Diagnostic test incorporates artificial intelligence and could shorten the time clinical laboratories need to determine patients’ risk for antimicrobial resistance
Sepsis continues to be a major killer in hospitals worldwide. Defeating it requires early diagnosis, including antimicrobial susceptibility testing (AST), and timely administration of antibiotics. Now, in a pilot study, scientists at Seoul National University in South Korea have developed a new clinical laboratory test that uses artificial intelligence (AI) to pinpoint the condition sooner, enabling faster treatment of the deadly bacterial infection.
Sepsis, also known as septicemia or blood poisoning, is a serious medical condition that occurs when the body overreacts to an infection or injury. This often takes place in hospitals through blood-line infections and exposure to deadly bacteria. The dangerous reaction causes extensive inflammation throughout the body. If not treated early, sepsis can lead to organ failure, tissue damage, and even death.
Research teams around the world are creating new technologies and approaches to slash time to answer from when blood specimen is collected to a report of whether the patient is or is not positive for sepsis. The Seoul National University scientists’ new approach is yet another sign for microbiologists and clinical laboratory managers of the priority test developers are giving to solving the problem of diagnosing sepsis faster than using blood culture methodology, which requires several days of incubation.
“Sepsis strikes over 40 million people worldwide each year, with a mortality rate ranging from 20% to 50%,” said Sunghoon Kwon, PhD (above), professor of electrical and computer engineering at Seoul National University and senior author of the study, in an interview with The Times in the UK. “This high mortality rate leads to over 10 million deaths annually. Thus, accurate and prompt antibiotic prescription is essential for treatment,” he added. Clinical laboratories play a critical role in the testing and diagnosis of sepsis. (Photo copyright: Seoul National University.)
Reducing Time to Diagnosis
Seoul National University’s approach begins with drawing a sample of the patient’s blood. The researchers then attach special peptide molecules to magnetic nanoparticles and add those nanoparticles to the blood sample. The particles bind to the harmful pathogens in the blood.
The harmful bacteria are then collected using magnets. Their DNA is extracted, amplified, and analyzed to establish the type of microbes that are present in the sample.
The pathogens are exposed to antibiotics and an AI algorithm evaluates their growth patterns to forecast what treatments would be most beneficial to the patient. This last step is known as antimicrobial susceptibility testing or AST.
“The principle is simple,” said Sunghoon Kwon, PhD, professor of electrical and computer engineering at Seoul National University and senior author of the study, in a Nature podcast. “We have a magnetic nanoparticle. The surface of the magnetic nanoparticle we coat in a peptide that can capture the bacteria.”
Kwon is the CEO of Quantamatrix, the developer of the test.
The complete process can be performed on one machine and results are available in about 12 hours, which reduces typical AST time by 30 to 40 hours when compared to traditional processes.
“Sepsis progresses very quickly, with the survival rate dropping with each passing hour,” Kwon told The Times UK. “Every minute is crucial.”
Preventing Antimicrobial Resistance
The team assessed the performance of their test on 190 hospital patients who had a suspected sepsis infection. The test achieved a 100% match in the identification of a bacterial species. The test also achieved an efficiency of 96.2% for capturing Escherichia coli (E. coli) and 91.5% for capturing Staphylococcus aureus.
“Treatment assessment and patient outcome for sepsis depend predominantly on the timely administration of appropriate antibiotics,” the authors wrote in Nature.
“However,” they added, “the clinical protocols used to stratify and select patient-specific optimal therapy are extremely slow,” due to existing blood culture procedures that may take two or three days to complete.
“The microbial load in patient blood is extremely low, ranging between 1 and 100 colony-forming units (CFU) ml−1 and is vastly outnumbered by blood cells,” the study authors explained. “Due to this disparity, prior steps—including blood culture (BC) to amplify the number of pathogens followed by pure culture to subculture purified colonies of isolates—have been essential for subsequent pathogen species identification (ID) and AST.”
Further research, studies and regulatory approval are needed before this technique becomes available, but the South Korean scientists believe it could be ready for use within two to three years. They also state their test can help prevent antimicrobial resistance (AMR) and bolster the strength of existing antibiotics.
Previous Studies
The Seoul National University study is just the latest effort by scientists to develop faster methods for clinical laboratory testing and diagnosing of sepsis.
In September, Dark Daily reported on a similar test that uses digital imaging and AI to determine sepsis risk for emergency room patients.
According to the Centers for Disease Control and Prevention (CDC), at least 1.7 million adults develop sepsis annually in the US, and that at least 350,000 die as a result of the condition. CDC also lists sepsis as one of the main reasons people are readmitted to hospitals.
Microbiologists and clinical laboratory managers should be aware that scientists are prioritizing the creation of new testing methods for faster detection of sepsis. Various research teams around the world are devising technologies and approaches to reduce the time needed to diagnose sepsis to improve patient outcomes and save lives.
With FDA clearance already approved, hospital infection control teams and their clinical laboratories may have another diagnostic tool for diagnosing blood infections
Controlling sepsis in hospitals continues to be a major concern in nations around the world, including in the United States. Now, a new 10-minute clinical laboratory blood test that uses artificial intelligence (AI) and digital images to spot biomarkers of the potentially fatal condition may soon be available for use in hospitals. The test, which was approved to be marketed in the US in 2022 by the federal Food and Drug Administration (FDA), may be “one of the most important breakthroughs in modern medical history,” according to US researchers, Good News Network (GNN) reported.
“Early detection of sepsis is an invaluable capability for healthcare professionals. Quickly identifying sepsis is critical to saving lives, but until now, we’ve lacked a reliable tool to either recognize the condition or explore alternate diagnoses,” said O’Neal in an LSU press release.
“IntelliSep is truly a game changer,” said Hollis O’Neal, MD (above), Associate Professor of Medicine at Louisiana State University Health Sciences Center in Baton Rouge. “The test provides hospital staff with information needed to identify and treat septic patients efficiently and reduce the financial and health burdens of overtreatment for hospitals and patients.” Clinical laboratories may have a new blood test for sepsis by the end of the year. (Photo copyright: Louisiana State University.)
How IntelliSep Works
The IntelliSep test analyzes blood samples extracted from emergency room patients who present with sepsis symptoms by squeezing white blood cells through a tiny tube to determine how the cells react and if they change shape. White blood cells in patients with sepsis are softer and spongier and their shape compresses and elongates, increasing the likelihood of developing sepsis.
Images are taken of the cells using an ultra-high-speed camera that can capture up to 500,000 frames per second. The images are the analyzed by an AI-powered computer which calculates the total number of elongated white blood cells to determine if sepsis is present.
IntelliSep then separates patients into three bands of risk for developing sepsis:
Band 1 (low)
Band 2 (medium)
Band 3 (high)
Results of the test are available to emergency room personnel in less than 10 minutes.
“Sepsis is notorious as the ‘silent killer’ because it is so easily missed early on, when a patient’s symptoms can often be mistaken for other less serious illnesses,” Michael Atar, PhD, DDS, Associate Professor, Pediatric Dentistry at New York University told Good News Network. “Rapid diagnosis and treatment is crucial to a good outcome, but there has never been a single, reliable diagnostic test available to doctors, costing precious time and people’s lives.”
Atar is a lead medical technology investor and an advisor to Cytovale.
‘Holy Grail’ of Sepsis Diagnosis
To complete the IntelliSep study, researchers enrolled 1,002 ER patients who presented with signs of sepsis. IntelliSep correctly identified patients who did not have sepsis with an accuracy rate of 97.5%. The technology showed an accuracy rate of 55% for positive sepsis results. Researchers also used IntelliSep to quickly diagnose and assess the severity of a sepsis infection.
There were no sepsis deaths reported in patients with low-risk scores. This indicates the test could help physicians rule out sepsis and seek other diagnoses for those patients.
“Cytovale’s IntelliSep device is, by any objective measure, the ‘holy grail’ that the medical community has been so desperate to find,” Atar told Good News Network. “The technology behind it is genuinely groundbreaking and it has the real-world, tried-and-tested potential to save millions of lives, year on year, across the planet.”
The technology is currently being used in a few hospitals in Louisiana and the inventors hope to have it available in at least 10 other hospitals by the end of the year.
Our Lady of the Lake Regional Medical Center, a not-for-profit Catholic healthcare ministry located in Baton Rouge, was one of the first hospitals to implement IntelliSep.
“Cytovale’s innovative technology will help drastically decrease the number of sepsis-related deaths in hospital settings, and we are honored that, since day one, we have been a part of the research that led to this technology,” said Chuck Spicer, President of Our Lady of the Lake Health in a news release.
Saint Francis Medical Center in Monroe, La., announced on September 3 that it has started using the IntelliSep test in its emergency rooms and staff are impressed by the impact on hospital efficiency.
“If it turns out negative then you don’t have to treat as many patients as you did before, which runs up costs, hospital bills and causes people to be in the hospital for longer periods of time,” said pulmonary disease physician Thomas Gullatt, MD, President, St. Francis Health, told KNOE News.
Patient Expectations for Treatment
Sepsis, also known as septicemia or blood poisoning, is a serious medical condition that occurs when the body improperly reacts to an infection or injury. The dangerous reaction causes extensive inflammation throughout the body and, if not treated early, can lead to organ failure, tissue damage, and even death.
The Centers for Disease Control and Prevention (CDC) reports at least 1.7 million adults develop sepsis annually in the US and at least 350,000 die as a result of the condition. It also states sepsis is one of the main reasons people are readmitted to hospitals.
Clinical laboratories should be aware of developments in the use of this new diagnostic assay and how it is aiding the diagnosis, antibiotic selection, and monitoring of patients with this deadly infection. Patients often learn about new technologies and come to their hospital or provider expecting to be treated with these innovations.
Shortage could disrupt the ability of clinical laboratories in hospitals and health systems to run certain tests for bloodstream infections
US clinical laboratories may soon experience a “disruption of availability” of BACTEC blood culture media bottles distributed by Becton Dickinson (BD). That’s according to the federal Centers for Disease Control and Prevention (CDC) which issued a Health Alert Network (HAN) Health Advisory to all clinical laboratory professionals, healthcare providers and facility administrators, and other stakeholders warning of the potential shortfall of critical testing supplies.
“This shortage has the potential to disrupt patient care by leading to delays in diagnosis, misdiagnosis, or other challenges in the clinical management of patients with certain infectious diseases,” the CDC stated in the health advisory.
The CDC advises healthcare providers and health departments that use the bottles to “immediately begin to assess their situations and develop plans and options to mitigate the potential impact of the shortage on patient care.”
The advisory notes that the bottles are a key component in continuous-monitoring blood culture systems used to diagnose bloodstream infections and related conditions, such as endocarditis, sepsis, and catheter-related infections. About half of all US laboratories use the BD blood culture system, which is compatible only with the BACTEC bottles, the CDC advisory states.
Infectious disease specialist Krutika Kuppalli, MD (above), Chair of the Infectious Diseases Society of America (IDSA) and a Medical Officer for COVID-19 Health Operations at the World Health Organization, outlined the potential impact of the shortage on healthcare providers and clinical laboratories. “Without the ability to identify pathogens or [their susceptibility to specific antibiotics], patients may remain on broad antibiotics, increasing the risk of antibiotic resistance and Clostridium difficile-associated diarrhea,” she told STAT. “Shortages may also discourage ordering blood cultures, leading to missed infections that need treatment.” (Photo copyright: Loyola University Health System.)
FDA Advises Conservation of Existing BACTEC Supplies
The CDC advisory followed a July 10 notice from the US Food and Drug Administration (FDA) that also warned healthcare providers of “interruptions in the supply” of the bottles. The supply disruption “is expected to impact patient diagnosis, follow up patient management, and antimicrobial stewardship efforts,” the FDA’s letter states. “The FDA recommends laboratories and healthcare providers consider conservation strategies to prioritize the use of blood culture media bottles, preserving the supply for patients at highest risk.”
Hospitals have been warned that the bottle shortage could last until September, STAT reported.
BD issued a press release in which BD Worldwide Diagnostic Solutions President Nikos Pavlidis cast blame for the shortage on an unnamed supplier.
“We understand the critical role that blood culture testing plays in diagnosing and treating infections and are taking all available measures to address this important issue, including providing the supplier our manufacturing expertise, using air shipments, modifying BD manufacturing schedules for rapid production, and collaborating with the US Food and Drug Administration to review all potential options to mitigate delays in supply,” Pavlidis said. “As an additional stopgap measure, our former supplier of glass vials will restart production to help fill the intermittent gap in supply.”
Steps Clinical Laboratories Can Take
The CDC and FDA both suggested steps that clinical laboratories and other providers can take to conserve their supplies of the bottles.
Laboratories should strive to prevent contamination of blood cultures, which “can negatively affect patient care and may require the collection of more blood cultures to help determine whether contamination has occurred,” the CDC advised.
In addition, providers should “ensure that the appropriate volume is collected when collecting blood for culture,” the advisory states. “Underfilling bottles decreases the sensitivity to detect bacteremia/fungemia and may require additional blood cultures to be drawn to diagnose an infection.”
Laboratories should also explore alternative options, such as “sending samples out to a laboratory not affected by the shortage.”
The FDA advised providers to collect blood cultures “when medically necessary” in compliance with clinical guidelines, giving priority to patients exhibiting signs of a bloodstream infection.
In an email to STAT, Andrew T. Pavia, MD, Professor of Internal Medicine and Pediatrics at the University of Utah, offered examples of situations where blood culture tests are unnecessary according to clinical guidelines.
“There are conditions like uncomplicated community acquired pneumonia or skin infections where blood cultures are often obtained but add very little,” he told STAT. “It will be critical though that blood cultures are obtained from patients with sepsis, those likely to have bloodstream infections, and very vulnerable patients.”
Hospitals Already Addressing Shortage
STAT reported that some hospitals have already taken measures to reduce the number of tests they run. And some are looking into whether they can safely use bottles past their expiration dates.
Sarah Turbett, MD, Associate Director of Clinical Microbiology Laboratories at Massachusetts General Hospital in Boston, told STAT that her team tested bottles “that were about 100 days past their expiration date to see if they were still able to detect pathogens with the same efficacy as bottles that had not yet expired. They saw no difference in the time to bacterial growth—needed to detect the cause of an infection—in the expired bottles when compared to bottles that had not expired.”
Turbett pointed to a letter in the Journal of Clinical Microbiology and Infection in which European researchers found that bottles from a different brand “were stable for between four and seven months after their expiration dates,” STAT reported.
During a Zoom call hosted by the CDC and the IDSA, hospital representatives asked if the FDA would permit use of expired bottles. However, “a representative of the agency was not able to provide an immediate answer,” STAT reported.
With sepsis being the leading cause of death in hospitals, these specimen bottles for blood culture testing are essential in diagnosing patients with relevant symptoms. This is a new example of how the supply chain for clinical laboratory instruments, tests, and consumables—which was a problem during the SARS-CoV-2 pandemic—continues to be problematic in unexpected ways.
Taking a wider view of supply chain issues that can be disruptive to normal operations of clinical laboratories and anatomic pathology groups, the market concentration of in vitro diagnostics (IVD) manufacturers means fewer vendors offering the same types of products. Consequently, if a lab’s prime vendor has a supply chain issue, there are few options available to swiftly purchase comparable products.
A separate but related issue in the supply chain involves “just in time” (JIT) inventory management—made famous by Taiichi Ohno of Toyota back in the 1980s. This management approach was designed to deliver components and products to the user hourly, daily, and weekly, as appropriate. The goal was to eliminate the cost of carrying large amounts of inventory. This concept evolved into what today is called the “Lean Manufacturing” method.
However, as was demonstrated during the SARS-CoV-2 pandemic, manufacturers and medical laboratories that had adopted JIT found themselves with inadequate numbers of components and finished products.
In the case of the current shortage of BD blood culture media bottles, this is a real-world example of how market concentration limited the number of vendors offering comparable products. At the same time, if this particular manufacturer was operating with the JIT inventory management approach, it found itself with minimal inventories of these media bottles to ship to lab clients while it addressed the manufacturing problems that caused this shortage.
Infection control teams and clinical laboratory managers may want to look at this new product designed to improve the diagnosis and treatment of sepsis
Accurate and fast diagnosis of sepsis for patients arriving in emergency departments is the goal of a new product that was just cleared by the federal Food and Drug Administration (FDA). It is also the newest example of how artificial intelligence (AI) continues to find its way into pathology and clinical laboratory medicine.
Sepsis is one of the deadliest killers in US hospitals. That is why there is interest in the recent action by the FDA to grant marketing authorization for an AI-powered sepsis detection software through the agency’s De Novo Classification Request. The DNCR “provides a marketing pathway to classify novel medical devices for which general controls alone, or general and special controls, provide reasonable assurance of safety and effectiveness for the intended use, but for which there is no legally marketed predicate device,” the FDA’s website states.
Unlike a single analyte assay that is run in a clinical laboratory, Prenosis’ AI/ML software uses 22 diagnostic and predictive parameters, along with ML algorithms, to analyze data and produce a clinically actionable answer on sepsis.
It is important for clinical laboratory managers and pathologists to recognize that this diagnostic approach to sepsis brings together a number of data points commonly found in a patient’s electronic health record (EHR), some of which the lab generated and others the lab did not generate.
“Sepsis is a serious and sometimes deadly complication. Technologies developed to help prevent this condition have the potential to provide a significant benefit to patients,” said Jeff Shuren, MD, JD, Director of the FDA’s Center for Devices and Radiological Health, in a statement. “The FDA’s authorization of the Prenosis Sepsis ImmunoScore software establishes specific premarket and post-market requirements for this device type.” Clinical laboratory EHRs contain some of the data points Prenosis’ diagnostic software uses. (Photo copyright: US Food and Drug Administration.)
How it Works
To assist doctors diagnose sepsis, the ImmunoScore software is first integrated into the patient’s hospital EHR. From there, it leverages 22 parameters including:
White blood cell count to produce a score that informs caregivers of the patient’s risk for sepsis within 24 hours, MedTech Dive reported.
Instead of requiring a doctor or nurse to look at each parameter separately, the SaMD tool uses AI “to evaluate all those markers at once”, CNBC noted. It then produces a risk score and four discrete risk stratification categories (low, medium, high, and very high) which correlate to “a patient’s risk of deterioration” represented by:
By sharing these details—a number from one to 100 for each of the 22 diagnostic and predictive parameters—Sepsis ImmunoScore helps doctors determine which will likely contribute most to the patient’s risk for developing sepsis, MedTech Dive reported.
“A lot of clinicians don’t trust AI products for multiple reasons. We are trying very hard to counter that skepticism by making a tool that was validated by the FDA first, and then the second piece is we’re not trying to replace the clinician,” Bobby Reddy Jr., PhD, Prenosis co-founder and CEO, told MedTech Dive.
Big Biobank and Blood Sample Data
Prenosis, which says its goal is the “enabling [of] precision medicine in acute care” developed Sepsis ImmunoScore using the company’s own biobank and a dataset of more than 100,000 blood samples from more than 25,000 patients.
AI algorithms drew on this biological/clinical dataset—the largest in the world for acute care patients suspected of having serious infections, according to Prenosis—to “elucidate patterns in rapid immune response.”
“It does not work without data, and the data started at Carle,” said critical care specialist Karen White, MD, PhD, Carle Foundation Hospital, St. Louis, MO, in the news release. “The project involved a large number of physicians, research staff, and internal medicine residents at Carle who helped recruit patients, collect data, and samples,” she said.
Opportunity for Clinical Laboratories
Sepsis is a life-threatening condition based on an “extreme response to an infection” that affects nearly 1.7 million adults in the US each year and is responsible for 350,000 deaths, according to US Centers for Disease Control and Prevention (CDC) data.
A non-invasive diagnostic tool like Sepsis ImmunoScore will be a boon to emergency physicians and the patients they treat. Now that the FDA has authorized the SaMD diagnostic tool to go to market, it may not be long before physicians can use the information it produces to save lives.
Clinical laboratory managers inspired by the development of Sepsis ImmunoScore may want to look for similar ways they can take certain lab test results and combine them with other data in an EHR to create intelligence that physicians can use to better treat their patients. The way forward in laboratory medicine will be combining lab test results with other relevant sets of data to create clinically actionable intelligence for physicians, patients, and payers.
Some hospital organizations are pushing back, stating that the new regulations are ‘too rigid’ and interfere with doctors’ treatment of patients
In August, the Biden administration finalized provisions for hospitals to meet specific treatment metrics for all patients with suspected sepsis. Hospitals that fail to meet these requirements risk the potential loss of millions of dollars in Medicare reimbursements annually. This new federal rule did not go over well with some in the hospital industry.
Sepsis kills about 350,000 people every year. One in three people who contract the deadly blood infection in hospitals die, according to the Centers for Disease Control and Prevention (CDC). Thus, the federal government has once again implemented a final rule that requires hospitals, clinical laboratories, and medical providers to take immediate actions to diagnose and treat sepsis patients.
The effort has elicited pushback from several healthcare organizations that say the measure is “too rigid” and “does not allow clinicians flexibility to determine how recommendations should apply to their specific patients,” according to Becker’s Hospital Review.
Perform blood tests within a specific period of time to look for biomarkers in patients that may indicate sepsis, and to
Administer antibiotics within three hours after a possible case is identified.
It also mandates that certain other tests are performed, and intravenous fluids administered, to prevent blood pressure from dipping to dangerously low levels.
“These are core things that everyone should do every time they see a septic patient,” said Steven Simpson, MD, Professor of medicine at the University of Kansas told Fierce Healthcare. Simpson is also the chairman of the Sepsis Alliance, an advocacy group that works to battle sepsis.
Simpson believes there is enough evidence to prove that the SEP-1 guidelines result in improved patient care and outcomes and should be enforced.
“It is quite clear that this works better than what was present before, which was nothing,” he said. “If the current sepsis mortality rate could be cut by even 5%, we could save a lot of lives. Before, even if you were reporting 0% compliance, you didn’t lose your money. Now you actually have to do it,” Simpson noted.
“We are encouraged by the increased attention to sepsis and support CMS’ creation of a sepsis mortality measure that will encourage hospitals to pay more attention to the full breadth of sepsis care,” Chanu Rhee, MD (above), Infectious Disease/Critical Care Physician and Associate Hospital Epidemiologist at Brigham and Women’s Hospital told Healthcare Finance. The new rule, however, requires doctors and medical laboratories to conduct tests and administer antibiotic treatment sooner than many healthcare providers deem wise. (Photo copyright: Brigham and Women’s Hospital.)
Healthcare Organizations Pushback against Final Rule
“By encouraging the use of broad spectrum antibiotics when more targeted ones will suffice, this measure promotes the overuse of the antibiotics that are our last line of defense against drug-resistant bacteria,” the AHA’s letter states.
In its recent coverage of the healthcare organizations’ pushback to CMS’ final rule, Healthcare Finance News explained, “The SEP-1 measure requires clinicians to provide a bundle of care to all patients with possible sepsis within three hours of recognition. … But the SEP-1 measure doesn’t take into account that many serious conditions present in a similar fashion to sepsis … Pushing clinicians to treat all these patients as if they have sepsis … leads to overuse of broad-spectrum antibiotics, which can be harmful to patients who are not infected, those who are infected with viruses rather than bacteria, and those who could safely be treated with narrower-spectrum antibiotics.”
CMS’ latest rule follows the same evolutionary path as previous federal guidelines. In August 2007, CMS announced that Medicare would no longer pay for additional costs associated with preventable errors, including situations known as Never Events. These are “adverse events that are serious, largely preventable, and of concern to both the public and healthcare providers for the purpose of public accountability,” according to the Leapfrog Group.
In 2014, the CDC suggested that all US hospitals have an antibiotic stewardship program (ASP) to measure and improve how antibiotics are prescribed by clinicians and utilized by patients.
Research Does Not Show Federal Sepsis Programs Work
He points to analysis which showed that though use of broad-spectrum antibiotics increased after the original 2015 SEP-1 regulations were introduced, there has been little change to patient outcomes.
“Unfortunately, we do not have good evidence that implementation of the sepsis policy has led to an improvement in sepsis mortality rates,” Rhee told Fierce Healthcare.
Rhee believes that the latest regulations are a step in the right direction, but that more needs to be done for sepsis care. “Retiring past measures and refining future ones will help stimulate new innovations in diagnosis and treatment and ultimately improve outcomes for the many patients affected by sepsis,” he told Healthcare Finance.
Sepsis is very difficult to diagnose quickly and accurately. Delaying treatment could result in serious consequences. But clinical laboratory blood tests for blood infections can take up to three days to produce a result. During that time, a patient could be receiving the wrong antibiotic for the infection, which could lead to worse problems.
The new federal regulation is designed to ensure that patients receive the best care possible when dealing with sepsis and to lower mortality rates in those patients. It remains to be seen if it will have the desired effect.
