Sepsis Diagnostic & Company Spin-out
Submitting InstitutionsUniversity of Liverpool,
Liverpool School of Tropical Medicine
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
Research at the University of Liverpool (UoL) has developed and proven a
straightforward diagnostic test method for bacterial blood infections.
This was urgently needed as sepsis is a medical emergency that lacks
adequate and rapid diagnostic tests particularly for low cost early
detection. UoL's research has demonstrated that a simple optical test that
can be conducted during routine testing of coagulation is an effective
diagnostic, prognostic and monitoring marker for sepsis that can be
routinely applied in clinical settings. There are now established UK and
international laboratory standards in place. In 2010 a spinout company was
formed to exploit four patents and incorporate the technology into a
point-of-care device suitable for all clinical settings. The company,
Sepsis Ltd, has attracted £1.45m of investment.
Sepsis is a bacterial infection of the blood that causes whole body
inflammation and is the leading cause of death worldwide. It affects 18
million people and 30% of cases die from it. In addition, sepsis is
increasing by 1.5% each year. This is because of an ageing population and
antibiotic-resistant bacteria. A major problem is that prompt diagnosis of
sepsis is difficult. Early diagnosis is crucial to avoid complications,
secure appropriate antibiotic treatment and can be life-saving. There is a
pressing need for rapid detection systems that can indicate bacterial
infection at the patient bedside because conventional blood cultures take
over 24 hours to produce a result.
The pioneering research, led by Prof Cheng Hok Toh at the UoL, was first
published in 1997 following investigations into the routine coagulation
test for sepsis used in intensive care setting . It was found that
during this course of this measurement of the activated partial
thromboplastin time (aPTT), optical measurements could distinguish between
samples where sepsis was present and not. This optical measurement was
called the aPTT biphasic waveform and is straightforward to generate.
The next step in the UoL research was to investigate the potential of the
aPTT biphasic waveform as a diagnostic, prognostic and monitoring marker
for sepsis and sepsis related complications. There were two threads to
this research. The first was based on further prospective and large
clinical cohort studies to ascertain the sensitivity and specificity of
the aPTT biphasic waveform measurements for this application. It was found
that this new measurement was sensitive, rapid and selective. Of
particular importance was the finding that it was more sensitive than the
established aPTT coagulation test; it could detect sepsis at an earlier
stage which enables earlier diagnosis and treatment. It was found to be at
least as sensitive as the two existing sepsis biomarker measurements —
procalcitonin and C reactive protein, which are expensive and take hours
for a result and therefore, not routinely used in the UK. This is the
first significant research output, that aPTT biphasic waveform
measurements have been found to be a superior indicator in clinical sample
for the presence of sepsis .
The second thread to the UoL research was to investigate the underlying
molecular mechanism and establish its function. It was found to involve a
calcium-dependent complex between C reactive protein and very low density
lipoprotein, which can slow down normal bacterial clearance by the body.
It is the knowledge of this molecular mechanism that has enabled the
development of new assays for sepsis . These assays form the key
technology platform for routine point-of-care use of the laboratory-based
aPTT waveform directly into clinical settings. Four patents have also
arisen from this research [4-7].
References to the research
1. Downey C, Kazmi R, Toh CH. Novel and diagnostically applicable
information from optical waveform analysis of blood coagulation in
disseminated intravascular coagulation. B J Haem 1997; 98: 68-73.
Citations: 47 Impact Factor: 4.942
2. Toh CH, Samis J, Downey C, Walker J, Becker L, Bruffato N,
Tejidor L, Jones G, Houdijk W, Giles AR, Koschinsky M, Ticknor L, Paton
R, Wenstone R, Nesheim ME. Biphasic transmittance waveform
in the APTT coagulation assay is due to the formation of a calcium
dependant complex of C-reactive protein with very-low-density-lipoprotein
and is a novel marker of impending disseminated intravascular coagulation.
Blood 2002, 100, 2522-2529. Citations: 70 Impact Factor: 9.060
3. Toh CH, Ticknor LO, Downey C, Giles AR, Paton R, Wenstone
R. Early identification of sepsis and mortality risks through
simple, rapid clot-waveform analysis. Intensive Care Medicine 2003, 29,
55-61. Citations: 46 Impact Factor: 5.258
Patents arising directly from the research.
4. WO00046603A1 (2000) describes "A method and apparatus for predicting
the presence of haemostatic dysfunction in a patient sample."
5. WO01013125A1 (2000) describes "A Method for predicting the presence of
haemostatic dysfunction in a patient sample." http://www.wipo.int/pctdb/en/wo.jsp?WO=2001013125
6. WO01096864A2 (2001) describes "A method for detecting a
lipoprotein-acute phase protein complex and predicting an increased risk
of system failure of mortality."
7. WO03073099A1 (2003) describes "A Method for diagnosing and monitoring
haemostatic dysfunction, severe infection and systemic inflammatory
2005-2007. MRC (G0400488). The role of very low density
lipoprotein in enhancing thrombin generation in sepsis. £89,408, Toh
CH, N Rhodes, M Leuwer.
2007-2010. NIHR Biomedical Research Centre Project 3515, A
Prospective Study of the aPTT Waveform and Lipoprotein-Complexed C
Reactive Protein Assays in the Early Diagnosis and Prognosis of Sepsis.
£330,820, Toh CH, Welters I, Williamson PR
2010. NIHR Innovation for Invention Future Product Development Stage
1: (II-FS-0509-12093). A Point-of-Care Test for Sepsis based on
Calcium-induced Turbidity in Blood, £100k, Toh CH, Myers P.
2010-2012. Technology Strategy Board. Rapid point-of-care
detection of bacterial sepsis. £160k, Toh CH
2011-2014. NIHR Innovation for Invention Late Stage Development:
((II-LS-1010-10045). A Point-of-Care Test for Sepsis based on
Calcium-induced Turbidity in Blood, £300k, Toh CH, Myers P.
Details of the impact
The impacts in this section have all occurred in 2008 or later and have
occurred as a direct result of the UoL research.
As already mentioned, sepsis is a major cause of mortality and morbidity.
In England, Wales and Northern Ireland, 27% of adult admissions to
critical care in the period December 1995 to January 2005 were found to
progress to severe sepsis within the first 24 hours. Hospital mortality in
2004 in this geography was estimated to be 44.7% for those with severe
sepsis or 14,000 cases. Other estimates are higher. Prompt diagnosis and
treatment is essential with one study reporting a 7.6% increase in
mortality for each hour that antibiotic treatment was delayed in patients
with septic shock [18,19].
Following publication of the UoL research, there was recognition that the
aPTT biphasic waveform measurements could be important through enabling
earlier diagnosis to lead onto clinical benefits for patients and economic
benefits for health system providers. Several influential journal
editorials drew international attention to the research outputs [14-17].
This led to demonstration of the benefits in two disease areas where
infection is a common and important complication, namely heart bypass
surgery and the treatment of cancer [8,9]. The superiority of the aPTT
biphasic waveform over the leading sepsis biomarker, procalcitonin, in
clinical settings has also been investigated and confirmed .
This work led the British Committee for Standards in Haematology, a
leading professional body in the UK, to invite Toh and others to specify
laboratory standards for diagnosing the sepsis-related complication of
disseminated intravascular coagulation (DIC). These were published in 2009
 and included the aPTT waveform. These measurements are being promoted
by laboratories among their clinical customers and also by haematologists
requiring these measurements to improve clinical outcomes. Whilst
initially focussed on patients in intensive care settings, the rapid,
reliable and low cost measurement is leading to the test being used in
emergency rooms, post-surgical wards and oncology. This increase in
testing for sepsis is leading to earlier diagnosis and appropriate
treatment. Through improved diagnosis, it is also reducing the use of
antibiotics through an accurate distinction between bacterial and viral
disease . The research is therefore clearly and directly impacting
upon clinical and laboratory medicine practitioners in the UK and also
specialists, including haematologists, emergency and critical care
physicians and paediatricians. Patients are benefiting through improved
treatment and reduction in the burden of sepsis on the NHS.
In a similar way, Toh was asked to contribute to the International
Society on Thrombosis Haemostasis's work to establish standards
internationally for diagnosing DIC and for laboratories offering the aPTT
biphasic waveform test to ensure that there is international consistency
in its application. Guidelines were published in Feb 2013 and work on
standardising the use of aPTT biphasic waveform measurements throughout
the world is ongoing . They are impacting upon laboratories,
clinicians and patients in a similar way to the UK.
These advances have also been integrated into UK and international
training in haematology .
A new spinout company, Sepsis Ltd, was formed in 2010 and has acquired
the four patents arising from the UoL research. Its objective is to
develop devices incorporating aPTT biphasic waveform technology that can
be used at points of care for the routine testing of sepsis, from GP
surgeries to emergency rooms. The company has secured £250k of investment
funding and £1.2m from the Technology Strategy Board. It has already
developed a prototype device and by the end of 2013 will employ 3 people.
Sources to corroborate the impact
Each source listed below provides evidence for the corresponding numbered
claim made in section 4 (details of the impact).
- Delannoy, et al. Effect of cardiopulmonary bypass on aPTT waveform
analysis, serum procalcitonin and CRP concentrations. Crit Care 2009;
- Hussain, et al. The biphasic transmittance waveform: an early marker
of sepsis in patients with neutropenia. Thromb Haemost 2008; 100: 146-8.
- Zakariah A, et al. Combination of biphasic transmittance waveform with
blood PCT levels for diagnosis of sepsis in acutely ill patients. Crit
Care Med 2008; 36: 1507-12.
- Clinical guidelines: Guidelines for the diagnosis and management of
disseminated intravascular coagulation. Br J Haematol 2009; 94: 387-94.
- Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK,
Nielsen JD, Dempfle CE, Levi M, Toh CH; Guidance for diagnosis and
treatment of DIC from harmonization of the recommendations from three
guidelines. (2013) The Scientific Standardization Committee on DIC of
the International Society on Thrombosis Haemostasis. http://www.ncbi.nlm.nih.gov/pubmed/23379279
- Postgraduate Haematology (Wiley-Blackwell) 6th Edition (2010), edited
by Victor Hoffbrand, Daniel Catovsky, Edward GD Tuddenham and Tony
Green. Chapter on Acquired Coagulation Disorders features the aPTT
Journal editorials on the aPTT biphasic waveform in sepsis
- ten Cate H. The biphasic waveform in plasma: identifying the
sepsis-coagulation crossroad. J Thromb Haemost 2004; 2: 1534-5.
- Thomas K. Transmitting and absorbing new information on the early
identification of sepsis patients: aPTT waveform. Crit Care Med 2006;
- Dempfle CE, Borggrefe M. The hidden sepsis marker: aPTT waveform
analysis. Thromb Haemost 2008; 100: 9-10.
- Schneider CP, Angele MK, Hartl WH. aPTT waveform analysis as specific
sepsis marker in cardiopulmonary bypass surgery. Crit Care 2010; 14:
Evidence of the serious nature of septic shock
- Harrison DA, et al. The epidemiology of severe sepsis in England,
Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high
quality clinical database, the ICNARC Case Mix Programme Database.
Critical Care 2006, 10:R42 doi:10.1186/cc4854 http://ccforum.com/content/10/2/R42
- Gaieski D, et al. Impact of time to antibiotics on survival in
patients with severe sepsis or septic shock in whom early goal-directed
therapy was initiated in the emergency department. Crit Care Med 2010;
38; 3. DOI: 10.1097/CCM.0b013e3181cc4824