Sepsis, or blood poisoning, is a global healthcare problem. More common than heart attacks, and claiming more lives than any cancer, the condition is one the biggest killers in the developed world1. Such a high mortality rate is largely due to the fact that current diagnostic methods cannot diagnose patients in time to treat them.
However, photonics is enabling the development of systems that can diagnose sepsis in hours, as opposed to days typically required by existing techniques. These faster systems promise to not only save countless lives, but help to prevent antibiotic resistance and reduce the global health-economic burden.
Sepsis occurs when an infection spreads through the bloodstream to other areas of the body, causing tissue damage and organ failure. It is often described as a silent killer, as its symptoms often suggest less serious illnesses such as influenza, making it extremely difficult to identify for both healthcare professionals and the public.
But even if doctors manage to recognise the condition, treating sepsis carries its own challenges. Doctors must identify the bacteria that caused the infection in order to deliver the most effective treatment. However, this is a time-consuming and complex process, explained Professor Jürgen Popp, director of the Institute of Photonic Technology (IPHT) in Jena, Germany: ‘Most of the currently existing microbiological approaches to characterise microorganisms rely on cultivation (i.e. the pathogens will be cultivated from patient blood samples) which often takes several days.’
Seeing as most cases of sepsis end fatally within around 48 hours, it is clear that current diagnostic methods are not fast enough. ‘Currently, there is no really good test system that can unequivocally diagnose sepsis at an early stage,’ said Professor Popp.
Sepsis is one of the biggest killers in the United States, claiming more lives than prostate cancer, breast cancer, and AIDS combined. In England, sepsis is the second leading cause of death after cardiovascular disease, and in Germany, it is the third.
Healthcare authorities are indeed struggling to deal with the challenge of sepsis. In December 2015, the UK’s National Health Service (NHS) released a ‘sepsis action plan’ on how to reduce the number of deaths from the condition2. The plan said doctors are limited by their ‘lack of laboratory services’ in their ’ability to distinguish between sepsis, severe sepsis and septic shock’.
But not being able to diagnose and treat sepsis effectively is also contributing to an even larger healthcare crisis; antibiotic resistance. Due to the seriousness of the condition, if a doctor suspects sepsis then they will start the patient on broad-spectrum antibiotics, as previously mentioned – there simply isn’t enough time to wait for lab results. This overuse of broad-spectrum antibiotics contributes to the creation of ‘superbugs’, strains of bacteria that are resistant to several types of antibiotic treatments.
‘Treatment with broad spectrum antibiotics increases the likelihood of the infectious agent mutating in order to resist the antibiotic,’ explained Dr Kavita Aswani, senior applications scientist, life sciences, Excelitas. ‘This is how the whole MRSA issue in hospitals came about. Bacteria and other infectious agents are becoming smarter and developing resistance to antibiotics, making it trickier to treat these infections.
‘There is a need to be able to identify sepsis infections quickly… so the physician doesn’t have to start the patient on a broad range of antibiotics. They can treat the patient according to the infection they have,’ Aswani said.
The speed of light
It’s not all bad news, however. There are many research institutions and biomedical companies working to tackle the shortcomings associated with sepsis diagnosis, and photonics diagnostic systems are being developed that promise to reduce the time it takes to treat the condition.
According to Professor Popp, an effective system that would ensure the early diagnosis and treatment of sepsis would be, ‘a multi-parameter device that only needs minimal blood or other body liquids… to quickly (in less than five hours) identify the sepsis-causing pathogens, their antibiotic resistance, and the specific host for choosing the appropriate initial antibiotic therapy to save lives in intensive care units,’ he said.
HemoSpec is one such project working towards this goal, aiming to develop an innovative photonic device for the early, fast and reliable medical diagnosis of sepsis using only a minimal amount of a patient’s blood. Coordinated by the IPHT, the EU project involves two hospitals, Germany’s Centre for Sepsis Control and Care (CSCC), the University hospital of Athens, the Italian Research Council (CNR), as well as four companies: France’s Horiba Scientific; biomedical software company, Bmd (Portugal); ViroGates, an international Biotech company (Denmark); and biomedical instrument manufacturer, Data Med (Italy).
HemoSpec will combine three complementary biophotonic technologies into one device: automated microfluidic sample handling with integrated holographic blood count; simultaneous multiplex fluorescence biomarker sensing; and detailed Raman spectroscopic leukocyte characterisation.
As part of the project, the IPHT is developing a digital inline holographic microscope for the blood count. The institute is also developing Raman spectroscopy techniques, whereby light is sent through the body fluid sample, and as the light hits a pathogen, it is scattered, creating a characteristic fingerprint. The pathogen can then be identified against a Raman spectroscopic pathogen database. This Raman method can also be used to determine the overall chemical composition and molecular structure of the blood cells, which is useful for differentiating patients from varying disease groups, including inflammatory response syndrome, severe sepsis, and septic shock.
The advantage to Raman spectroscopy is that it can identify even single bacteria, and therefore does not require cell cultivation steps. ‘We could demonstrate the unique potential of Raman spectroscopy to bypass time-consuming cultivation procedures, enabling an identification of sepsis pathogens directly out of body liquids in less than three hours,’ said Professor Popp.
Such a short analysis time has been achieved through the development of an automated Raman setup for use in clinics, the BioParticle Explorer, together with innovative pathogen isolation strategies, such as the use of dielectrophoresis (DEP) Raman chips. DEP chips allow for the analysis of extremely small sample sizes, through the miniaturisation of complex chemical and physical procedures onto a single microchip-based device.
The Raman setup has also been used to investigate a bacteria’s potential resistance, so that the patient can be treated with a targeted antibiotic that reliably kills the pathogen. ‘Not only has the identification been realised, but also the characterisation of bacteria-drug interaction as a first step towards antibiotic susceptibility testing. Changes in the bacterial Raman spectra due to antibiotic treatment can be identified already after 30 minutes of treatment,’ Professor Popp remarked.
In addition, the device will not just be faster than existing diagnostic methods, but will provide doctors with a much more definitive result, according to Professor Popp. ‘Most of the existing devices identify one of the many biomarkers or symptoms… and because they measure only one of the many biomarkers they are not as reliable,’ he explained. ‘They can only provide certain probabilities, which can guide the physicians in their therapy.’
IPHT and HemoSpec are now working to prove the reliability of photonic analysis for a better diagnosis clinical trial. ‘I am very optimistic that we will see this Raman approach as point-of-care test for a fast identification of pathogens, and the determination of their antibiotic resistances, within the next 10 years as diagnostic tool in daily clinical practice’, Prefessor Popp commented.
Enabling light
The development of faster, more reliable systems such as these would not have been possible without the advances made in photonics and optics technologies over the last decade. Not only has photonics become smaller, cheaper, and longer lasting, laser sources have become more efficient and powerful, and detectors more sensitive.
‘Advances [in power, cost, efficiency] were very important for addressing many of the relevant biomedical questions we are investigating currently and that will hopefully benefit the physicians,’ added Professor Popp. ‘Many of the biomedical differences/variances that are probed with photonic technologies are very small, such as the differences in the immune response in sepsis patients with an infection and in patients with a systemic inflammatory response syndrome without an infection.’
Popp continued: ‘To tackle those differences with photonic devices requires good laser sources, high-quality spectrometers and sensitive detectors. In order to be ultimately applied in the hospital routine, all those components have to be cost-efficient, small and user-friendly, allowing non-specialised persons to operate the developed photonic technologies.’
Recently, the IPHT established the InfectoGnostics research campus, a public-private partnership developing new methods in infection diagnostics. In a triad of technology, application and production, more than 30 partners from science, medicine and industry are developing marketable solutions for rapid and cost-effective on-site analysis (point-of-care testing) of infections.
Developing marketable solutions was a theme of the Association for Molecular Pathology’s scientific meeting, which took place in Austin, Texas in November 2015. The four-day event involved companies showcasing the latest medical diagnostic systems and demonstrated how companies develop strategies to address specific markets. ‘A term that I heard at this conference was “sample-to-result” – how quickly can you give the sample and get the result? This is what is driving companies right now,’ noted Joe Delfino, vice president of sales, life science and analytical, Excelitas.
‘There will always be a desire to improve the sample-to-result time to create the optimal patient outcome experience,’ Delfino added. ‘Whether it is a routine doctor visit for strep, or a potentially life threatening complication of a critical infection like sepsis – the ability to identify the infection quickly and begin treatment is critical to medical care professionals.’
Medical diagnostics represents a growing area for photonics, including for Excelitas, as medical device companies and research bodies strive to meet healthcare authorities’ demand for faster diagnosis of sepsis and infectious diseases.
‘There is so much going on between the different medical companies who are all trying to keep ahead of the competition and become smaller, faster, and cheaper,’ noted Excelitas’ Aswani. ‘Where we come in is working with companies to provide the light source, work to get the light to the sample, and then get the results from your sample to the detectors.’
‘From R&D/feasibility study through to optical-mechanical design and system architecture, Excelitas is involved at the beginning stages of a project to influence design and manufacturability,’ added Delfino.
A question of when
It is fair to say that a more effective solution for diagnosing sepsis is imperative for not only reducing mortality, but for preventing the overuse of antibiotics and reducing the health-economic burden.
Although it is not likely that a complete, definitive solution for sepsis will be seen hospitals in 2016, recent developments – such the IPHT Raman system – represent a new hope for tackling this huge health problem. ‘I am convinced that various diagnostic approaches for a fast and reliable diagnosis of sepsis will be developed in the future,’ Professor Popp concluded.
References
1 http://www.electrooptics.com/admin/www.world-sepsis-day.org
