be beneficial for both method standardization in future research and clinical usage in rural and low income communities.

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Financial & competing interests disclosure
This work was financially supported by Natural Sciences and Engineering Research Council of Canada. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Table 1. Summarizing the components of the diagnostic accuracy of a biomarker.
Diagnostic measure	Definition	100% indicates
Sensitivity	True positives/(true positives + false negatives)	All detected diseased samples are truly diseased
Specificity	True negatives/(true negatives + false positives)	All detected healthy samples are truly healthy
PPV	True positives/(true positives + false positives)	Only truly diseased samples are detected as diseased
NPV	True negatives/(true negatives + false negatives)	Only truly healthy samples are detected as healthy
PLR	Sensitivity/(1 specificity)	Ratio specifies that a positive test outcome is more likely to indicate a diseased state
NLR	(1 – sensitivity)/specificity	Ratio specifies that a negative test outcome is more likely to indicate a nondiseased state

NLR: Negative likelihood ratio; NPV: Negative predictive value; PLR: Positive likelihood ratio; PPV: Positive predictive value.

Table 2. Reported diagnostic accuracy values of C-reactive protein, procalcitonin, serum amyloid A, mannan and antimannan, and IFN-γ-inducible protein 10.
Biomarker	Cutoff value	Diagnostic accuracy values (%)				Ref.
Biomarker	Cutoff value	Sensitivity	Specificity	PPV	NPV	Ref.
CRP	1.56–110 mg/l	30–97.2	75–100	31–100	81–97	[5,20,27,28,34,37–40]
PCT	0.3–8.05 ng/ml	74.8–100	70–100	55–100	56.3–100	[4,9,21,34,37,38,40,53]
SAA	8–68 mg/l	76.4–98.4	92.3–100	85–100	58–99	[4,28,40]
M	0.1–1 ng/ml	67–78	73–100	58–100	72.7–87	[29,45]
M and AM	0.1–0.25 ng/ml; 2.6–4 AU/ml^†	73–100	73.9–80	36–80	95–100	[29,70]
IP-10	260–1700 pg/ml	67–93	59.4–89	77^‡	97^‡	[52,72,73]

^†Cutoff value for AM.
^‡Only reported by one study.
AM: Antimannan; AU: Arbitrary units; CRP: C-reactive protein; IP-10: IFN-g-inducible protein 10; M: Mannan; NPV: Negative predictive value; PCT: Procalcitonin; PPV: Positive predictive value; SAA: Serum amyloid A.

Table 3. Assays measuring C-reactive protein.
Assay	Manufacturer	Lower detection limit (mg/l)^†	Sample used	Ref.
IMx system	Abbott Laboratories (IL, USA)	0.05^‡	Serum	[41]
BN II analyzer	Dade Behring (IL, USA)	5	Serum	[4]
BN ProSpec analyzer	Dade Behring (IL, USA)	0.16	Serum	[20,42]
CRPLX Tina-quant kit	Roche-Hitachi (Basel, Switzerland)	0.4	Serum	[28,39,44,64]
Advia 1650 analyzer	Bayer HealthCare Diagnostics (Leverkusen, Germany)	N/A	Serum	[48]
Micros CRP 200	Horiba Medical (Montpellier, France)	2^§	Serum	[44]
Automated turbidmetric analyzer	Boehringer-Mannheim (Ingelheim, Germany)	3	Serum	[27]
Vitros 250 Dry Chemistry System	Ortho Clinical Diagnostics (NJ, USA)	7	Plasma	[43]
QuickRead CRP	Orion Diagnostica (Espoo, Finland)	8	20 μl of whole blood	[5]
NycoCard CRP	Axis-Shield PoC AS (Dundee, Scotland)	8	5 μl of whole blood	[5,37,38]

^†If functional sensitivity values were not made available, the reported lower detection limits are listed, which may be lower than the functional sensitivity values.
^‡Stated in [90].
^§Stated on manufacturer's website.
N/A: Not available.

Table 4. Available assays measuring procalcitonin.
Assay	Manufacturer	Lower detection limit^§	Run time (per measurement)	Sample used	Ref.
LUMItest – immunoluminometric assay	BRAHMS	0.5 ng/ml	2.75 h	20 μl of serum	[4,9,17,33,38,40,45,46,63]
LUMItest^†	BRAHMS	0.3 ng/ml	1.5 h	Serum	[91]
LIAISON BRAHMS PCT – immunoluminometric assay	DiaSorin	0.1 ng/ml	40 min	Serum	[21,27,91]
Kryptor – TRACE assay	BRAHMS	0.06 ng/ml	50 min, 19–45 min^‡	Serum	[56,63,64,91]
PCT kit – ELISA	USCNLIFE	7.8 pg/ml	4.5–5 h^#	100 μl of serum or plasma^#	[15]
VIDAS – enzyme-linked fluorescent immunoassay	bioMérieux	0.09 ng/ml	20 min	Serum	[34,53,56,62,91]
PCT-Q – semi-quantitative immunochromatographic kit	BRAHMS	0.5 ng/ml	20–45 min	200 μl of serum or plasma	[34,37,43,57,59,91]

^†Revised version.
^‡Subsequent serial measurements.
^§If functional sensitivity values were not made available, the reported lower detection limits are listed, which may be lower than the functional sensitivity values.
#Stated on manufacturer's website.

Table 5. Available assays measuring serum amyloid A.
Assay	Manufacturer	Lower detection limit (mg/l)^†	Sample used	Ref.
BN II analyzer	Dade Behring (IL, USA)	68	Serum	[4,40]
BN ProSpec analyzer	Dade Behring (IL, USA)	0.758	Serum	[20,48]
IMx system	Abbott Laboratories (IL, USA)	0.02^‡	Serum	[41]
SAA ELISA kit	BioSource International (CA, USA)	1.9	Serum	[47]
LZ TEST 'Eiken' SAA kit	Eiken Chemical Co. Ltd (Japan)	0	3 μl of serum	[28]
N Latex SAA kit	Siemens Healthcare Diagnostics (IL, USA)	0.75^§	Serum	[44]

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