Lab on a Chip · Lab on a Chip CRITICAL REVIEW Cite this: Lab Chip,2019,19,728 Received 16th October 2018, ... Point of care (POC) technologies based on biomolecular analysis provide

Lab on a Chip

CRITICAL REVIEW

Cite this: Lab Chip, 2019, 19, 728

Received 16th October 2018,Accepted 31st January 2019

DOI: 10.1039/c8lc01102h

rsc.li/loc

Point of care technologies for sepsis diagnosis andtreatment

Taylor Oeschger, a Duncan McCloskey, a Varun Kopparthy, b

Ankur Singhb and David Erickson *bc

Sepsis is a rapidly progressing, life threatening immune response triggered by infection that affects millions

worldwide each year. Current clinical diagnosis relies on broad physiological parameters and time consum-

ing lab-based cell culture. If proper treatment is not provided, cases of sepsis can drastically increase in se-

verity over the course of a few hours. Development of new point of care tools for sepsis has the potential

to improve diagnostic speed and accuracy, leading to prompt administration of appropriate therapeutics,

thereby reducing healthcare costs and improving patient outcomes. In this review we examine developing

and commercially available technologies to assess the feasibility of rapid, accurate sepsis diagnosis, with

emphasis on point of care.

Introduction

Sepsis is a life-threatening condition caused by the body's re-sponse to microbial infection, which triggers a cascade ofevents that can lead to organ failure and death.1 Global esti-mates suggest that there were 31.5 million cases of sepsis in2016, with 5.3 million resulting in death.2 The Center for Dis-ease Control reports that one in three fatalities in US hospi-tals are related to sepsis.3 Neonatal sepsis is also a major con-cern, with the World Health Organization estimating anannual death incidence of over 1 million.4

The current standard for clinical sepsis diagnosis, referredto as sequential organ failure assessment (SOFA), was definedby the Third International Sepsis Consensus Task Force in2016.5 This scoring system informs of cumulative organ dys-function that results from a dysregulated host response to in-fection. The SOFA score factors in respiration (arterial oxygenpartial pressure to fractional inspired oxygen), coagulation(platelet count), liver function (bilirubin levels), cardiovascu-lar function (mean arterial pressure or intervention), centralnervous system function (Glasgow Coma Scale), and renalfunction (creatinine and urine output).5 For each poorly func-tioning organ system, one point is assigned, with a score of 2points or more representing a positive sepsis diagnosis. Apositive SOFA score is associated with a hospital mortalityrate of >10%.5 Quick SOFA (qSOFA) offers a rapid alternative

to SOFA by using only a subset of the SOFA scoring includingaltered mentation, systolic blood pressure below 100 mm Hg,and a respiratory rate of 22 per minute or greater.5 qSOFAdoes not require laboratory testing and it can be repeated asneeded. SOFA replaces the standard established in 2001known as systemic inflammatory response syndrome (SIRS)criteria.6 SIRS scoring involves two or more of: temperaturegreater than 38 °C or less than 36 °C, heart rate above 90beats per minute, respiratory rate greater than 20 per minute,or white blood cell count greater than 12 000/μL or less than4000/μL.7 SOFA has shown greater prognostic accuracy whencompared to SIRS and qSOFA.8

Sepsis diagnosis has improved with the implementationof the SOFA scoring system; however, it still lacks specificityand requires multiple measurements. SOFA scoring leads tomisdiagnoses in approximately 30% of patients, leading tounnecessary administration of antibiotics, which increaseshospital costs and contributes to antibiotic resistance.9 Giventhat survival rate decreases by 7.7% for every hour delay inthe administration of antimicrobial therapy, rapid detectionis vital for patient survival.10 Additionally, many of the SOFAcriteria require infrastructure and testing equipment, such asblood analyzers, that may be unavailable in developinghealthcare communities. Due to these factors, it would bepreferable to have a simpler, single test to diagnosis sepsis atthe point of need that can replace SOFA scoring without de-creased accuracy.

Point of care (POC) technologies based on biomolecularanalysis provide rapid, actionable information to a patient orhealth professional at the time and site of evaluation andtreatment.11 These technologies are typically low cost, easy touse, and rapid with few infrastructure requirements making

728 | Lab Chip, 2019, 19, 728–737 This journal is © The Royal Society of Chemistry 2019

aMeinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853,

USAb Sibley School of Mechanical and Aerospace Engineering, Cornell University,

Ithaca, NY 14853, USA. E-mail: [email protected] Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA

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Lab Chip, 2019, 19, 728–737 | 729This journal is © The Royal Society of Chemistry 2019

them applicable in a variety of settings worldwide.12 Micro-fluidics,13 lateral flow,14,15 dipstick,15 and smartphone16 tech-nologies have been used to investigate sepsis biomarkerssuch as proteins, nucleic acids, human cells, microbes, orpathogens.17 POC technology is capable of utilizing smallsample volumes, such as a fingerprick blood sample, andcompact standalone devices or only the most basic laboratoryequipment, such as microscopes. These factors allow POC di-agnostics the potential to reach patients in limited-resourcehealthcare communities.12 Additionally, use of POC testing attriage in US hospitals has been shown to reduce emergencyroom care times by 1 hour compared to traditional laboratorytesting, decreasing hospital costs and saving lives.18 POC di-agnostics are actively being explored for nutrition,19–22 infec-tious disease,11,13,23 cancer,24–27 and HIV/AIDS.28–30

Sepsis POC diagnostics are a potential solution for risk-stratification of new patients, guiding initial treatment, moni-toring progression of infection, and evaluating patients' re-sponse to treatment (Fig. 1A).31 Ideal testing times should beon the order of tens of minutes to allow antibiotic interven-tion to prevent spread of infection and organ failure. POCtests used in US hospitals may require high diagnostic accu-racy to compete with laboratory testing while low resource

settings may prioritize inexpensive production, long-termlow-cost storage, and ease of use.

Research on POC sepsis devices has been conducted usinga variety of biomarkers (Fig. 1B). Here we categorize them inthree sections including blood plasma protein quantification,leukocyte monitoring, and pathogen detection. Relevantblood plasma proteins include C-reactive protein (CRP),procalcitonin (PCT), interleukins, and lactate. Leukocyte ac-tivity is measured through antibody capture or intrinsic prop-erty characterization while pathogen isolation is accom-plished though many unique techniques such as magneticseparation. In this review, specific technologies are presentedand evaluated for their respective advantages and disadvan-tages. Inclusion in this review is limited to the previous 10years and application in a POC device or setting. A compre-hensive review of all sepsis biomarkers outside of POC32–36

and the pathophysiology of sepsis37,38 can be found elsewhere.

Assays for blood plasma proteins

During sepsis, various proteins are expressed or secreted intothe blood as a response to infection – cytokines, interleukins,acute-phase proteins, and receptor proteins concentrationsare all increased. Presently, the most frequently investigatedbiomarkers for POC diagnostics are interleukin-6 (IL-6),C-reactive protein (CRP), and procalcitonin (PCT).39 IL-6 is acytokine released near the onset of infection that correlateswell with severity and outcomes in septic patients, where de-creasing levels are predictive of survival.40,41 A recent meta-analysis found the area under receiver operating characteris-tic curve (AUROC) value for IL-6 to be 0.79, indicating moder-ate diagnostic sensitivity.36 CRP is expressed as a response tocytokines like IL-6 (ref. 42) and has an AUROC value of0.77.36 PCT release is dependent on the severity of infection43

with a half-life of around 24 hours and an AUROC value of0.85,36 where decreasing levels correlate with better survivalrates.39 IL-26 in combination with PCT exhibits greater diag-nostic ability than either IL-26 or PCT alone.44 Other proteinstested as standalone biomarkers include lactate, sTREM-1,neopterin, TNF-α, E-selectin, S-100, presepsin, LBP, CD64,DcR3, endocan, sICAM-1, and C3a.36 Some of these markershave AUROC values greater than 0.9; however, the supportingliterature is sparse so more extensive research is needed tobe conclusive.

Single-analyte devices have the advantage of simplicityand are being tested for POC sepsis diagnosis. Blood lactatelevel has been used as a standalone sepsis biomarker for riskstratification of emergency room patients.45 Gaieski et al.46

reported that fingerprick sampling of lactate reduced themean time from triage to result by 40% from standard labo-ratory analysis. Rascher et al.47 have developed a microfluidicdevice to detect PCT via immunofluorescence with a limit ofdetection (LOD) of 0.04 ng mL−1 in less than ten minutes.Okamura et al.48 have developed an assay, called PATHFAST,to detect presepsin, showed higher specificity compared toother single biomarkers.49 A chemiluminescent enzyme

Fig. 1 A) Recommended use of POC sepsis chip in clinical care.Adapted with permission from ref. 69. B) Categories of whole bloodsepsis diagnostics are listed on the top and ordered by relative speedand accuracy depicted as gradients on the bottom.

Lab on a Chip Critical review

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immunoassay is used to run whole blood samples with re-sults in 17 minutes. Valera et al.50 have adapted a previouslydesigned biochip platform28,51,52 to sense IL-6 using latexbeads. Measurements with this device took 5 minutes eachand the limit of detection was 127 pg mL−1. Min et al.53 areable to detect IL-3 levels within 1-hour using their POC devicewith a reported AUROC value of 0.91 (Fig. 2). The smartphonefunctions as a touch-screen interface, as well as providing datastorage and system controls. POC devices commonly integratesmartphone technology due to their imaging, computation,communication, and networking capabilities, as well as theirfamiliarity and simplicity to almost all age groups.54

Multiplexed biomarker detection has the potential to in-crease diagnostic power. Shapiro et al.55 suggested the mosteffective panel to assess patient risk would include neutro-phil gelatinase-associated lipocalin, interleukin-1ra, and pro-tein C. Buchegger et al.56 have developed a miniaturized pro-tein microarray chip for the detection of IL-6, IL-8, IL-10, TNFalpha, S-100, PCT, E-selectin, CRP, and neopterin. The devicehas been tailored for sepsis POC testing in neonates, build-ing on a previous device.57 Improvements include a reducedpatient sample volume of 4 μL, implementation of a single-step process, reduced incubation times, and the addition ofinternal calibration. For the previous iteration of this device,Sauer et al.57 reported that the 2.5 hour single-step protocolsuffered from lower sensitivity than the 4 hour multi-stepprotocol. However, the new device shows no loss of sensitivitywhen utilizing streptavidin conjugated magnetic particles topromote mixing and binding within the smaller sample vol-ume. Complete sample processing was kept at 2.5 hours forthe single-step process due to decreasing accuracy foranalytes S-100 and CRP when incubation time was reduced.Kemmler et al.58 have developed a microarray biochip usingCRP, IL-6, PCT, and NPT. The device uses an on-chip immu-nofluorescence assay that lasts only 25 minutes and requiresbetween 10–75 μL of sample. However, due to the high LODof IL-6 and PCT, this device is only applicable for clinicallyrelevant levels in the mid to high range. The clinically rele-

vant region of interest for PCT is between 0.05 and 50 ngmL−1, while the PCT LOD for this device is 0.34 ng mL−1.Schotter et al.59 reported a magnetic lab-on-a-chip device forthe detection of the sepsis-related cytokines IL-6, IL-8, IL-10,and TNF-α using embedded magneto resistive sensors.

Leukocyte intrinsic properties asimmune markers

Identifying and monitoring the systemic inflammatory re-sponse is important because immune-paralysis is common inlate stage sepsis, so this can be used as a marker of sepsis imi-tation and progression. Neutrophils have gained attention be-cause of detectable changes in morphology, mechanics, andmotility in septic conditions.1,59–62 Neutrophil CD64 expres-sion63,64 has been shown to increase under septic conditions,making it a potential biomarker for sepsis.65–67 In response tobacterial infection, neutrophil CD64 was demonstrated to beupregulated as early as 1 hour after infection.68

Zhang et al.69 developed a POC device with a herringbone-shaped cell capture chamber for affinity separation of CD64cells within 2 hours. The device demonstrated an AUROC of0.90 when compared to sepsis diagnosis based on qSOFA in atrial of 10 patient samples.69 The technology was then ex-panded to include CD69 and the combined panel increasedthe AUROC to 0.98 when tested with 12 qSOFA positive clini-cal samples.70 Prieto et al.71 used iso-dielectric separation todifferentiate electrical properties of activated and non-activated leukocytes. Using mouse models, they demon-strated that their on-a-chip electrical cell profiling stronglycorrelated with flow cytometry.71 This device offers continu-ous monitoring of sepsis progression; however, it has notbeen tested clinically. Hassan et al.72 designed a microfluidicbiochip to electrically quantify CD64 antigen expression onneutrophils (Fig. 3A). Their device can produce test results in30 minutes and offers an alternative to hematology analyzersand flow cytometers which may not be available in a POC set-ting.72 This technology builds on previous POC devices thatelectronically quantifies cells from whole blood samples.52,73,74

This device demonstrated an AUROC of 0.77 which is betterthan the AUROC of a subset of SIRS parameters (temperature,pulse, respirations and systolic blood pressure) which wasfound to be 0.7.72 Applications of cell capture and quantifica-tion on a chip is not limited to sepsis, and reviews of thesetechnologies can be found elsewhere.75–77

Neutrophils undergo changes in their intrinsic propertiesduring infection and observing them can inform on diseaseprogression. The most frequently studied is neutrophil motil-ity.9,60,61 Neutrophils, even once isolated from blood, exhibita spontaneous migration signature specific to sepsis.61 Ellettet al.9 created a microfluidic assay to capitalize on this princi-ple (Fig. 3B). Using continuous fluorescent imaging and amachine learning algorithm, they quantified reverse migra-tion, oscillation, and pauses of neutrophils isolated from afinger prick blood sample. The assay is robust, requires mini-mal handling, and automated imaging and analysis. It

Fig. 2 Example smart phone enabled POC interleukin detectiondevice. Reproduced with permission from ref. 53.

Lab on a ChipCritical review

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requires a four-hour time-lapse microscopy step followed bytwo-and-a-half-hour image processing, a longer time scalethan some POC technologies but still clinically relevant. In adouble blinded clinical trial using SOFA scoring, the deviceobtained an AUROC of 0.99 with 97% sensitivity and 98%specificity.9

While many of the blood plasma assays and leukocytetechnologies hold promise, there is not currently a point ofcare technology that has sensitivity and specificity in the 90thpercentile and can produce results in under an hour.

Pathogen isolation as a diagnosticand treatment

With advances in miniaturization and development of lab-on-a-chip systems, direct isolation and detection of pathogenic

bacteria from the blood for sepsis therapy and diagnosis hasbeen explored. Microfluidic devices for pathogen isolation, ly-sis, and DNA extraction have been reported to identify patho-gens and aid in antibiotic selection. Techniques utilizingdielectrophoresis, inertial effects, surface acoustic waves, andcentrifugal microfluidics have been developed for separationof infectious agents from blood cells. Lab-on-a-chip systemswith integrated bacterial separation, chemical or mechanicalcell lysis, and DNA extraction for PCR or sequence specificcapture have shown promise for rapid sepsis diagnosis.78–80

Artificial spleen type devices for the direct removal ofpathogens and endotoxins from whole blood were developedfor therapeutic applications (Fig. 4A). Similar to dialysis,these devices process whole blood by capturing a broad rangeof infectious agents using ligand and antibody coatedmagnetic beads,81–85 porous membranes,86 biomimetic cell

Fig. 3 A) Microfluidic CD64 expression quantification device with lysing and quenching zones for erythrocyte removal. False-colored fluorescentimage of CD64+ cells captured on anti-CD64 coated pillars in the CD64 cell depletion zone. Reproduced with permission from ref. 74. B) Micro-fluidic assay for spontaneous neutrophil motility from a drop of blood. Reproduced with permission from ref. 9.

Fig. 4 A) Example pathogen removal apparatus. Adapted with permission from ref. 86. B) Magnetic bead capture of S. aureus and E. coli.Reproduced with permission from ref. 81. C) Magnetic opsonin and biospleen device for pathogen removal and blood cleansing. Reproduced withpermission from ref. 81. D and E) Acoustic separation of bacteria and blood cells. Reproduced with permission from ref. 89.


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margination,87,88 acoustophoresis,89,90 and elasto-inertial-based migration.91 Table 1 lists the miniaturized pathogenremoval devices for sepsis treatment. A comparison of patho-gen separation rate and removal efficiency is shown amongthese devices. Lee et al.84 developed magnetic nanoparticlesmodified with a synthetic ligand that binds to both Gram-positive and Gram-negative bacteria. Yung et al.82 developedmannose-binding lectin (MBL) coated magnetic nanobeadsthat do not activate complement factors or coagulation(Fig. 4B and C). They reported processing of up to 1.25 L h−1

of blood and greater than 90% removal of pathogenic organ-isms in rats. Lopes et al.85 reported separation of six Gram-positive species, two Gram-negative species, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-resistant Staphylococcus aureus (MRSA) in whole blood viamutated lysozyme coated magnetic beads. Hou et al.87 devel-oped an extracorporeal biomimetic microfluidic device basedon microcirculatory cell margination for non-specific removalof pathogens and cellular components. This method canreach up to ∼1–2 L h−1 throughput and when multiplexedcould produce a 100-fold higher throughput. An acousticmicrofluidic method (Fig. 4D and E) was recently reportedby Ohlsson et al.89,90 based on size separation of pathogens.This method is label-free and resulted in a greater than80% bacterial separation from a whole blood sample. Theseminiaturized devices for sepsis pathogen removal have apotential for POC applications. By improving clearance ratesand efficiency, these devices could be effective in aidingsepsis treatment. Separation rates similar to blood dialysismachines (∼1–2 L h−1) would require at least 5 hours to fil-ter all the blood from an average person. Since survival de-creases by the hour, a flow rate closer to ∼4–5 L h−1 ismore desirable for therapeutic POC applications. Such char-acteristics can be achieved by 1) multiplexing microfluidicdevices for high throughput, 2) utilizing high affinity target

binding antibodies, and 3) minimizing technological com-plexity for separation.

The blood cleansing approach is promising for the directremoval of pathogens from blood, however, this method willnot remove infection localized within organs. With the bloodcleansing technology in infancy, significant processing timesof several hours are required to remove the circulating infec-tion which is slower than desirable. The removal of bloodpathogens has been shown to delay disease progression, pro-viding time to identify the contamination and administertargeted antibiotics, thus improving overall survival. Combin-ing on-chip DNA extraction and blood cleansing technologycould be used to perform pathogen-specific analysis whiletargeted antibacterial therapies are investigated.

Commercial devices

Most of the technologies discussed thus far are in researchand development, but it is also important to consider thosethat are commercially available. Commercial technologiescurrently available for sepsis diagnosis range from simple de-vices like blood analysers to more complex systems for mo-lecular diagnostics and mass spectroscopy. Table 2 providesa complete summary of commercially available diagnostictechnologies for sepsis, with an evaluation of their feasibilityat the POC. We have categorized them into blood analysers,microbiology based, molecular diagnostic based, and patho-gen removal. Currently, most of these methods requiremicroarrays, polymerase chain reaction (PCR), or other com-plex laboratory equipment that may be unavailable in lowresource settings. We predict that the commercial market willalso experience a shift towards POC sepsis diagnostics in thecoming years.

Bacterial cultures are time consuming (24 to 48 hours),delaying the switch from broad spectrum antibiotics to more

Table 1 State-of-the-art pathogen removal devices and techniques

Group Device Targets Separation method SampleSeparationrate

Reportedpathogenclearance

Ingber81 Microfluidic Fungi (C. albicans) Magnetic separation withantibody coated beads

Whole blood 20 ml h−1 80%

Kohane84 Microfluidic E. coli MNPs modified withbis-Zn-DPA

Bovine whole blood 60 ml h−1 100%

Ingber82 Microfluidic S. aureus, E. coli Magnetic beads withengineered humanopsonin-MBL

Rat whole blood 1.25 L h−1 >90%

Russom91 Microfluidic E. Coli Elasto-inertial microfluidicswith viscoelastic effect

Whole blood 60 μl h−1 76%

Han87 Microfluidic E. coli, leukocytes,cytokines

Passive cell migration Spiked whole blood 150 ml h−1 70%

Krieger85 Manual Six Gram-positive andtwo Gram-negativespecies, MSSA, MRSA

LysE35A-coated beads Whole blood N/A 85%

Zahn86 Microfluidic E. Coli Porous polycarbonate (PCTE)membrane with 2 um pores

Whole blood 50 μl min−1 22%

Laurell90 Microfluidic devicewith acoustictransducer

P. Putida Size based separation usingacoustic impedance

Whole blood 200 μl min−1 80%


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Table 2 Commercially available technologies for sepsis diagnosis and treatment

Device Company Technology SampleTurnaroundtime

Sepsisdiagnosis

FDAclearance Point-of-care?

Blood analyzersEPOC® bloodanalysis system

SiemensHealthineers

Blood gas analyzerwith room temperaturetest card

Wholeblood

<1 min qSOFAscoring

Yes Portable, 92 μl bloodsample

Microbiology basedSepti-Chek Becton

DickinsonBlood culture withmedia

Wholeblood

∼38 h Pathogenidentification

Yes Requires laboratoryequipment

Oxoid signal Thermo FisherScientific

Blood culture withmedia

Wholeblood

24 h Pathogenidentification

Yes Requires laboratoryequipment

Molecular diagnostic basedQuickFISH/PNAFISH

AdvanDx Fluorescence in situhybridization

Positivebloodculture

∼1.5 h Pathogenidentification

Yes Requires microarrayequipment

hemoFISH Miacomdiagnostics

Fluorescence in situhybridization


0.5 h Pathogenidentification

Yes Requires microarrayequipment

Prove-it/Verigene Luminex PCR amplification andarray detection



No Requires PCR equipment

FilmArray Biofirediagnostics

Real-time PCR Positivebloodculture


Yes Requires FilmArraysystem

HYPLEX BAG Multiplex PCR with endpoint detection using anenzyme-linked sandwichassay in a microtiter plate



No Requires PCR andcomplex instrumentation

ACCU-PROBE Gen-probe Chemiluminescent DNAprobes (rRNA)




PLEX-ID BAC Abbott PCR amplification withelectrospray ionizationmass spectrometricanalysis



No/CEmarking

Requires PCR andcomplex instrumentation

Staph SR BectonDickinson

Multiplex PCR Positivebloodculture


Yes Requires PCR equipment

StaphPlex Qiagen PCR amplification andarray detection




MALDI-TOF bioMérieux Matrix assisted laserdesorption



No Requires complexinstrumentation

Magicplex Seegene Multiplex PCR Wholeblood



SeptiFast Roche Multiplex PCR Wholeblood



SepsiTest Molzym,Germany

PCR and sequencing Wholeblood

8–12 h Pathogenidentification


VYOO SIRS lab Multiplex PCR and gelelectrophoresis

Wholeblood



Xpert MRSA/SA Cepheid Real-time multiplexPCR

Wholeblood



VAPChip EppendorfArraytechnologies,Belgium

Multiplex PCR andhybridization

Wholeblood



DiagCORE STATdiagnostics

48 plex real-time PCR Wholeblood

0.5–1.2 h Pathogenidentification

No/CEmarking

Requires PCR equipment

T2 Candida T2 biosystems,USA

Miniaturized magneticresonance

Wholeblood


Yes Requires complexinstrumentation

Pathogen removal devicesCytosorb Cytosorb Removes cytokines

with filterWholeblood

Up to 24 hours aday, for up to 7consecutive days

Bacterialremoval

No/CEmarking

Requires extracorporealequipment withfiltration in a hospital


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effective targeted therapies. Mature molecular diagnostictechniques such as PCR and fluorescent in situ hybridization(FISH) have emerged as rapid diagnostic alternatives forpathogen identification.92–94 These techniques require up to12 hours, but recently, turnaround times as small as 30 mi-nutes are reported for the identification of 14 bacterial spe-cies by a Miacom system using FISH from positive blood cul-ture test. Standard blood culture takes 1–3 days to increasebacterial concentration to the detectable limit for moleculardiagnostic testing. By eliminating the blood culture, technol-ogies such as SeptiFast (Roche) can identify 25 different com-mon sepsis pathogens within 6 hours, DiagCORE (STAT Diag-nostics) can perform a 48 plex real-time PCR test thatrecognizes relevant pathogens in 30 to 80 minutes, and T2Candida panel detects fungal infections in whole blood sam-ples using a PCR system. Although commercial systems exist,many of these technologies are not suitable for POC use. Theresearch on sepsis POC technologies highlighted in this arti-cle could reduce the time to detection and aid in targetedantibacterial therapies at the point of need.

Commercial biomarker tests that indicate early organ dys-function and predict septic shock have been developed. Mo-lecular fingerprinting prior to and during treatment, includ-ing cytokine profiling95–97 and PCT tests,98 are beingclinically evaluated. Many innovations are unfolding in thebiomarker space such as adrenomedullin, which is a bio-marker for septic shock shown to increase in blood 1–2 daysbefore shock occurs.99 Devices for extracorporeal filtering ofthe infection also exist in the market. Products like Cytosorb(CE-marked) filter proinflammatory cytokines to control im-mune response while Alteco Medical's LPS Adsorber andSpectral Medical's LPS-binding Toraymyxin devices removeendotoxins released by pathogens. For POC applications,there is a need to develop and improve these commercial de-vices for both rapid and accurate diagnosis of sepsis.

Conclusions

In this review, we examined developing and commerciallyavailable technologies to assess the feasibility of rapid, accu-rate sepsis diagnosis with emphasis on POC. As with manytechnologies, there is conflict between speed and accuracy.Some of these devices, such as the EPOC blood analysis sys-tem (Siemens Healthineers), are very fast but have limiteduse and require secondary testing and evaluation for a com-

plete diagnosis. Others have strong monitoring potential buttake hours of complex analysis.

Studies indicate that diagnosing sepsis using a single bio-marker is challenging,100 however, biomarker panels haveshown promise.56–58,101 Additional barriers to pathogen de-tection exist due to the breadth of infectious agents, relativelyhigh limits of detection, and long culture times. Recent re-search has produced strong evidence for the use of immunesystem markers as indicators of sepsis over serum bio-markers. Neutrophils have been of special interest due totheir critical role in innate immunity and rapid response toinfection.102 We predict that markers of the immune re-sponse to sepsis will continue to be well studied in the com-ing years.

Some experts have called into question the homogeneityof sepsis as a disease.103–109 They argue that the term sepsisitself is too broad and that different classifications of sepsisshould exist. If this is true, a single diagnostic device for alltypes of sepsis may not be possible. Based on a functionalanalysis, Sweeney et al.103 proposed three subtypes of sepsis:inflammopathic, adaptive, and coagulopathic. Davenportet al.107 suggest two phenotypes based on immune responsestates, prognoses, and genetic variation, whereas, Wonget al.104–106 proposed three subtypes based on genome-wideexpression profiling. The heterogeneous disease progressionsand immune responses associated with sepsis, may beunminding the efforts to standardize diagnostics and treat-ments. Additional research is required to determine the ex-tent of heterogeneity in sepsis and the corresponding effectson diagnostics and therapies. It is possible that, rather thana single biomarker or panel to diagnosis all cases of sepsis, itwill be necessary to utilize different diagnostics at differenttimes and for different subsets of septic patients.100 We pre-dict that research on the homogeneity of sepsis will be of in-creasing interest in the coming years.

The transition to SOFA scoring makes benchmarking POCdiagnostic devices challenging. While some devices are testedagainst SOFA scoring, others are still being tested against lessaccurate SIRS scoring.5,8,9,110 A standardized protocol forcomparison should be established to increase the power ofreported results. POC devices should continue to be designedwith an emphasis on low-cost and long term stability, and ad-ditional thought should be given to how diagnostic outcomescan inform treatment. Additionally, further development ofdiagnostics could expand the ability to differentiate stages

Table 2 (continued)

Device Company Technology SampleTurnaroundtime

Sepsisdiagnosis

FDAclearance Point-of-care?

LPS Adsorber Altecomedical,Sweden

Peptide binding ofendotoxin with porouspolyethylene matrix

Wholeblood

Not available Bacterialremoval

No/CEmarking


LPS-bindingToraymyxindevice

Spectralmedical

Ionic binding ofpolymyxin-B andlipid A to endotoxin

Wholeblood

Recommendeddosing: 2 hhemoperfusion in24 h period

Bacterialremoval

No/CEmarking



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and progression of sepsis, rather than septic versus not sep-tic.100 POC technology for the diagnosis or treatment of sep-sis would be especially beneficial due to the rapid diseaseprogression and impact on populations worldwide. A success-ful POC sepsis diagnostic could improve health care access,save lives, reduce healthcare costs, and minimize sufferingboth in countries with well-developed healthcare systems andin low-resource settings. In the last 10 years, significant prog-ress has been made, but additional research is vital to de-velop a successful POC device for sepsis.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

DE acknowledges support from the US National Institutes ofHealth through grant R01EB021331 (FeverPhone). AS ac-knowledges support from the US National Institutes of Healththrough grant R01AI132738-01A1.

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