The ability to diagnose sepsis in minutes

An MIT-invented microfluidics device could help doctors diagnose sepsis, a leading cause of death in U.S. hospitals, by automatically detecting elevated levels of a sepsis biomarker in about 25 minutes, using less than a finger prick of blood. Image: Felice Frankel

When time matters in hospitals, automated system can detect an early biomarker for the potentially life-threatening condition.

A novel sensor designed by MIT researchers could dramatically accelerate the process of diagnosing sepsis, a leading cause of death in U.S. hospitals that kills nearly 250,000 patients annually.

Sepsis occurs when the body’s immune response to infection triggers an inflammation chain reaction throughout the body, causing high heart rate, high fever, shortness of breath, and other issues. If left unchecked, it can lead to septic shock, where blood pressure falls and organs shut down. To diagnose sepsis, doctors traditionally rely on various diagnostic tools, including vital signs, blood tests, and other imaging and lab tests.

In recent years, researchers have found protein biomarkers in the blood that are early indicators of sepsis. One promising candidate is interleukin-6 (IL-6), a protein produced in response to inflammation. In sepsis patients, IL-6 levels can rise hours before other symptoms begin to show. But even at these elevated levels, the concentration of this protein in the blood is too low overall for traditional assay devices to detect it quickly.

In a paper being presented this week at the Engineering in Medicine and Biology Conference, MIT researchers describe a microfluidics-based system that automatically detects clinically significant levels of IL-6 for sepsis diagnosis in about 25 minutes, using less than a finger prick of blood.

In one microfluidic channel, microbeads laced with antibodies mix with a blood sample to capture the IL-6 biomarker. In another channel, only beads containing the biomarker attach to an electrode. Running voltage through the electrode produces an electrical signal for each biomarker-laced bead, which is then converted into the biomarker concentration level.

“For an acute disease, such as sepsis, which progresses very rapidly and can be life-threatening, it’s helpful to have a system that rapidly measures these nonabundant biomarkers,” says first author Dan Wu, a PhD student in the Department of Mechanical Engineering. “You can also frequently monitor the disease as it progresses.”

Joining Wu on the paper is Joel Voldman, a professor and associate head of the Department of Electrical Engineering and Computer Science, co-director of the Medical Electronic Device Realization Center, and a principal investigator in the Research Laboratory of Electronics and the Microsystems Technology Laboratories.

Integrated, automated design

Traditional assays that detect protein biomarkers are bulky, expensive machines relegated to labs that require about a milliliter of blood and produce results in hours. In recent years, portable “point-of-care” systems have been developed that use microliters of blood to get similar results in about 30 minutes.

But point-of-care systems can be very expensive since most use pricey optical components to detect the biomarkers. They also capture only a small number of proteins, many of which are among the more abundant ones in blood. Any efforts to decrease the price, shrink down components, or increase protein ranges negatively impacts their sensitivity.

In their work, the researchers wanted to shrink components of the magnetic-bead-based assay, which is often used in labs, onto an automated microfluidics device that’s roughly several square centimeters. That required manipulating beads in micron-sized channels and fabricating a device in the Microsystems Technology Laboratory that automated the movement of fluids.

The beads are coated with an antibody that attracts IL-6, as well as a catalyzing enzyme called horseradish peroxidase. The beads and blood sample are injected into the device, entering into an “analyte-capture zone,” which is basically a loop. Along the loop is a peristaltic pump — commonly used for controlling liquids — with valves automatically controlled by an external circuit. Opening and closing the valves in specific sequences circulates the blood and beads to mix together. After about 10 minutes, the IL-6 proteins have bound to the antibodies on the beads.

Automatically reconfiguring the valves at that time forces the mixture into a smaller loop, called the “detection zone,” where they stay trapped. A tiny magnet collects the beads for a brief wash before releasing them around the loop. After about 10 minutes, many beads have stuck on an electrode coated with a separate antibody that attracts IL-6. At that time, a solution flows into the loop and washes the untethered beads, while the ones with IL-6 protein remain on the electrode.

The solution carries a specific molecule that reacts to the horseradish enzyme to create a compound that responds to electricity. When a voltage is applied to the solution, each remaining bead creates a small current. A common chemistry technique called “amperometry” converts that current into a readable signal. The device counts the signals and calculates the concentration of IL-6.

“On their end, doctors just load in a blood sample using a pipette. Then, they press a button and 25 minutes later they know the IL-6 concentration,” Wu says.

The device uses about 5 microliters of blood, which is about a quarter the volume of blood drawn from a finger prick and a fraction of the 100 microliters required to detect protein biomarkers in lab-based assays. The device captures IL-6 concentrations as low as 16 picograms per milliliter, which is below the concentrations that signal sepsis, meaning the device is sensitive enough to provide clinically relevant detection.

A general platform

The current design has eight separate microfluidics channels to measure as many different biomarkers or blood samples in parallel. Different antibodies and enzymes can be used in separate channels to detect different biomarkers, or different antibodies can be used in the same channel to detect several biomarkers simultaneously.

Next, the researchers plan to create a panel of important sepsis biomarkers for the device to capture, including interleukin-6, interleukin-8, C-reactive protein, and procalcitonin. But there’s really no limit to how many different biomarkers the device can measure, for any disease, Wu says. Notably, more than 200 protein biomarkers for various diseases and conditions have been approved by the U.S. Food and Drug Administration.

“This is a very general platform,” Wu says. “If you want to increase the device’s physical footprint, you can scale up and design more channels to detect as many biomarkers as you want.”

Learn more: Microfluidics device helps diagnose sepsis in minutes

 

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A new pathway to regulate immune response and control inflammatory diseases like sepsis and meningitis

Non-coding RNA (ncRNA) regulates cytokines expression, immune response, and inflammation

Researchers at The University of Texas at Arlington have found a potential new pathway to regulate immune response and potentially control inflammatory diseases of the central nervous system such as meningitis and sepsis.

“We need to know what turns on inflammatory response to bacterial infection to be able to modulate the process,” said Subhrangsu Mandal, the UTA associate professor of chemistry who led the research.

“If we can do so, we can control inflammatory diseases of the central nervous system that have been hard to treat up to now, such as sepsis and meningitis, as well as cancer and muscular dystrophy, which can also be seen a kind of inflammation,” he added.

Mandal and his team’s research findings were published in Scientific Reports.

The researchers have found that the long non-coding RNA molecule HOTAIR present in white blood cells has the capacity to signal these cells to activate immune response in the presence of bacteria. RNA, or ribonucleic acid, is present in all living cells. Its primary role is to carry instructions from DNA.

“Knowing that HOTAIR has a role in the signaling pathway also means that we can use it as a biomarker for bacterial infection,” he added. “Simple blood tests could indicate infection much more quickly, enabling better treatment for patients of rapidly-moving diseases such as septic shock and meningitis, which have been hard to treat up to now.”

The researchers used the resources of UTA’s North Texas Genome Center to demonstrate that noncoding RNA expression – including HOTAIR –  is induced in white blood cells treated with lipopolysaccharide, which are molecules found on the outer membrane of bacterial cells. The research showed that HOTAIR gene was expressed alongside cytokines, which are excreted by cells as part of immune response, and inflammatory response genes such as iNOS. As a result, it is possible to conclude that HOTAIR is a key regulator for pathogen-induced cytokine expression, immune response and inflammation.

“Long non-coding RNAs like HOTAIR are emerging as key regulators of cell signaling processes and many are expressed in immune cells and play a critical role in immune response,” Mandal said. “Previous research carried out with Marco Brotto in UTA’s College of Nursing and Health Innovation had already established a link between low flow of oxygen to tissues and HOTAIR, which has been linked to cancer.”

“Having a resource like the North Texas Genome Center really means that we can multiply our work looking at non-coding RNAs in general, a burgeoning field in biochemistry,” he added.

Fred MacDonnell, UTA chair of chemistry and biochemistry, congratulated Mandal on this new research.

“Basic science related to the pathways for immune response is critical as there have been very few successes up to now developing treatments for extreme inflammations like sepsis and meningitis, “ MacDonnell said.

Learn more: UTA researchers find new pathway to regulate immune response and control inflammatory diseases like sepsis, meningitis

 

 

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Created: An artificial intelligence system that could help treat patients with sepsis

via Imperial College London

AI doctor could boost chance of survival for sepsis patients

The technology, developed by researchers from Imperial College London, was found to predict the best treatment strategy for patients.

Our new AI system was able to analyse a patient’s data – such as blood pressure and heart rate – and decide the best treatment strategy.Dr Aldo FaisalStudy author

The system ‘learnt’ the best treatment strategy for a patient by analysing the records of about 100,000 hospital patients in intensive care units and every single doctor’s decisions affecting them.

The findings, published in the journal Nature Medicine, showed the AI system made more reliable treatment decisions than human doctors.

The team behind the technology say the tool could be used alongside medical professionals, to help doctors decide the best treatment strategy for patients.

Sepsis, also known as blood poisoning, is a potentially fatal complication of an infection, and kills around 44,000 every year in the UK.

In the study, researchers looked back at US patient records from 130 intensive care units over a 15 year period to explore whether the AI system’s recommendations might have been able to improve patient outcomes, compared with standard care. The researchers now hope to trial the system, called AI Clinician, in intensive care units in the UK.

Choosing the best treatment

Dr Aldo Faisal, senior author from the Department of Bioengineeringand the Department of Computing at Imperial, said: “Sepsis is one of the biggest killers in the UK – and claims six million lives worldwide – so we desperately need new tools at our disposal to help patients. At Imperial, we believe that AI for Healthcare is the solution. Our new AI system was able to analyse a patient’s data – such as blood pressure and heart rate – and decide the best treatment strategy. We found that when the doctor’s treatment decision matched what the AI system recommended, they had a better chance of survival.”

The team used the AI system to assess which particular treatment approach to sepsis was most successful.

Sepsis can cause a drastic drop in blood pressure which can leave organs deprived of blood flow and oxygen, and can ultimately lead to multiple organ failure and death.

Sepsis is a devastating condition which claims far too many lives in the UK. We need to be better at spotting the signs early and artificial intelligence has the potential to do this quickly and more effectively than humans.Lord O’ShaughnessyHealth minister

To raise blood pressure and keep the heart pumping, doctors give extra fluids, usually in the form of a salt solution, as well as medication that tightens blood vessels and raises blood pressure, called vasopressors.

Professor Anthony Gordon, senior author from the Department of Surgery & Cancer at Imperial explained: “We know that most patients with sepsis need fluid drips and in more severe cases also need vasopressors to

maintain blood pressure and blood flow. There is still much debate amongst clinicians about how much fluid to give and when to start vasopressors. There are clinical guidelines but they provide general advice. The AI Clinician is able to learn what is the best option for each individual patient at that moment in time.”

Health Minister Lord O’Shaughnessy added: “Sepsis is a devastating condition which claims far too many lives in the UK. We need to be better at spotting the signs early and artificial intelligence has the potential to do this quickly and more effectively than humans – supporting doctors so they can spend more time with patients.

“We’re already making steps to improve diagnosis with our new sepsis tool, but we must also embrace any new technology solutions that can improve patient care and save lives.”

To help doctors decide which approach would boost a patient’s chance of survival, the research team created an AI system that would assess a patient’s vital signs and recommend the best treatment approach.

Artificial intelligence

The system analysed the medical records of 96,000 US patients with sepsis in intensive care units. Using a process called reinforcement learning – where robots learn how to make decisions and solve a problem – the AI Clinician went through each patient’s case and worked out the best strategy of keeping a patient alive. The system calculated 48 variables including age, vital signs and pre-existing conditions.

The system then predicted the best treatment strategy for each patient with sepsis. The results revealed that 98 per cent of the time, the AI system matched or was better than the human doctors’ decision.

The AI Clinician was able to ‘learn’ from far more patients than any doctor could see in a lifetime.Professor Anthony GordonStudy author

The study also found that mortality was lowest in patients where the human doctor’s doses of fluids and vasopressor matched the AI system’s suggestion. However, when the doctor’s decision differed from the AI system, a patient had a reduced chance of survival.

The team found when the doctor’s decision varied from the AI Clinician’s suggestion, it was on average to administer too much fluid and too little vasopressor but importantly it varied between individual patients.

The team say the findings show the AI Clinician could help doctors decide the best treatment strategy for patients.

Professor Gordon explained “The AI Clinician was able to ‘learn’ from far more patients than any doctor could see in a lifetime. It has learnt from 100,000 patients and ‘remembered’ them all equally whereas doctors are always susceptible to recall bias, where they particularly remember recent cases or unusual cases”.

Dr Faisal explained: “An intensive care doctor will see roughly 15,000 patients by the time they retire. Yet this system has seen nearly 100,000 patients, it has the life time experience of 8 doctors, and has learned from each of those cases what the best decisions were for each situation.”

Next steps

Dr Faisal added: “The explosion in Artificial Intelligence applications in healthcare is currently focused on mimicking the perceptual ability of human doctors, e.g. recognising a tumour from a brain scan as used in diagnostics. However, doctors do more than just diagnose, they treat people. Our AI Clinician system focuses on capturing this cognitive capacity of doctors: Imagine having a doctor watching over you every second of every day, administering a course of treatment, observing how you respond to the treatment, and then adjusting the treatment as your condition evolves.

“The AI Clinician technology we developed can have many applications in medicine, whenever we need to choose, observe and adjust treatment. Whenever there are large amounts of patient data the AI Clinician can assess and learn from, the system can be used. We have applied this technology previously to treatment in diabetes and in anaesthesia during surgery, and can use this to optimise the delivery of expensive treatments e.g. in cancer therapy”.

The team now plan to trial the AI Clinician in UK hospitals. Dr Faisal added: “The only way for any technology to help a patient is to turn it into a product that doctors and hospitals can prescribe, therefore we are seeking to commercialise.”

This work was only possible through the collaboration of artificial intelligence and clinician scientists pioneered at Imperial.

Dr Faisal said: “We broke down boundaries and silos that held back traditional approaches to healthcare, by training a novel generation of PhD students to look at AI and Healthcare as one problem, not two.”

Learn more: AI doctor could boost chance of survival for sepsis patients

 

 

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A new portable device can quickly find sepsis infection from a single drop of blood

University of Illinois researchers and physicians at Carle Foundation Hospital developed a rapid test for sepsis that counts white blood cells and certain protein markers on their surface to monitor a patient’s immune response.
Image by Janet Sinn-Hanlon

Quick test finds signs of sepsis in a single drop of blood

A new portable device can quickly find markers of deadly, unpredictable sepsis infection from a single drop of blood.

A team of researchers from the University of Illinois and Carle Foundation Hospital in Urbana, Illinois, completed a clinical study of the device, which is the first to provide rapid, point-of-care measurement of the immune system’s response, without any need to process the blood.

This can help doctors identify sepsis at its onset, monitor infected patients and could even point to a prognosis, said research team leader Rashid Bashir, a professor of bioengineering at the U. of I. and the interim vice dean of the Carle Illinois College of Medicine. The researchers published their findings in the journal Nature Communications.

Researchers and physicians from the U. of I. and Carle Foundation Hospital developed a rapid test to find sepsis markers in a single drop of blood. Pictured, front row, from left: Astha Tanna and Dr. Karen White. Second row: Umer Hassan, Rashid Bashir, Tanmay Ghonge, Dr. Bobby Reddy Jr. and Ishan Taneja. Third row: Dr. Tor Jenson, Dr. James Kumar and Jacob Berger.

Photo by L. Brian Stauffer

Sepsis is triggered by an infection in the body. The body’s immune system releases chemicals that fight the infection, but also cause widespread inflammation that can rapidly lead to organ failure and death.

Sepsis strikes roughly 20 percent of patients admitted to hospital intensive care units, yet it is difficult to predict the inflammatory response in time to prevent organ failure, said Dr. Karen White, an intensive care physician at Carle Foundation Hospital. White led the clinical side of the study.

“Sepsis is one of the most serious, life-threatening problems in the ICU. It can become deadly quickly, so a bedside test that can monitor patient’s inflammatory status in real time would help us treat it sooner with better accuracy,” White said.

Sepsis is routinely detected by monitoring patients’ vital signs – blood pressure, oxygen levels, temperature and others. If a patient shows signs of being septic, the doctors try to identify the source of the infection with blood cultures and other tests that can take days – time the patient may not have.

The new device takes a different approach.

“We are looking at the immune response, rather than focusing on identifying the source of the infection,” Bashir said. “One person’s immune system might respond differently from somebody else’s to the same infection. In some cases, the immune system will respond before the infection is detectable. This test can complement bacterial detection and identification. We think we need both approaches: detect the pathogen, but also monitor the immune response.”

The small, lab-on-a-chip device counts white blood cells in total as well as specific white blood cells called neutrophils, and measures a protein marker called CD64 on the surface of neutrophils. The levels of CD64 surge as the patient’s immune response increases.

The researchers tested the device with blood samples from Carle patients in the ICU and emergency room. When a physician suspected infection and ordered a blood test, a small drop of the blood drawn was given to the researchers, stripped of identifying information to preserve patient confidentiality. The team was able to monitor CD64 levels over time, correlating them with the patient’s vital signs. Researchers found that the results from the rapid test correlated well with the results from the traditional tests and with the patients’ vital signs.

“By measuring the CD64 and the white cell counts, we were able to correlate the diagnosis and progress of the patient – whether they were improving or not,” said Umer Hassan, a postdoctoral researcher at Illinois and the first author of the study. “We hope that this technology will be able to not only diagnose the patient but also provide a prognosis. We have more work to do on that.”

Bashir’s team is working to incorporate measurements for other inflammation markers into the rapid-testing device to give a more complete picture of the body’s response, and to enable earlier detection. They also have a startup company, Prenosis Inc., that is working to commercialize the device.

“We want to move the diagnosis point backward in time,” Bashir said. “The big challenge in sepsis is that no one knows when you get infected. Usually you go to the hospital when you already feel sick. So the goal is that someday you can be testing this at home, to detect infection even earlier if you can.”

Learn more: Quick test finds signs of sepsis in a single drop of blood

 

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Preventing sepsis by promoting disease tolerance to infection

Iron based sculpture by Portuguese Artist Rui Chafes “Extinguish my eyes” (2005)”.

Sepsis is a major global healthcare problem that affects over 18 million individuals per year, every single year, corresponding to 1,400 deaths per day. In Europe and the US alone, there are an estimated 135,000 and 215,000 causalities and €7.6 and €17.4 billion related treating costs, respectively.

Using experimental models of sepsis in mice the research team led by Miguel Soares at the Instituto Gulbenkian de Ciência in Portugal discovered an unsuspected mechanism that is protective against sepsis. This study that provides new avenues for therapeutic approaches against sepsis appears in the June 15 issue of the prestigious scientific journal Cell*.

Despite being more common than heart attack and more lethal than cancer, the large majority people do not really know what sepsis is. Briefly, it consists of an uncontrolled body’s response to an infection that is spreading towards different parts of the body, also know as a systemic infection. The immune system of the infected individual does try to kill the microbes responsible for the infection, and in many cases manages to do so, but in the process causes profound alterations in the normal functioning of vital organs, such as, the brain, heart, liver, kidney or lungs. In more severe cases blood pressure also drops and those organs ultimately stop functioning properly and as a result the patient dies.

It is well know that sepsis patients vary in their response to infection and disease severity, depending on the type of infection as well as on their genetic characteristics, coexisting illnesses and age. A long lasting unsolved mystery relates to why despite an effective control of the infectious microorganisms by the use antibiotics, some patients succumb while others recover from the infection. Over the past five years the research team led by Miguel Soares has put forward the concept that those individuals that do not succumb to sepsis develop a protective response that maintains the function of vital organs, conferring disease tolerance to the infection. Using experimental models of sepsis in mice they now discovered a mechanism that is vital to confer disease tolerance to sepsis.

“We knew that a key element to promote disease tolerance to infection is how the levels of iron are controlled in different tissues while other colleagues had shown that the pathogenesis of sepsis is associated with deregulation of glucose (sugar) metabolism. What we found is that these two phenomena are intimately linked in that controlling iron metabolism is required to sustain the production of glucose in the liver so that glucose can be used as a vital source of energy by other organs”, says Miguel Soares.

Sebastian Weis a Medical Doctor doing is post-doctoral training with Miguel Soares induced sepsis in laboratory mice and compared how disease progresses in mice that express or not ferritin, a protein that controls iron in the liver. He found that ferritin is absolutely required for the liver to produce glucose after an infection and hence to protect mice from succumbing to sepsis.

“Typically in mice, after infection, there is an increase of blood glucose levels followed by a quick drop, which can become lethal. In humans with infectious disease this also occurs in a subset of patients and is know to lead to higher death rates. Our results showed that ferritin controls glucose production in the liver so that blood glucose levels are maintained within a range that allows survival. Without ferritin, the glucose levels continued to drop and mice eventually die from sepsis”, explains Sebastian Weis, co-first author of the manuscript and currently a researcher and clinician at the Jena University Hospital, Germany, where part of the experiments were conducted.”

Another key piece of this puzzle was provided by Ana Rita Carlos, a PhD working as a post-doctoral fellow with Miguel Soares. She found that the reason why ferritin is required for the liver to produce glucose relies on a molecular mechanism that controls the expression of one of the key genes involved in this process, known as glucose 6 phosphatase. When ferritin is absent, iron deregulates the expression of Glucose 6 phosphatase and the liver loses its capacity to secrete glucose. When this occurs, glucose cannot be delivered and used by other vital organs as a source of energy. This is required to maintain the function of those organs in response to infection and as such to prevent the development of lethal forms of sepsis. This protective mechanism does no influence the microorganisms that are the underlying cause of the disease and as such is said to confer disease tolerance to sepsis.

“It is very interesting that while essential to support many vital cellular functions iron must be tightly controlled in the liver so that it cannot interfere with the production of glucose. The molecular mechanism via which this occurs relies on the expression of ferritin, a protein complex that binds iron and devoid iron from interfering with glucose production” explains Ana Rita Carlos, also a co-first author of the manuscript.

“This is a great example on how basic research conducted in a multidisciplinary environment such as the one provided by the Instituto Gulbenkian de Ciência, without an immediate commercial interest, can have a global impact on the treatment of a major disease that affects over 18 million individuals per year worldwide. Our mission is to make discoveries so that these can be eventually translated into treatments of major diseases”. says Miguel Soares.

Learn more: A Rusty and Sweet Side of Sepsis

 

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