Point-of-care sensors for the management of sepsis

Abstract

Point-of-care sensors that enable the fast collection of information relevant to a patient’s health state can facilitate improved health access, reduce healthcare costs and improve the quality of healthcare delivery. In the diagnosis of sepsis — defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and the leading cause of in-patient death and of hospital readmission in the United States — predicting which infections will lead to life-threatening organ dysfunction and developing specific anti-sepsis treatments remain challenging because of the significant heterogeneity of the host response. Yet the use of point-of-care devices could reduce the time from the onset of a patient’s infection to the administration of appropriate therapeutics. In this Perspective, we describe the current state of point-of-care sensors for the diagnosis and monitoring of sepsis, and outline opportunities in the use of these devices to dramatically improve patient care.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Current clinical workflow for the management of sepsis.
Fig. 2: Diagnostic needs and the ideal POC sensor.
Fig. 3: Tiered strategy for POC sensor development.

References

  1. 1.

    Fleischmann, C. et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am. J. Respir. Crit. Care Med. 193, 259–272 (2016).

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Fleischmann, C. et al. The global burden of pediatric and neonatal sepsis: a systematic review. Lancet Respir. Med. 6, 223–230 (2018).

    Article  Google Scholar 

  3. 3.

    Van Dillen, J. et al. Maternal sepsis: epidemiology, etiology and outcome. Curr. Opin. Infect. Dis. 23, 249–254 (2010).

    Article  PubMed  Google Scholar 

  4. 4.

    Lagu, T. et al. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit. Care Med. 40, 754–761 (2012).

    Article  PubMed  Google Scholar 

  5. 5.

    Gaieski, D. F., Edwards, M., Kallan, K. J. & Carr, B. J. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit. Care Med. 41, 1167–1174 (2013).

    Article  PubMed  Google Scholar 

  6. 6.

    Seymour, C. W. et al. Time to treatment and mortality during mandated emergency care for sepsis. N. Engl. J. Med. 376, 2235–2244 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Alam, N. et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir. Med. 6, 40–50 (2018).

    Article  PubMed  Google Scholar 

  8. 8.

    Gander, R. M. et al. Impact of blood cultures drawn by phlebotomy on contamination rates and health care costs in a hospital emergency department. J. Clin. Microbiol. 47, 1021–1024 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Sitdikov, R. A. et al. Target capture system. US patent 9599610 (2014).

  10. 10.

    Puttaswamy, S., Lee, B. D. & Sengupta, S. Novel electrical method for early detection of viable bacteria in blood cultures. J. Clin. Microbiol. 49, 2286–2289 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Sengupta, S., Puttaswamy, S. & Chang, H. C. Rapid detection of viable bacteria system and method. US patent 8,635,028 (2014).

  12. 12.

    FAST technology. Qvella Corporation https://www.qvella.com/technology (2018).

  13. 13.

    LiDia. DNA Electronics http://www.dnae.com/lidia.html (2018).

  14. 14.

    Accelerate Pheno system. Accelerate Diagnostics http://acceleratediagnostics.com/products/accelerate-pheno-system/#features (2018).

  15. 15.

    Niemz, A., Ferguson, T. M. & Boyle, D. S. Point-of-care nucleic acid testing for infectious diseases. Trends Biotechnol. 29, 240–250 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    BioMérieux 510(k) Substantial Equivalence Determination Decision Memorandum K162827, VIDAS B·R·A·H·M·S PCT clearance submission to FDA (FDA, 2017).

  18. 18.

    Faix, J. D. Biomarkers of sepsis. Crit. Rev. Clin. Lab. Sci. 50, 23–36 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    de Jong, E., van Oers, J. A., Beishuizen, A., Vos, P. & Vermeijden, W. J. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect. Dis. 16, 819–827 (2016).

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Pierrakos, C. & Vincent, J. L. Sepsis biomarkers: a review. Crit. Care 14, R15 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kibe, S., Adams, K. & Barlow, G. Diagnostic and prognostic biomarkers of sepsis in critical care. J. Antimicrob. Chemother. 66, ii33–ii40 (2010).

    Google Scholar 

  22. 22.

    Schuetz, P. et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect. Dis. 18, 95–107 (2018).

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Huang, D. T. et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N. Engl. J. Med. 379, 236–249 (2018).

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Shapiro, N. I. et al. A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit. Care Med. 37, 96–104 (2009).

    Article  PubMed  Google Scholar 

  25. 25.

    Paulus, P., Jennewein, C. & Zacharowski, K. Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis? Biomarkers 16, S11–S21 (2011).

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Angus, D. C. & Poll, T. Sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Hotchkiss, R. S. et al. Sepsis and septic shock. Nat. Rev. Dis. Primers 2, 16045 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Poll, T. V. D., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 17, 407–420 (2017).

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Chauhan, N., Tiwari, S. & Jain, U. Potential biomarkers for effective screening of neonatal sepsis infections: an overview. Microb. Pathog. 107, 234–242 (2017).

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Seymour, C. W. et al. Delays from first medical contact to antibiotic administration for sepsis. Crit. Care Med. 45, 759–765 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Pitt, W. G. et al. Rapid separation of bacteria from blood — review and outlook. Biotechnol. Prog. 32, 823–839 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Mutlu, B. R. et al. Non-equilibrium inertial separation array for high-throughput, large-volume blood fractionation. Sci. Rep. 7, 9915 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Fachin, F. et al. Monolithic chip for high-throughput blood cell depletion to sort rare circulating tumor cells. Sci. Rep. 7, 10936 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Martel, J. M. et al. Continuous flow microfluidic bioparticle concentrator. Sci. Rep. 5, 11300 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Hassan, U., Watkins, N. N., Reddy, B., Damhorst, G. & Bashir, R. Microfluidic differential immuno-capture biochip for specific leukocyte counting. Nat. Protoc. 11, 714–726 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Hassan, U. et al. A microfluidic biochip for complete blood cell counts at the point-of-care. Technology 3, 201–213 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Hassan, U. et al. A point-of-care microfluidic biochip for quantification of CD64 expression from whole blood for sepsis stratification. Nat. Commun. 8, 15949 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Valera, E., Shia, W. W. & Bailey, R. C. Development and validation of an immunosensor for monocyte chemotactic protein 1 using a silicon photonic micro-ring resonator biosensing platform. Clin. Biochem. 49, 121–126 (2016).

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Liu, D. et al. A fully integrated distance readout ELISA-chip for point-of-care testing with sample-in-answer-out capability. Biosens. Bioelectron. 96, 332–338 (2017).

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Islam, F. et al. An electrochemical method for sensitive and rapid detection of FAM134B protein in colon cancer samples. Sci. Rep. 7, 133 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Tacke, F. et al. Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Crit. Care Med. 42, 1096–1104 (2014).

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Roderburg, C. et al. Circulating microRNA-150 serum levels predict survival in patients with critical illness and sepsis. PLoS ONE 8, e54612 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Bomsztyk, K. et al. Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction. Crit. Care 19, 225 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Hur, S. C., Henderson-MacLennan, N. K., McCabec, E. R. B. & Carlo, D. D. Deformability based cell classification and enrichment using inertial microfluidics. Lab Chip 11, 912–920 (2011).

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Wang, G. et al. Stiffness dependent separation of cells in a microfluidic device. PLoS ONE 8, e75901 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. 47.

    Rassaei, L., Olthuis, W., Tsujimura, S., Sudhölter, E. R. & van den Berg, A. Lactate biosensors: current status and outlook. Anal. Bioanal. Chem. 406, 123–137 (2014).

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Angus, D. C. Defining sepsis: a case of bounded rationality and fuzzy thinking?. Am. J. Respir. Crit. Care Med. 194, 14–15 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Ellett, F. et al. Diagnosis of sepsis from a drop of blood by measurement of spontaneous neutrophil motility in a microfluidic assay. Nat. Biomed. Eng. 2, 207–214 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Jämsä, J., Huotari, V., Savolainen, E. R., Syrjälä, H. & Ala-Kokko, T. Analysis of the temperature affects on leukocyte surface antigen expression. J. Clin. Lab. Anal. 25, 118–125 (2011).

    Article  PubMed  Google Scholar 

  51. 51.

    How to find and effectively use predicate devices. US Food and Drug Administration https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm134571.htm (2017).

  52. 52.

    Haak, B. W. & Wiersinga, W. J. The role of the gut microbiota in sepsis. Lancet 2, 135–143 (2017).

    PubMed  Google Scholar 

  53. 53.

    Dickson, R. P. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat. Microbiol. 1, 16113 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. 54.

    Budden, K. F. et al. Emerging pathogenic links between microbiota and the gut–lung axis. Nat. Rev. Microbiol. 15, 55–63 (2017).

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Fired, J. On World Sepsis Day, a call for much-needed research funding. Noozhawk https://www.noozhawk.com/article/dr._jeffrey_fried_world_sepsis_day (2014).

  56. 56.

    Sepsis: a word to know, a meaning to learn. Sepsis Alliance News https://www.sepsis.org/sepsis-alliance-news/sepsis-word-know-meaning-learn/ (2017).

Download references

Acknowledgements

The authors thank B. Davis, J. Kumar, V. Reddi, J. Eardley, E. Iniguez, N. Topudurti, G. Damhorst and I. Taneja for useful discussions around clinical care for septic patients, technology development and data analytics.

Author information

Affiliations

Authors

Contributions

B.R., U.H. and R.B. conceived and designed the article. C.S., T.S.I., D.C.A., L.Y., W.W., K.W. and A.V. helped in identifying the primary clinical needs in sepsis and provided intellectual input on the best solutions to these needs. B.R. and U.H. made the figures and table. All authors provided input and reviewed the article. B.R., U.H. and R.B. edited the manuscript.

Corresponding author

Correspondence to R. Bashir.

Ethics declarations

Competing interests

B.R., R.B. and U.H. have financial interests in Prenosis Inc. The remaining authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Reddy, B., Hassan, U., Seymour, C. et al. Point-of-care sensors for the management of sepsis. Nat Biomed Eng 2, 640–648 (2018). https://doi.org/10.1038/s41551-018-0288-9

Download citation

Further reading