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Potential for important benefits in both management and outcome:

‘Rapid diagnosis of sepsis’ symposium

With the goal of discussing new technologies and improved methods for diagnosing sepsis, microbiologists and intensivists from a number of hospitals gathered to share their findings and experiences. The key focus of the meeting was the new LightCycler SeptiFast polymerase chain reaction (PCR) test from Roche Diagnostics and the potential advantages and challenges of using this test for sepsis diagnosis in routine practice.

CHANGING RATES OF SEPSIS INCIDENCE AND MORTALITY

Setting the scene, the meeting’s chairman Dr Richard Beale, Director of Perioperative and Critical Care Medicine at Guy’s and St Thomas’s Hospital, London, outlined the overall problem of sepsis in the ICU. Dr Beale referred to a major US epidemiological study of sepsis, showing that the incidence of sepsis and the number of sepsis related deaths are both increasing (although the overall mortality rate among patients with sepsis is declining).1

The review of discharge data on approximately 750 million hospitalisations in the US over a 22-year period identified 10,319,418 cases of sepsis. Between 1979 and 2000, there was an annual increase in the incidence of sepsis of 8.7%. The rate of sepsis due to fungal organisms increased by 207% during this period. Gram positive bacteria became the predominant pathogens after 1987.

In terms of severe sepsis, data from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database (which was gathered from 343,860 admissions to 172 critical care units in England, Wales and Northern Ireland between December 1995 and January 2005) also show a rise over the last decade.2  In total, 92,672 admissions (27%) were of patients identified as having severe sepsis in the first 24 hours following admission. This figure rose from 23.5% in 1996 to 28.7% in 2004 (from an estimated 18,500 to 31,000 admissions). Hospital mortality for admissions with severe sepsis decreased from 48.3% in 1996 to 44.7% in 2004, but the total number of deaths increased from an estimated 9,000 to 14,000.

“The magnitude of severe sepsis as a public health issue is very substantial, yet it does not get the recognition, profile or investment that other commonly recognised conditions get. Sepsis is poorly recognised by the public, patients, doctors and nurses,” said Dr Beale.

CURRENT SEPSIS MANAGEMENT

In an attempt to reduce mortality and rates of sepsis and improve standards of care, the European Society of Intensive Care Medicine, the International Sepsis Forum and the Society of Critical Care Medicine have launched a global programme, ‘The Surviving Sepsis Campaign’. As part of the programme new evidence-based guidelines for the management of severe sepsis and septic shock have now been produced.3,4 The Surviving Sepsis Campaign, in collaboration with the Institute for Healthcare

Improvement in the USA, has developed two ‘bundles’ – or packages – of care, for the treatment of severe sepsis: the Severe Sepsis Resuscitation Bundle (to be completed in six hours from the onset of severe sepsis) and the Severe Sepsis Management Bundle (to be completed in 24 hours from onset).

However, a prospective observational study on 101 consecutive adult patients with severe sepsis or septic shock at two National Health Service teaching hospitals in England showed a lack of compliance with the bundles.5 The rate of compliance with the six-hour sepsis bundle was 52%. Compared with the compliant group, the noncompliant group had a more than twofold increase in hospital mortality. Compliance with the 24-hour sepsis bundle was achieved in 30% of eligible candidates (21/69). Hospital mortality was increased in the non-compliant group from 29% to 50%, with a 76% increase in risk for death. “Mortality was much higher where there was non-compliance, but within hospitals we struggle to get a compliance rate above 50–60%,” said Dr Beale. “Against this background, early diagnostics offer potentially enormous benefits to us. Even where every effort is made, initial blood cultures still get missed, and there are delays in receiving results. There is a clear opportunity for other rapid diagnostic techniques”.

POTENTIAL BENEFITS OF USING PCR TECHNOLOGY

The CE-marked LightCycler SeptiFast assay from Roche Diagnostics first became available in the UK in 2006. A key advantage of the test, which can detect and identify 25 different bacterial and fungal species pathogens directly from the blood sample, is its speed. Prior incubation or culture steps are not required, and a laboratory can provide a result within six hours (from sample preparation to final report). Therefore, this can enable faster treatment with a specific antibiotic and the detection of fungal pathogens (which currently can take up to eight days to detect using blood culture).

The test is now being trialled in a number of intensive care units within the UK to assess how the assay could work in routine practice to improve sepsis diagnosis and management. Of the five hospitals whose staff presented their results at the Sepsis Symposium, all found that SeptiFast had good diagnostic accuracy with high rates of specificity and sensitivity. From the Salford Royal NHS Foundation Trust, where a study was conducted among 101 patients (150 samples) requiring blood culture for suspected severe sepsis, it was reported that SeptiFast had a sensitivity rate of 87% (59–98%) and a specificity rate of 92% (86–96%) when compared with culture.

“We were very impressed with the diagnostic accuracy of SeptiFast,” said Professor Paul Dark, Research Director & Honorary Consultant Intensivist, Salford Royal NHS Foundation Trust, who presented the results. “For our environment, the most significant advantage is the early diagnosis alongside pathogen identification. As a practising intensive care clinician, you have to make difficult and quick decisions about whether or not to start antibiotics and which spectrum of cover. We feel that having the results in four to six hours would help to guide the most appropriate therapeutic interventions alongside current evidence-based guidelines. Our ability to get patients into the right bundle of care early is very important and can save lives.”

At Sheffield Teaching Hospitals a trial was carried out among 56 GITU and HDU patients, with samples taken at the same time as blood cultures (207 samples in total). SeptiFast gave a positivity rate of 31.9%, compared to a blood culture positivity rate of 24.6%.

SeptiFast was negative on two occasions where the blood culture system isolated significant organisms, as the two organisms in question were unusual and as such, are not in the SeptiFast Master List (25 top target organisms),” said Steve Davies, Bacteriology Departmental Manager at Northern General Hospital. “Everything else that SeptiFast identified as a significant organism, when negative in blood culture, was picked up in another microbiology sample in that patient – so it was conclusive evidence of the sensitivity of SeptiFast.”

IS PCR QUICKER THAN BLOOD CULTURE?

The benefits of using SeptiFast nevertheless varied from one centre to another and not all hospitals were able to take advantage of the ability to get a fast result.

Gary Creed, Clinical Physiologist, who presented the results of the trial at St Thomas’s Hospital, questioned: “Is PCR quicker than blood culture? That depends on the set-up and whether there is someone in the unit designated to do the testing.” The St Thomas’s study found that SeptiFast had a 32% positivity rate compared with a 12% positivity rate with blood culture. Elaine Green, Department of Microbiology, Great Ormond Street Hospital (GOSH), stated that SeptiFast was rarely faster than blood cultures, due to the study set-up, and 66 samples were excluded, for a variety of reasons. After analysing the results from 124 samples from 52 patients, the hospital concluded that the fungal diagnosis was potentially beneficial. “We are very interested in expanding and looking into the fungal diagnosis, as this is an area where we felt SeptiFast gave us additional information,” said Ms Green.

Summarising the results she concluded that staff at GOSH would like to look at the possibility of using this assay in a specific time-managed process for oncology and haematology patients. However, any further use of SeptiFast would still be in the form of continued collaboration with Roche on a research basis - rather than purchased as a diagnostic test.

Presenting the results of a trial on unselected patients on ICU/HDU undergoing blood cultures, Dr Andrew Sails, Head of Research and Development, at the Health Protection Agency, Newcastle, concluded that there was particular interest in the ability of SeptiFast to identify line colonisation. “SeptiFast detected significantly more pathogens than conventional blood culture and picked up more multiple infections,” he said. “But it’s impossible to compare the results as these are two completely different technologies. For us, SeptiFast was not faster than blood culture, but this is because samples were forwarded to another laboratory.”

WHERE TO FROM HERE? THE PRACTICAL CHALLENGES

While clinicians presented positive findings from their trials, many questions were raised about the assay and it was agreed that while the assay cannot yet replace traditional microbiology, it has the potential to offer important benefits that could make a real difference.

There are, nevertheless, a number of practical considerations that need to be addressed, and until these are managed effectively within hospitals, it was agreed that it would be difficult to implement SeptiFast into routine practice. The key issues discussed were costs, staff resources, staff training and how to decide on which patients the test should be used. As Steve Davies commented: “SeptiFast is a good system and we would like to introduce it, but who is going to pay for it? The consumables are quite expensive and it’s also labour intensive. To set up seven samples it takes approximately two and a half hours.”

Gary Creed pointed out that, optimally, the test should be available 24 hours a day, at clinicians’ requests. “But to perform the test in real time you would need a significant increase in staff numbers. This could be one of the most important tests that we do, but the biggest challenge is the money.”

Trusts, however, may well be prepared to invest in this technology if they are convinced there is a proven benefit. “The first major benefit is around getting the right antibiotics early. There is a potential to narrow therapy down to stop unnecessary therapy, with cost and ecological savings,” said Dr Beale.

A reduction in bed usage could certainly make a convincing argument. Professor Benito Regueiro, Microbiologist at the University of Santiago de Compostela, Spain, has now begun using SeptiFast in clinical practice. In an observational study he conducted, involving 53 patients, he calculated that giving clinicians SeptiFast results to guide decision-making had made a significant impact. Ultimately, this resulted in a lower mortality rate and a reduction of 15 days’ bed usage per episode.

Specialists will also need to consider how the therapy can be narrowed down for use among specific patients; it was suggested that these could include critically ill, cardiac surgery and oncology transplant patients.

INNOVATION IN COMBINATION WITH CONVENTIONAL TECHNIQUES

If the challenges are addressed, and a precise role for SeptiFast is agreed within individual hospitals, then the consensus was that this assay could be a highly useful addition to traditional microbiology and should be used routinely.

Roche Diagnostics has described SeptiFast as a significant innovation due to the fact that it is the first in-vitro diagnostic (IVD) to address sepsis from the perspective of the organism affecting the patient; it is the first time that a multiplex PCR assay has been brought to market at this level; and it is also one of the first technology assays that is IVD validated and targets microbiology. The company is currently working with hospitals to help them to successfully implement the assay into practice, while also looking at how future developments may further enhance SeptiFast’s role in sepsis diagnosis. For instance, a fully automated SeptiFast assay could certainly prove useful, but there substantial technical complexities involved.

This assay may not be the sole solution for reversing the trend of increasing sepsis rates or reducing the associated mortality, but given the convincing evidence for its sensitivity and its capability for achieving such a rapid result, it has the potential to be a key part of the wider picture in this endeavour.

Dr Beale concluded: “SeptiFast is a very useful test. It provides us with additional information that can be used in combination with other results for a holistic approach. I think that we can all agree that we need to be doing something in addition to current practice to improve the diagnosis and management of sepsis.”

REFERENCES

1. Martin GS, Mannino DM, Eaton S, Moss M. The Epidemiology of Sepsis in the United States from 1979 through 2000. NEJM 2003; 348: 1546–1554.

2. Harrison DA, Welch CA, Eddleston JM. 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. Crit Care 2006; 10: R42.

3. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296–327.

4. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34: 17–60.

5. Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis - prospective observational study. Crit Care 2005; 9: R764–770. ■

 

 

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