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Stanford Medicine Scientists Sequence Patient’s Whole Genome in Just Five Hours Using Nanopore Genome Sequencing, AI, and Cloud Computing

And in less than eight hours, they had diagnosed a child with a rare genetic disorder, results that would take clinical laboratory testing weeks to return, demonstrating the clinical value of the genomic process

In another major genetic sequencing advancement, scientists at Stanford University School of Medicine have developed a method for rapid sequencing of patients’ whole human genome in as little as five hours. And the researchers used their breakthrough to diagnose rare genetic diseases in under eight hours, according to a Stanford Medicine news release. Their new “ultra-rapid genome sequencing approach” could lead to significantly faster diagnostics and improved clinical laboratory treatments for cancer and other diseases.

The Stanford Medicine researchers used nanopore sequencing and artificial intelligence (AI) technologies in a “mega-sequencing approach” that has redefined “rapid” for genetic diagnostics. The sequence for one study participant—completed in just five hours and two minutes—set the first Guinness World Record for the fastest DNA sequencing to date, the news release states.

The Stanford scientists described their new method for rapid diagnosis of genetic diseases in the New England Journal of Medicine (NEJM) titled, “Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting.”

Euan Ashley, MD, PhD

“A few weeks is what most clinicians call ‘rapid’ when it comes to sequencing a patient’s genome and returning results,” said cardiovascular disease specialist Euan Ashley, MD, PhD (above), professor of medicine, genetics, and biomedical data science, at Stanford University in the news release. “The right people suddenly came together to achieve something amazing. We really felt like we were approaching a new frontier.” Their results could lead to faster diagnostics and clinical laboratory treatments. (Photo copyright: Stanford Medicine.)

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Need for Fast Genetic Diagnosis 

In their NEJM paper, the Stanford scientists argue that rapid genetic diagnosis is key to clinical management, improved prognosis, and critical care cost savings.

“Although most critical care decisions must be made in hours, traditional testing requires weeks and rapid testing requires days. We have found that nanopore genome sequencing can accurately and rapidly provide genetic diagnoses,” the authors wrote.

To complete their study, the researchers sequenced the genomes of 12 patients from two hospitals in Stanford, Calif. They used nanopore genome sequencing, cloud computing-based bioinformatics, and a “custom variant prioritization.”

Their findings included:

  • Five people received a genetic diagnosis from the sequencing information in about eight hours.
  • Diagnostic rate of 42%, about 12% higher than the average rate for diagnosis of genetic disorders (the researchers noted that not all conditions are genetically based and appropriate for sequencing).
  • Five hours and two minutes to sequence a patient’s genome in one case.
  • Seven hours and 18 minutes to sequence and diagnose that case.

How the Nanopore Process Works

To advance sequencing speed, the researchers used equipment by Oxford Nanopore Technologies with 48 sequencing units called “flow cells”—enough to sequence a person’s whole genome at one time.

The Oxford Nanopore PromethION Flow Cell generates more than 100 gigabases of data per hour, AI Time Journal reported. The team used a cloud-based storage system to enable computational power for real-time analysis of the data. AI algorithms scanned the genetic code for errors and compared the patients’ gene variants to variants associated with diseases found in research data, Stanford explained.

According to an NVIDIA blog post, “The researchers accelerated both base calling and variant calling using NVIDIA GPUs on Google Cloud. Variant calling, the process of identifying the millions of variants in a genome, was also sped up with NVIDIA Clara Parabricks, a computational genomics application framework.”

Rapid Genetic Test Produces Clinical Benefits

“Together with our collaborators and some of the world’s leaders in genomics, we were able to develop a rapid sequencing analysis workflow that has already shown tangible clinical benefits,” said Mehrzad Samadi, PhD, NVIDIA Senior Engineering Manager and co-author of the NEJM paper, in the blog post. “These are the kinds of high-impact problems we live to solve.”

In their paper, the Stanford researchers described their use of the rapid genetic test to diagnose and treat an infant who was experiencing epileptic seizures on arrival to Stanford’s pediatric emergency department. In just eight hours, their diagnostic test found that the infant’s convulsions were attributed to a mutation in the gene CSNK2B, “a variant and gene known to cause a neurodevelopmental disorder with early-onset epilepsy,” the researchers wrote.

“By accelerating every step of this process—from collecting a blood sample to sequencing the whole genome to identifying variants linked to diseases—[the Stanford] research team took just hours to find a pathogenic variant and make a definitive diagnosis in a three-month-old infant with a rare seizure-causing genetic disorder. A traditional gene panel analysis ordered at the same time took two weeks to return results,” AI Time Journal reported.

New Benchmarks

The Stanford research team wants to cut the sequencing time in half. But for now, the five-hour rapid whole genome sequence can be considered by clinical laboratory leaders, pathologists, and research scientists a new benchmark in genetic sequencing for diagnostic purposes.

Stories like Stanford’s rapid diagnosis of the three-month old patient with epileptic seizures, point to the ultimate value of advances in genomic sequencing technologies.

Donna Marie Pocius

Related Information:

Fastest DNA Sequencing Technique Helps Undiagnosed Patients Find Answers in Mere Hours

Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting

Stanford Researchers Use AI to Sequence and Analyze DNA in Five Hours

World Record-Setting DNA Sequencing Technique Helps Clinicians Rapidly Diagnose Critical Care Patients

Ultima Genomics Delivers the $100 Genome

Study Shows School-Aged Children Can Successfully Swab Themselves for COVID-19 Tests, But Is This Something That Can Help Short-Staffed Medical Laboratories?

Encouraging patients—even children—to be more directly involved in their own medical care may reduce the burden on healthcare workers and might even help those clinical laboratories struggling to hire enough phlebotomists to collect specimens

Researchers at Emory University School of Medicine have concluded a study which found that school-aged children can successfully use a nasal swab to obtain their own SARS-CoV-2 test specimens. This may come as a surprise to hospital and clinical laboratory personnel who have performed nasal swabbing for COVID-19 tests. Some people, adults included, find the procedure so uncomfortable it brings tears.

And yet, after being shown a 90-second how-to video and given a handout with written instructions and pictures, 197 Atlanta children who had COVID-19 symptoms between July and August of 2021 performed their own self-swabbing. A healthcare worker then collected a second swabbed sample. All samples were submitted to a clinical laboratory for PCR analysis.

The Emory study provides another example of how the healthcare system is engaging patients to be directly involved in their own medical care. Results of the study could positively impact clinical laboratories facing a shortage of personnel, as well as schools where children have to take repeated COVID-19 tests with the assistance of trained professionals.

The Emory researchers published their findings in the Journal of the American Medical Association (JAMA), titled, “Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents.”

Child self swabbing for COVID-19

In a study with 197 school-age children, researchers at Emory University School of Medicine found that children could self-swab themselves for COVID-19 testing after watching a 90-second instructional video. Clinical laboratory leaders who are short on personnel may find these results intriguing. (Photo copyright: Emory University.)

How Did the Children Do?

The self-collected swabs and those collected by a healthcare worker agreed 97.8% of the time for a positive result and 98.1% of the time for a negative result. The analysis showed that both collection methods identified the 44% of symptomatic kids who were positive for COVID-19.

“Seeing how closely the results line up between the children and trained healthcare workers is a strong indicator that these age groups are fully capable of swabbing themselves if given proper instruction,” said Jesse Waggoner, MD, an Assistant Professor of Infectious Diseases with the Emory University School of Medicine and one of the lead authors on the study, in an Emory University press release.

A higher percentage of children age eight and under needed assistance, such as more instruction before correctly completing self-collection—21.8% compared to 6.1% for children older—but SARS-CoV-2 detection among the two age groups did not differ.

Does FDA Approve of Self-Swabbing?

The US Food and Drug Administration (FDA) has not authorized COVID-19 tests that include self-swabbing by children under age 14. However, data from the Emory study, published in JAMA, is now available to test manufacturers seeking authorization for pediatric self-collection.  

“Pediatric self-swabbing will support expanded testing access and should make it even easier to test school age populations with fewer resources,” said Tim Stenzel, MD, PhD, Director of the Office of In Vitro Diagnostics at the FDA, in the Emory statement. “This study furthers our knowledge of test accuracy with these types of samples and provides test manufacturers with data to support their EUA (Emergency Use Authorization) requests to the FDA.”

Self-swabbing versus Clinical Laboratory Worker

While it has been longstanding medical practice to have healthcare workers collect samples for respiratory tract infection testing, the Emory researchers suggest that allowing children to collect their own COVID-19 samples could be one way to reduce the burden of a shortage of healthcare workers.

The researchers also believe pediatric self-swabbing would expand access to diagnostic tests and make it easier to test school-age populations.

“Every minute of a healthcare worker’s time is at a premium,” said senior study author Wilbur Lam, MD, Professor of Pediatrics and Biomedical Engineering, Emory University and Georgia Tech, in a National Institutes of Health (NIH) press release. “Why not allow a kid to self-swab? It’s a win-win! They would rather do it themselves and it frees up the healthcare worker to do other things,” he added.

In 2020, a Stanford University School of Medicine study published in JAMA showed test samples collected by adults who swabbed their own nasal passages were as accurate as those collected by healthcare workers. This study involved 30 participants who had previously tested positive for COVID-19.

Though the Emory University and Stamford University studies were small, they agreed in their findings which is significant. Clinical laboratory executives and pathologists should expect this trend toward direct-to-consumer and other forms of self-testing to continue, even among young patients.

Andrea Downing Peck

Related Information:

Can Children Swab Themselves for COVID-19? New Study Suggests Yes

Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents

NIH-Funded Pediatric COVID-19 Testing Study Finds School-Aged Children Can Self-Swab

Self-Swabbing Tests for COVID-19 Accurate and Safe, Study Reports

Assessment of Sensitivity and Specificity of Patient-Collected Lower Nasal Specimens for Severe Acute Respiratory Syndrome Coronavirus 2 Testing

UCSF and Stanford Researchers Investigate Why Some Infected with COVID-19 Are Asymptomatic, While Others Become Severely Ill or Die

Might clinical laboratories soon be called on to conduct mass testing to find people who show little or no symptoms even though they are infected with the coronavirus?    

Clinical laboratory managers understand that as demand for COVID-19 testing exceeds supplies, what testing is done is generally performed on symptomatic patients. And yet, it is the asymptomatic individuals—those who are shown to be infected with the SARS-CoV-2 coronavirus, but who experience no symptoms of the illness—who may hold the key to creating effective treatments and vaccinations.

So, as the COVID-19 pandemic persists, scientists are asking why some people who are infected remain asymptomatic, while others die. Why do some patients get severely ill and others do not? Researchers at the University of California San Francisco (UCSF) and Stanford University School of Medicine (Stanford Medicine) are attempting to answer these questions as they investigate viral transmission, masking, immunity, and more.

And pressure is increasing on researchers to find the answer. According to Monica Gandhi, MD, MPH, an infectious disease specialist and Professor of Medicine at UCSF, millions of people may be asymptomatic and unknowingly spreading the virus. Gandhi is also Associate Division Chief (Clinical Operations/Education) of the Division of HIV, Infectious Diseases, and Global Medicine at UCSF’s Zuckerberg San Francisco General Hospital and Trauma Center.

“If we did a mass testing campaign on 300 million Americans right now, I think the rate of asymptomatic infection would be somewhere between 50% and 80% of cases,” she told UCSF Magazine.

On a smaller scale, her statement was borne out. In a study conducted in San Francisco’s Mission District during the first six weeks of the city’s shelter-in-place order, UCSF researchers conducted SARS-CoV-2 reverse transcription-PCR and antibody (Abbott ARCHITECT IgG) testing on 3,000 people. Approximately 53% tested positive for COVID-19 but had no symptoms such as fever, cough, and muscle aches, according to data reported by Carina Marquez, MD, UCSF Assistant Professor of Medicine and co-author of the study, in The Mercury News.

While their study undergoes peer-review, the researchers published their findings on the preprint server medRxiv, titled, “SARS-CoV-2 Community Transmission During Shelter-in-Place in San Francisco.”

Pandemic Control’s Biggest Challenge: Asymptomatic People

In an editorial in the New England Journal of Medicine (NEJM), Gandhi wrote that transmission of the virus by asymptomatic people is the “Achilles heel of COVID-19 pandemic control.”

In her article, Gandhi compared SARS-CoV-2, the coronavirus that causes COVID-19, to SARS-CoV-1, the coronavirus that caused the 2003 SARS epidemic. One difference lies in how the virus sheds. In the case of SARS-CoV-2, that takes place in the upper respiratory tract, but with SARS-CoV-1, it takes place in the lower tract. In the latter, symptoms are more likely to be detected, Gandhi explained. Thus, asymptomatic carriers of the coronavirus may go undetected.

Viral loads with SARS-CoV-1, which are associated with symptom onset, peak a median of five days later than viral loads with SARS-CoV-2, which makes symptom-based detection of infection more effective in the case of SARS-CoV-1,” Gandhi wrote. “With influenza, persons with asymptomatic disease generally have lower quantitative viral loads in secretions from the upper respiratory tract than from the lower respiratory tract and a shorter duration of viral shedding than persons with symptoms, which decreases the risk of transmission from paucisymptomatic persons.”

Rick Wright of Redwood City, CA
Rick Wright (above), an insurance broker in Redwood City, Calif., was infected with the COVID-19 coronavirus while aboard a Diamond Princess Cruise. He underwent 40 days of isolation, and though he consistently tested positive for the coronavirus, he experienced no symptoms of the illness. “I never felt sick. Not a cough, wheezing, headache. Absolutely nothing,” he told Mercury News. (Photo copyright: The Mercury News.)

Stanford Studies Immune Responses in COVID-19 Patients

Meanwhile, scientists at the Stanford University School of Medicine were on their own quest to find out why COVID-19 causes severe disease in some people and mild symptoms in others.

“One of the great mysteries of COVID-19 infections has been that some people develop severe disease, while others seem to recover quickly. Now, we have some insight into why that happens,” Bali Pulendran, PhD, Stanford Professor of Pathology, Microbiology, and Immunology and Senior Author of the study in a Stanford Medicine news release.

The study, published in Science, titled, “Systems Biological Assessment of Immunity to Mild Versus Severe COVID-19 Infection in Humans,” was based on analysis of 76 patients with COVID-19 and 69 healthy people from Hong Kong and Atlanta. The researchers pointed to flailing immune systems and “three molecular suspects” in the blood of COVID-19 patients they studied.

The Stanford research suggested that three molecules—EN-RAGE, TNFSF14, and oncostatin-M—“correlated with disease and increased bacterial products in human plasma” of COVID-19 patients. 

“Our multiplex analysis of plasma cytokines revealed enhanced levels of several proinflammatory cytokines and a strong association of the inflammatory mediators EN-RAGE, TNFSF14, and OSM with clinical severity of the disease,” the scientists wrote in Science.

Pulendran hypothesized that the molecules originated in patients’ lungs, which was the infection site. 

“These findings reveal how the immune system goes awry during coronavirus infections, leading to severe disease and point to potential therapeutic targets,” Pulendran said in the news release, adding, “These three molecules and their receptors could represent attractive therapeutic targets in combating COVID-19.”

Clinical Laboratories May Do More Testing of Asymptomatic People

The research continues. In a televised news conference, President Trump said COVID-19 testing plays an important role in “preventing transmission of the virus.” Clearly this is true and learning why some people who are infected experience little or no symptoms may be key to defeating COVID-19.

Thus, as the nation reopens, clinical laboratories may want to find ways to offer COVID-19 testing beyond hospitalized symptomatic patients and people who show up at independent labs with doctors’ orders. As supplies permit, laboratory managers may want to partner with providers in their communities to identify people who are asymptomatic and appear to be well, but who may be transmitting the coronavirus. 

—Donna Marie Pocius

Related Information:

We Thought It Was Just a Respiratory Virus—We Were Wrong

Coronavirus: Why Don’t People Get Sick Despite Being Infected?

Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control COVID-19

Study Reveals Immune System-Deviations in Severe COVID-19 Cases, a Stanford Study Shows

Why Do Some Get Sick and Others Don’t? Study May Unravel Mystery

Systems Biological Assessment of Immunity to Mild Versus Severe COVID-19 Infection in Humans

Pooled Testing may Provide a Method of Increasing the Number of Coronavirus Tests Being Performed in the US

Pooled testing could become a critical tool for clinical laboratories to spot the SARS-CoV-2 coronavirus among asymptomatic and pre-symptomatic individuals

COVID-19 testing for individuals has expanded in the US, but the number of people actually tested remains a small proportion of the country’s total population and clinical laboratory testing supply shortages continue to hamper progress. A technique known as pooled testing may help. Federal experts hope it will substantially increase the number of individuals who are tested for the SARS-CoV-2 coronavirus before it makes a possible resurgence in the fall.

One-by-one, some of the nation’s largest clinical laboratory organizations are developing the capability to do pooled testing. For example, on July 18, the Food and Drug Administration (FDA) announced it had issued Quest Diagnostics (NYSE:DGX) an Emergency Use Authorization (EUA) for its SARS-CoV-2 rRT-PCR test, and that it is valid for up to four individual samples as a pooled test.

Quest’s rRT-PCR test was the first COVID-19 diagnostic test to be authorized for use with pooled samples, the FDA noted in a new release.

Stephen M. Hahn, MD, FDA Commissioner
In the FDA’s statement announcing Quest’s EUA for its rRT-PCR test, Stephen M. Hahn, MD (above), FDA Commissioner, said, “This EUA for sample pooling is an important step forward in getting more COVID-19 tests to more Americans more quickly while preserving testing supplies.” He added, “Sample pooling becomes especially important as infection rates decline and we begin testing larger portions of the population.” (Photo copyright: CBS News.)

Following the announcement of Quest’s EUA, on July 24 the FDA announced LabCorp’s (NYSE:LH) EUA for its COVID-19 real-time reverse transcription polymerase chain reaction (rRT-PCR) test. The test, the EUA states, is intended for the “qualitative detection of nucleic acid from SARS-CoV-2 in upper and lower respiratory specimens” in individuals suspected of COVID-19, using “a matrix pooling strategy (i.e., group pooling strategy), containing up to five individual upper respiratory swab specimens (nasopharyngeal, mid-turbinate, anterior nares or oropharyngeal swabs) per pool and 25 specimens per matrix.”

Exponentially Increasing Testing

In pooled testing, instead of performing a coronavirus test on every specimen received by a clinical laboratory, samples from each individual specimen are taken and then combined with samples from other specimens. A single test is then performed on the entire collection of specimen samples.

If the results of the pooled samples are negative for coronavirus, it is safe to assume that all the specimens in the batch are negative for the virus. If the pooled sample comes back positive, then it will be necessary to go back to the original specimens in that pooled sample and test each specimen individually.

In an exclusive interview with Dark Daily’s sister print publication The Dark Report, Steven H. Hinrichs, MD, Chair of the Department of Pathology and Microbiology at the University of Nebraska Medical Center (UNMC), noted that one pitfall of pooled testing is that it works best in areas of low virus prevalence.

“For pooled testing, the ideal level of low prevalence would be an infection rate below 10%,” he said, adding, “For COVID-19 test manufacturers, pooled testing has the potential to reduce the number of standard tests labs run by roughly 40% to 60%, depending on the population being tested.

“Cutting the number of COVID-19 tests would be a disadvantage for test manufacturers, because pooled tests would identify large numbers of uninfected individuals who would not require standard testing with EUA tests.

“On the other hand, this policy would be a significant advantage for US labs because pooled testing would cut the number of standard tests,” he continued. “Clinical labs would save money on tests, reagents, and other supplies. It would also ease the burden on the lab’s technical staff,” Hinrichs concluded.

 In research published in the American Journal of Clinical Pathology (AJCP) titled, “Assessment of Specimen Pooling to Conserve SARS-CoV-2 Testing Resources,” Hinrichs and fellow researchers from UNMC and the University of Nebraska-Lincoln noted that “five is the ideal number to batch in a COVID-19 testing pool.”

“In our study, we show that it’s reasonable to pool five samples, although we realized that some people may want to pool 10 samples at once,” noted Hinrichs. “But even if one sample is positive in a pool of five, then testing five samples at once saves 80% of our costs if all of those samples are negative. But, if one sample is positive, each of those five samples needs to be retested using the standard test,” Hinrichs explained.

During an American Society for Microbiology (ASM) virtual conference, Deborah Birx, MD, White House Coronavirus Response Coordinator, said, “Pooling would give us the capacity to go from a half a million tests per day to potentially five million individuals tested per day,” STAT reported.

Advantages of using pooled testing for the coronavirus include:

  • Expanding the number of individuals tested,
  • Stretching laboratory supplies, and
  • Reducing the costs associated with testing.

Health officials believe that individuals who have COVID-19 and are asymptomatic are largely responsible for the rising number of coronavirus cases in the US, STAT reported.

“It allows you to test more frequently in a population that may have a low prevalence of disease,” Benjamin Pinsky, MD, PhD, Associate Professor, Departments of Pathology and Medicine at Stanford University School of Medicine, told STAT. “That would allow you to test a lot of negatives, but also identify individuals who are then infected, before they develop symptoms.”

Pooled testing also could be advantageous for communities where COVID-19 is not prevalent, in neighborhoods that need to be tested during an outbreak, and for schools, universities, organizations, and businesses that want to remain safely open while periodically monitoring individuals for the virus, CNN reported.

“The goal is to increase the capacity of testing in a relatively straightforward fashion,” Pinsky told STAT. “The caveat is that by pooling the sample, you’re going to reduce the sensitivity of the test.”

According to Pinsky, “pooling only makes sense in places with low rates of COVID-19, where you expect the large majority of tests to be negative. Otherwise, too many of the pools would come back positive for it to work as a useful surveillance tool,” STAT reported.

As Clinical Lab Testing Increases, Pooled Testing for COVID-19 Could Be Critical

Pooled testing has been used in other countries, including China, to test larger amounts of people for COVID-19.

“If you look around the globe, the way people are doing a million tests or 10 million tests is they’re doing pooling,” Birx said during the ASM virtual conference, CNN reported.

In a press release, the American Clinical Laboratory Association (ACLA) stated that about 300,000 tests for COVID-19 were performed per day in labs across the US in late June. That number was up from approximately 100,000 tests being performed daily in early April.

“All across the country, clinical laboratories are increasing the number of labs processing tests, purchasing additional testing platforms, and expanding the number of suppliers to provide critical testing materials,” said Julie Khani, ACLA President in the press release. “However, the reality of this ongoing global pandemic is that testing supplies are limited. Every country across the globe is in need of essential testing supplies, like pipettes and reagents, and that demand is likely to increase in the coming months.”

Clinical laboratory managers will want to keep an eye on these developments. As the need for COVID-19 testing increases, pooled testing may provide an efficient, cost-effective way to spot the coronavirus, especially among those who are asymptomatic or pre-symptomatic and who display no symptoms.

Pooled testing could become a critical tool in the diagnosis of COVID-19 and potentially decrease the overall number of deaths. 

—JP Schlingman

Related Information:

Labs Warn COVID-19 Testing Demand will Top Capacity Soon as New Hotspots Emerge

Safer Reopening will Require Millions More Covid-19 Tests Per Day. One Solution: ‘Pool Testing’

Pooling Coronavirus Tests Can Spare Scarce Supplies, But There’s a Catch

Here’s What Pooled Testing is and How It Can be Used for the Coronavirus

Coronavirus (COVID-19) Update: FDA Issues First Emergency Authorization for Sample Pooling in Diagnostic Testing

ACLA Update on COVID-19 Testing Capacity

LabCorp Receives Authorization for COVID-19 Sample Pooling

Is COVID-19 Pooled Testing Good for Labs, Bad for IVDs?

Stanford University Study Traces Hospital-Acquired Bloodstream Infections to Patients’ Own Digestive Tract

New bioinformatic tool finds gut microbiota may be ‘potential reservoir of bloodstream pathogens’ suggesting patients’ own bodies can be source of infections

Clinical laboratories in hospitals and health networks throughout the nation are collaborating in the priority effort to reduce deaths from sepsis and related blood infections. Now comes news that researchers at Stanford have identified an unexpected source of bloodstream infections. This finding may help medical laboratories contribute to faster and more accurate diagnoses of blood infections, particularly for hospital inpatients.

Lax infection-control practices often are blamed for hospital-acquired infections (HAIs). And HAIs certainly have been responsible for many tragic avoidable deaths. However, new research from Stanford University School of Medicine shows that hospital staff, other patients, or unclean instruments may not be solely responsible for all infections that present during hospital stays. According to Stanford researchers, a patient’s own digestive tract can be the surprising culprit for many bloodstream infections. This finding confirms a common belief that the patient’s microbiome probably is involved in many blood infections.

Clinical pathologists have become vital players in infection prevention programs, as hospitals intensify their focus on reducing HAIs. That’s especially in light of the Centers for Medicare and Medicaid Services (CMS) implementation of the pay-for-performance Hospital-Acquired Condition (HAC) Reduction Program. Now, Stanford researchers have found that for many hospital patients their own bodies may be the source of infections.

The researchers published their findings in Nature Medicine.

Bacteria Causing Blood Infections Found in Patients’ Stool Samples After Bone Marrow Transplants

Using a new bioinformatic computational tool called StrainSifter, the Stanford University team rapidly and accurately identified a surprising infection source in a group of hospitalized patients—microbes already living in the patients’ large intestines—a Stanford University news release explained.

The researchers analyzed blood and stool samples from 30 patients who developed bloodstream infections after receiving bone marrow transplants between October 2015 and June 2017 at Stanford Hospital. The researchers sought to determine whether the bacteria isolated from the patients’ blood also was found in stool specimens that had been collected prior to the transplants. The process required sequencing not only the patients’ DNA, but also analyzing the genomes of all the individual microbial strains resident in each patient’s stool.

“Just finding E. coli in a patient’s blood and again in the patient’s stool doesn’t mean they’re the same strain,” Ami Bhatt, MD, PhD, Assistant Professor of Hematology and Genetics at Stanford, explained in the news release. Bhatt served as senior author of the study. (Photo copyright: Stanford University.)

Analysis found that more than one-third of the patients’ stool samples (11) contained detectable levels of the same bacterial strain that had caused those patients’ bloodstream infections.

“Because the gut normally harbors more than 1,000 different bacterial strains, it’s looked upon as a likely culprit of bloodstream infections, especially when the identified pathogen is one known to thrive inside the gut,” Ami Bhatt, MD, PhD, Assistant Professor of Hematology and Genetics at Stanford, said in the news release. “But while this culpability has been assumed—and it’s an entirely reasonable assumption—it’s never been proven. Our study demonstrates that it’s true.”

Clinical and DNA data confirmed the gastrointestinal presence of Escherichia coli and Klebsiella pneumonia, common causes of pneumonia, urinary tract infections, and other potentially serious conditions. In addition, they found other disease-causing pathogens in the gut that they would not have expected to be there.

“We also find cases where typically nonenteric [outside the intestine] pathogens, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, are found in the gut microbiota, thereby challenging the existing informal dogma of these infections originating from environmental or skin sources,” Fiona Tamburini, a senior graduate student, and postdoctoral scholar Tessa Andermann, MD, MPH, Infectious Disease Medical Fellow, wrote in Nature Medicine.

New Tool for Precision Medicine

Bhatt believes being able to trace the source of bloodstream infections will help doctors provide more targeted treatments for HAIs and potentially lead to effective prevention methods. This will create a new opportunity for microbiology laboratories to provide the necessary diagnostic tests designed to guide therapeutic choices of attending physicians.

“Until now, we couldn’t pinpoint those sources with high confidence,” Bhatt said in the news release. “That’s a problem because when a patient has a bloodstream infection, it’s not enough simply to administer broad-spectrum antibiotics. You need to treat the source, or the infection will come back.”

Bhatt says the computational tool has the potential to allow medical practitioners to quickly identify whether a pathogen responsible for a patient’s bloodstream infection came from a break in the skin, leaked through the intestinal wall into the blood, or was passed on through an inserted catheter or other object.

Bhatt’s team focused on the intestines for their study because it’s the home of 1,000 to 2,000 different germs. Dark Daily has reported often on developments involving human gut bacteria (AKA, microbiome) in e-briefings going back to 2013. While these gut bacteria do not typically cause problems, Bhatt said, “It’s only when they show up in the wrong place—due, for example, to leaking through a disrupted intestinal barrier into the bloodstream—that they cause trouble.”

Because nearly 40% of immunocompromised patients who spend up to six weeks in a hospital develop bloodstream infections, the Stanford findings could signal a major breakthrough in preventing HAIs. However, larger studies are needed to validate the researchers’ contention that the gut is a “potential reservoir of bloodstreams pathogens.”

If true, microbiologists and clinical pathologists may in the future have a new method for helping hospitals identify, track, and treat blood-born infections as well as and preventing HAIs.

—Andrea Downing Peck

Related Information: 

Study Traces Hospital-Acquired Bloodstream Infections to Patients’ Own Bodies

Hospital-Acquired Condition Reduction Program Fiscal Year 2019 Fact Sheet

Precision Identification of Diverse Bloodstream Pathogens in the Gut Microbiome

Multiple Dark Daily E-briefings on Human Gut Bacteria (Microbiome)

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