Vibrational spectroscopic analysis of blood for diagnosis of infections and sepsis: a review of requirements for a rapid diagnostic test.

Infections and sepsis represent a growing global burden. There is a widespread clinical need for a rapid, high-throughput and sensitive technique for the diagnosis of infections and detection of invading pathogens and the presence of sepsis. Current diagnostic methods primarily consist of laboratory-based haematology, biochemistry and microbiology that are time consuming, labour- and resource-intensive, and prone to both false positive and false negative results. Current methods are insufficient for the increasing demands on healthcare systems, causing delays in diagnosis and initiation of treatment, due to the intrinsic time delay in sample preparation, measurement, and analysis. Vibrational spectroscopic techniques can overcome these limitations by providing a rapid, label-free and low-cost method for blood analysis, with limited sample preparation required, potentially revolutionising clinical diagnostics by producing actionable results that enable early diagnosis, leading to improved patient outcomes. This review will discuss the challenges associated with the diagnosis of infections and sepsis, primarily within the UK healthcare system. We will consider the clinical potential of spectroscopic point-of-care technologies to enable blood analysis in the primary-care setting.

[1]  Harald Labischinski,et al.  Microbiological characterizations by FT-IR spectroscopy , 1991, Nature.

[2]  Clare Griffiths,et al.  Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010 , 2013, BMJ Open.

[3]  S. Msika,et al.  Risk factors for postoperative infectious complications in noncolorectal abdominal surgery: a multivariate analysis based on a prospective multicenter study of 4718 patients. , 2003, Archives of surgery.

[4]  S. Y. Lee,et al.  Optical Biosensors for the Detection of Pathogenic Microorganisms. , 2016, Trends in biotechnology.

[5]  K. Wood,et al.  Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock* , 2006, Critical care medicine.

[6]  J. Padbury,et al.  Neonatal sepsis , 2013, Virulence.

[7]  Mitchell M. Levy,et al.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference , 2003, Intensive Care Medicine.

[8]  Dieter Naumann,et al.  Characterization and identification of microorganisms by FT-IR microspectrometry , 2003 .

[9]  E. Bouza,et al.  The Value of Combining Blood Culture and SeptiFast Data for Predicting Complicated Bloodstream Infections Caused by Gram-Positive Bacteria or Candida Species , 2013, Journal of Clinical Microbiology.

[10]  A. Voss Healthcare associated infections , 2009, BMJ : British Medical Journal.

[11]  M. Johnson,et al.  Circulating microRNAs in Sera Correlate with Soluble Biomarkers of Immune Activation but Do Not Predict Mortality in ART Treated Individuals with HIV-1 Infection: A Case Control Study , 2015, PloS one.

[12]  J. Rychert Benefits and Limitations of MALDI-TOF Mass Spectrometry for the Identification of Microorganisms , 2019, Journal of Infectiology.

[13]  A. Cross Anti-endotoxin vaccines , 2013, Virulence.

[14]  R. Hernández-Pando,et al.  Passive administration of purified secretory IgA from human colostrum induces protection against Mycobacterium tuberculosis in a murine model of progressive pulmonary infection , 2013, BMC Immunology.

[15]  J. Popp,et al.  Fast differentiation of SIRS and sepsis from blood plasma of ICU patients using Raman spectroscopy , 2014, Journal of biophotonics.

[16]  N. Webster,et al.  Clinical application of sepsis biomarkers , 2013, Journal of Anesthesia.

[17]  G. Cazorla,et al.  Glucose and lactate concentration determination on single microsamples by Fourier-transform infrared spectroscopy. , 2000, The Journal of laboratory and clinical medicine.

[18]  H. Schønheyder,et al.  Differential Contributions of Specimen Types, Culturing, and 16S rRNA Sequencing in Diagnosis of Prosthetic Joint Infections , 2018, Journal of Clinical Microbiology.

[19]  G. Dinant,et al.  Identifying important health system factors that influence primary care practitioners’ referrals for cancer suspicion: a European cross-sectional survey , 2018, BMJ Open.

[20]  Matthew E. Falagas,et al.  Substandard/Counterfeit Antimicrobial Drugs , 2015, Clinical Microbiology Reviews.

[21]  D. Wichmann,et al.  Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis - a prospective, observational study , 2013, BMC Immunology.

[22]  Z. Pan,et al.  A Novel Combination of Biomarkers to Herald the Onset of Sepsis Prior to the Manifestation of Symptoms , 2017, Shock.

[23]  D. Goldberg,et al.  Infections with Spore-forming Bacteria in Persons Who Inject Drugs, 2000–2009 , 2013, Emerging infectious diseases.

[24]  F. Tubach,et al.  Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial , 2010, The Lancet.

[25]  Y. C. Shen,et al.  The use of Fourier-transform infrared spectroscopy for the quantitative determination of glucose concentration in whole blood , 2003, Physics in medicine and biology.

[26]  J. Maurer,et al.  Antibiotics: Mode of Action, Mechanisms of Resistance, and Transfer , 2008 .

[27]  D. Jamieson,et al.  Pregnancy and infection. , 2014, The New England journal of medicine.

[28]  Gehua Wang,et al.  Traditional approaches versus mass spectrometry in bacterial identification and typing. , 2017, Clinica chimica acta; international journal of clinical chemistry.

[29]  G. Poston,et al.  Blood cultures in acute surgical admissions. , 2015, Annals of the Royal College of Surgeons of England.

[30]  Gary B. Smith,et al.  The measurement frequency and completeness of vital signs in general hospital wards: An evidence free zone? , 2017, International journal of nursing studies.

[31]  M. Levy,et al.  The SOFA score—development, utility and challenges of accurate assessment in clinical trials , 2019, Critical Care.

[32]  Donald M Yealy,et al.  Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. , 2012, American journal of respiratory and critical care medicine.

[33]  S. Ingleby,et al.  Making the journey safe: recognising and responding to severe sepsis in accident and emergency , 2016, BMJ quality improvement reports.

[34]  R. Bellomo,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[35]  M. Blades,et al.  Raman Spectroscopy of Blood and Blood Components , 2017, Applied spectroscopy.

[36]  Shiji Wang,et al.  Measuring both procalcitonin and C-reactive protein for a diagnosis of sepsis in critically ill patients , 2014, The Journal of international medical research.

[37]  M. Huleihel,et al.  FTIR microscopy as a method for identification of bacterial and fungal infections. , 2005, Journal of pharmaceutical and biomedical analysis.

[38]  Jürgen Popp,et al.  Culture independent Raman spectroscopic identification of urinary tract infection pathogens: a proof of principle study. , 2013, Analytical chemistry.

[39]  E. Ely,et al.  The immunopathogenesis of sepsis in elderly patients. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  M. Weinstein,et al.  Update on blood cultures: how to obtain, process, report, and interpret. , 2013, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[41]  N. Laforgia,et al.  Early and Late Infections in Newborns: Where Do We Stand? A Review. , 2016, Pediatrics and neonatology.

[42]  P. Póvoa,et al.  Biomarker-guided antibiotic therapy-strengths and limitations. , 2017, Annals of translational medicine.

[43]  Jürgen Popp,et al.  Raman spectroscopic identification of single bacterial cells under antibiotic influence , 2014, Analytical and Bioanalytical Chemistry.

[44]  L. Casserly,et al.  Cross-sectional audit on the relevance of Elevated National Early Warning Score in medical patients at a Model 2 hospital in Ireland , 2014, Irish Journal of Medical Science (1971 -).

[45]  G. Barlow,et al.  Diagnostic and prognostic biomarkers of sepsis in critical care. , 2011, The Journal of antimicrobial chemotherapy.

[46]  A. Shimabukuro-Vornhagen,et al.  Prognostic accuracy of SOFA, qSOFA and SIRS criteria in hematological cancer patients: a retrospective multicenter study , 2019, Journal of Intensive Care.

[47]  Sascha Sauer,et al.  Mass spectrometry tools for the classification and identification of bacteria , 2010, Nature Reviews Microbiology.

[48]  Reinhard Niessner,et al.  Label-Free in Situ Discrimination of Live and Dead Bacteria by Surface-Enhanced Raman Scattering. , 2015, Analytical chemistry.

[49]  R. Ware,et al.  HOspitalised Pneumonia Extended (HOPE) Study to reduce the long-term effects of childhood pneumonia: protocol for a multicentre, double-blind, parallel, superiority randomised controlled trial , 2019, BMJ Open.

[50]  Kevin J. Tracey,et al.  Sepsis definitions: time for change , 2013, The Lancet.

[51]  Tianhong Dai,et al.  Bioluminescence-Sensing Assay for Microbial Growth Recognition , 2016, J. Sensors.

[52]  A. Peitzman,et al.  Establishing position papers by the WSES , 2018, World Journal of Emergency Surgery.

[53]  Haitao Wang,et al.  The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma , 2014, BioMed research international.

[54]  F. Crauste,et al.  Model-Based Assessment of the Role of Uneven Partitioning of Molecular Content on Heterogeneity and Regulation of Differentiation in CD8 T-Cell Immune Responses , 2018, bioRxiv.

[55]  J. Popp,et al.  Vibrational spectroscopy—A powerful tool for the rapid identification of microbial cells at the single‐cell level , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[56]  Debbie Weston,et al.  Infection Prevention and Control , 2008 .

[57]  Jin Yang,et al.  Head-to-head comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: a meta-analysis , 2018, Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine.

[58]  B. Wood,et al.  Simultaneous ATR-FTIR Based Determination of Malaria Parasitemia, Glucose and Urea in Whole Blood Dried onto a Glass Slide. , 2017, Analytical chemistry.

[59]  M. Matthay,et al.  Sepsis: pathophysiology and clinical management , 2016, British Medical Journal.

[60]  K. Ho,et al.  C-reactive protein concentration as a predictor of in-hospital mortality after ICU discharge: a prospective cohort study , 2008, Intensive Care Medicine.

[61]  James M. Cameron,et al.  Shining a light on clinical spectroscopy: Translation of diagnostic IR, 2D-IR and Raman spectroscopy towards the clinic , 2019 .

[62]  Ashagre Molla,et al.  Clinical outcome and risk factors of neonatal sepsis among neonates in Felege Hiwot referral Hospital, Bahir Dar, Amhara Regional State, North West Ethiopia 2016: a retrospective chart review , 2017, BMC Research Notes.

[63]  S. Memtsoudis,et al.  Patient, Surgery, and Hospital Related Risk Factors for Surgical Site Infections following Total Hip Arthroplasty , 2015, TheScientificWorldJournal.

[64]  P. Vickerman,et al.  Shooting Up: Infections among people who inject drugs in the UK, 2018-an update, December 2019 , 2011 .

[65]  C. Okoli,et al.  Changes in smoking behaviours following a smokefree legislation in parks and on beaches: an observational study , 2013, BMJ Open.

[66]  J. Lenjisa,et al.  Assessment of the incidence of neonatal sepsis, its risk factors, antimicrobials use and clinical outcomes in Bishoftu General Hospital, neonatal intensive care unit, Debrezeit-Ethiopia , 2014 .

[67]  T. van der Poll,et al.  Moderate positive predictive value of a multiplex real-time PCR on whole blood for pathogen detection in critically ill patients with sepsis , 2019, European Journal of Clinical Microbiology & Infectious Diseases.

[68]  M. Ahn,et al.  Rapid tool for identification of bacterial strains using Fourier transform infrared spectroscopy on genomic DNA , 2019, Journal of applied microbiology.

[69]  M. Cecconi,et al.  Internal emergency department validation of the simplified MISSED score , 2014, European journal of emergency medicine : official journal of the European Society for Emergency Medicine.

[70]  D. Ecker,et al.  Improved Sensitivity for Molecular Detection of Bacterial and Candida Infections in Blood , 2014, Journal of Clinical Microbiology.

[71]  Fernando R Coelho,et al.  Diagnostic methods in sepsis: the need of speed. , 2012, Revista da Associacao Medica Brasileira.

[72]  Holly J. Butler,et al.  Enabling quantification of protein concentration in human serum biopsies using attenuated total reflectance – Fourier transform infrared (ATR-FTIR) spectroscopy , 2018, Vibrational Spectroscopy.

[73]  Tim Nutbeam,et al.  The sepsis six and the severe sepsis resuscitation bundle: a prospective observational cohort study , 2010, Emergency Medicine Journal.

[74]  Royston Goodacre,et al.  Surface-enhanced Raman scattering for the rapid discrimination of bacteria. , 2006, Faraday discussions.

[75]  O. Singh,et al.  Severe sepsis and septic shock in the elderly: An overview. , 2012, World journal of critical care medicine.

[76]  G. Gore,et al.  Use of C-reactive protein to tailor antibiotic use: a systematic review and meta-analysis , 2018, BMJ Open.

[77]  D. Molenaar,et al.  Microbial Communities in Sediments From Four Mildly Acidic Ephemeral Salt Lakes in the Yilgarn Craton (Australia) – Terrestrial Analogs to Ancient Mars , 2019, Front. Microbiol..

[78]  B. Trautner,et al.  Catheter-associated infections: pathogenesis affects prevention. , 2004, Archives of internal medicine.

[79]  David Farrell,et al.  Developing e-Bug web games to teach microbiology. , 2011, The Journal of antimicrobial chemotherapy.

[80]  K. Rolston Infections in Cancer Patients with Solid Tumors: A Review , 2017, Infectious Diseases and Therapy.

[81]  David T. Huang,et al.  Recognizing and managing sepsis: what needs to be done? , 2015, BMC Medicine.

[82]  J. Vincent,et al.  The Clinical Challenge of Sepsis Identification and Monitoring , 2016, PLoS medicine.

[83]  I. Fetzer,et al.  Evaluation of FT-IR spectroscopy as a tool to quantify bacteria in binary mixed cultures. , 2011, Journal of microbiological methods.

[84]  C. Chiang-Ni,et al.  Current status of MALDI-TOF mass spectrometry in clinical microbiology , 2019, Journal of food and drug analysis.

[85]  M. Kollef Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting it right up front. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[86]  Matthew J. Baker,et al.  Is Infrared Spectroscopy Ready for the Clinic? , 2019, Analytical chemistry.

[87]  C. Janeway Immunobiology: The Immune System in Health and Disease , 1996 .

[88]  K. Tracey,et al.  The "cytokine profile": a code for sepsis. , 2005, Trends in molecular medicine.

[89]  B. Mccarron,et al.  Acute infections in intravenous drug users. , 2013, Clinical medicine.

[90]  M. Cecconi,et al.  The REDS score: a new scoring system to risk-stratify emergency department suspected sepsis: a derivation and validation study , 2019, BMJ Open.

[91]  External validation of the MISSED score to predict mortality in patients with severe sepsis and septic shock in the emergency department , 2014, European journal of emergency medicine : official journal of the European Society for Emergency Medicine.

[92]  L. V. van de Poll-Franse,et al.  The Perceived Impact of Length of the Diagnostic Pathway Is Associated with Health-Related Quality of Life of Sarcoma Survivors: Results from the Dutch Nationwide SURVSARC Study , 2020, Cancers.

[93]  A. K. Mousa,et al.  Comment on “On Soft β-Open Sets and Soft β-Continuous Functions” , 2015, TheScientificWorldJournal.

[94]  D. Mannino,et al.  Ageing and the epidemiology of multimorbidity , 2014, European Respiratory Journal.

[95]  M. Levy,et al.  Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program* , 2014, Critical care medicine.

[96]  Nurul Huda,et al.  Molecular techniques for detecting and typing of bacteria, advantages and application to foodborne pathogens isolated from ducks , 2012, 3 Biotech.

[97]  J. Vincent,et al.  Sepsis biomarkers: a review , 2010, Critical care.

[98]  Lactate as a Biomarker for Sepsis Prognosis? , 2016, Infection & chemotherapy.

[99]  J. Parrillo,et al.  Serum lactate as a predictor of mortality in patients with infection , 2007, Intensive Care Medicine.

[100]  M. Manfait,et al.  FT‐IR microspectroscopy for early identification of some clinically relevant pathogens , 2006, Journal of applied microbiology.

[101]  E. Victor,et al.  Molecular profiling of sepsis in mice using Fourier Transform Infrared Microspectroscopy , 2016, Journal of biophotonics.

[102]  Changing trends in mortality : a cross-UK comparison , 1981 to 2016 , 2018 .

[103]  National early warning score (NEWS) is not suitable for all patients , 2012, BMJ : British Medical Journal.

[104]  D. Angus,et al.  Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. , 2016, American journal of respiratory and critical care medicine.

[105]  Jean-Marc Dinten,et al.  Single bacteria identification by Raman spectroscopy , 2014, Journal of biomedical optics.

[106]  B. Pécoul,et al.  Access to essential drugs in poor countries: a lost battle? , 1999, JAMA.

[107]  P Valenstein,et al.  Laboratory turnaround time. , 1996, American journal of clinical pathology.

[108]  N. Kissoon,et al.  Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future , 2017, Intensive Care Medicine.

[109]  Paul A Dayton,et al.  Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery , 2019, Nature Communications.

[110]  M. Weinstein Current blood culture methods and systems: clinical concepts, technology, and interpretation of results. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[111]  Dieter Naumann,et al.  FT-IR spectroscopy and FT-Raman spectroscopy are powerful analytical tools for the non-invasive characterization of intact microbial cells , 1995 .

[112]  D. Bloom,et al.  Infectious Disease Threats in the Twenty-First Century: Strengthening the Global Response , 2019, Front. Immunol..

[113]  Rapid Single-cell Detection and Identification of Bacteria by Using Surface-enhanced Raman Spectroscopy , 2017 .

[114]  Todd P. Coleman,et al.  Emerging Technologies for Molecular Diagnosis of Sepsis , 2018, Clinical Microbiology Reviews.

[115]  M. Howell,et al.  Quick Sepsis‐related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores for Detecting Clinical Deterioration in Infected Patients outside the Intensive Care Unit , 2017, American journal of respiratory and critical care medicine.

[116]  R. Landewé,et al.  Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis , 2007, Annals of the rheumatic diseases.

[117]  K. Reinhart,et al.  Rapid diagnosis of sepsis , 2013, Virulence.

[118]  B. Fu,et al.  Rapid and Visual Detection of Trichinella Spp. Using a Lateral Flow Strip-Based Recombinase Polymerase Amplification (LF-RPA) Assay , 2019, Front. Cell. Infect. Microbiol..

[119]  James M. Cameron,et al.  Stratifying Brain Tumour Histological Sub-Types: The Application of ATR-FTIR Serum Spectroscopy in Secondary Care , 2020, Cancers.

[120]  J. Tokars,et al.  Predictive value of blood cultures positive for coagulase-negative staphylococci: implications for patient care and health care quality assurance. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[121]  Verónica Ambriz-Aviña,et al.  Applications of Flow Cytometry to Characterize Bacterial Physiological Responses , 2014, BioMed research international.

[122]  D. Cozzolino,et al.  A review of methods for the detection of pathogenic microorganisms. , 2019, The Analyst.

[123]  B. Karon,et al.  Evaluation of lactate, white blood cell count, neutrophil count, procalcitonin and immature granulocyte count as biomarkers for sepsis in emergency department patients. , 2017, Clinical biochemistry.

[124]  M. Jackson Infection prevention and control. , 1992, Critical care nursing clinics of North America.

[125]  R. Price,et al.  Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling , 2016, PLoS medicine.

[126]  Á. Soriano,et al.  Evaluation of the Magicplex™ Sepsis Real-Time Test for the Rapid Diagnosis of Bloodstream Infections in Adults , 2019, Front. Cell. Infect. Microbiol..

[127]  D. McKenna,et al.  Serology of Culture-Confirmed Cases of Human Granulocytic Ehrlichiosis , 2000, Journal of Clinical Microbiology.

[128]  D. Naumann,et al.  Prospective Study of the Performance of Vibrational Spectroscopies for Rapid Identification of Bacterial and Fungal Pathogens Recovered from Blood Cultures , 2003, Journal of Clinical Microbiology.

[129]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[130]  P. Ward,et al.  The inflammatory response in sepsis. , 2013, Trends in immunology.

[131]  R. R. Guliev,et al.  Identification of microorganisms by Fourier-transform infrared spectroscopy , 2018, Bulletin of Russian State Medical University.

[132]  B. Wood,et al.  Spectroscopy goes viral: Diagnosis of hepatitis B and C virus infection from human sera using ATR-FTIR spectroscopy , 2019 .

[133]  B. Zimmer,et al.  Direct-from-Blood-Culture Disk Diffusion To Determine Antimicrobial Susceptibility of Gram-Negative Bacteria: Preliminary Report from the Clinical and Laboratory Standards Institute Methods Development and Standardization Working Group , 2018, Journal of Clinical Microbiology.

[134]  Jonathan Fielden,et al.  An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely ill Patients (SOAP) study , 2006, Intensive Care Medicine.

[135]  Eliézer Silva,et al.  Sepsis and pregnancy: do we know how to treat this situation? , 2013, Revista Brasileira de terapia intensiva.

[136]  Niranjan Kissoon,et al.  Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study , 2020, The Lancet.

[137]  R. Price,et al.  Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data , 2015, BMC Medicine.

[138]  A. Weinacker,et al.  Blood cultures in the critical care unit: improving utilization and yield. , 2002, Chest.