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.
Researchers at the university suggested their findings could lead to new genetic tests that could be offered by medical laboratories
New research conducted at the University of Utah suggests that clinical laboratories may someday be able to deploy genetic tests to indicate whether a couple has a higher-than-average risk of stillbirth.
This is yet another example of how researchers are cracking DNA’s code to understand how certain gene variants may affect the healthcare of offspring. The knowledge produced by this research, as confirmed by additional studies, may lead to genetic markers that medical laboratories can use to diagnose the risk of stillbirth using the parent’s DNA.
“Stillbirth is one of those problems that is so tragic and life-changing,” said study co-author Jessica Page, MD (above). “It is especially frustrating when you don’t have a good answer for why it happens. This knowledge may give us the opportunity to change how we risk stratify people and reduce their risk through prevention.” Should this research be validated, clinical laboratories may soon have new genetics tests to help doctors identify risk for stillbirth. (Photo copyright: Intermountain Healthcare.)
Can Stillbirth be Prevented?
Jessica Page, MD, an assistant professor in the Department of Obstetrics and Gynecology at the University of Utah School of Medical and co-author of the 2022 study, was lead author of a 2018 study that estimated nearly one-fourth of stillbirths are preventable.
“Stillbirth rate reduction has been slow in the US and we think many stillbirths may be potentially preventable,” she said in a university press release. “This is motivating us to look for those genetic factors so we can achieve more dramatic rate reduction.”
According to the press release, the University of Utah researchers found that stillbirth “can be inherited and tends to be passed down through male members of the family. That risk preferentially comes from the mother’s or father’s male relatives—their brothers, fathers, grandfathers, uncles, or male cousins. But the odds of a couple losing a baby to stillbirth are even greater when the condition comes from the father’s side of the family.”
The researchers made this discovery by analyzing data from the Utah Population Database (UPDB), which contains information on eight million people who were born in the state or have other connections there. The database is maintained by the Huntsman Cancer Institute at the University of Utah. It includes genealogical information and health records that allowed the researchers to trace incidence of stillbirths across multiple generations of families.
The researchers examined 9,404 stillbirth cases between 1978 and 2019, along with 18,808 live births that served as controls. They identified 390 multi-generational families with high numbers of stillbirths. Within that group, they looked at incidence of stillbirth among first-, second-, and third-degree relatives of stillborn babies. They then compared those numbers with data from unaffected families.
“We were able to evaluate multigenerational trends in fetal death as well as maternal and paternal lineages to increase our ability to detect a familial aggregation of stillbirth,” said genetic epidemiologist Tsegaselassie Workalemahu, PhD, lead author of the study. “Not many studies have examined inherited genetic risk for stillbirth because of a lack of data. The Utah Population Database allows for a more rigorous evaluation than has been possible in the past.”
Workalemahu described the research as “an important step toward identifying specific genes that increase the risk of stillbirth, which could one day lead to better diagnosis and prevention,” according to the university press release.
One caveat, the press release notes, is that Utah’s population is disproportionately of northern European descent. “Future studies will need to determine whether the trends hold true among people of different races and ethnicities,” it stated.
Call for More Testing
The University of Utah study is part of a larger effort to gain a greater understanding of the causes of stillbirths.
The story notes that “more than 20,000 pregnancies in the US end in stillbirth,” and in one in three of those cases, the cause is not determined.
Drucilla Roberts, MD, an obstetric and perinatal pathologist at Massachusetts General Hospital (MGH), told ProPublica that at a minimum, “the placenta should definitely be evaluated in every stillbirth.” But citing CDC data, the story notes that this is done in only 65% of stillbirths, and autopsies are performed in less than 20%.
“Experts blame the low rates on several factors,” the story states. “Because an autopsy often is performed in the days following a stillbirth, doctors and nurses have to ask families soon after they receive news of the death if they would like one. Many families can’t process the loss, let alone imagine their baby’s body being cut open. What’s more, many doctors aren’t trained in the advantages of an autopsy, or in communicating with parents about the exam.”
One consequence, ProPublica notes, is that clinicians are ill-equipped to advise patients on how to reduce risk in future pregnancies. The story describes the case of Karen Gibbins, MD, a maternal-fetal medicine specialist and an assistant professor of obstetrics and gynecology at the Oregon Health and Science University (OHSU) in Portland.
An Opportunity for Pathologists
Gibbins’ son was stillborn in 2018. She asked for an autopsy and learned that her son “had a rare disease caused by her antibodies attacking the cells in his liver,” the story states. When she became pregnant again, her doctor prescribed antibody infusions and she later gave birth to a healthy son. “If we had not had that autopsy, my third child would have died as well,” she told ProPublica.
This parent’s comment about the value of the autopsy done after her son’s stillbirth identifies an opportunity for the pathology profession. For several decades, health plans have become ever more reluctant to pay for autopsies. Yet, pathologists know the value that autopsies can provide.
The immediate value comes from revealing useful insights about all the health conditions of the deceased. The long-term value comes from the ability to gather the findings across a large number of autopsies that can contribute to new knowledge about health conditions that physicians use to improve the diagnoses of different health conditions.
Thus, with the publication of this peer-reviewed study about the connection between genetic variations and stillbirth, there is the opportunity for some of the nation’s pathology societies to advocate for funding a pilot program to fund more autopsies of stillborn babies, specifically to add more knowledge about the role of gene mutations as a causative factor in stillbirths.
Researchers found that early in life intestinal microorganisms “educate” the thymus to develop T cells; findings could lead to improved immune system therapeutics and associated clinical laboratory tests
The researchers published their findings in Nature. They used engineered mice as the test subjects and say the study could lead to a greater understanding of human conditions such as Type 1 and Type 2 diabetes and inflammatory bowel disease (IBD). In turn, this new knowledge could lead to new diagnostic tests for clinical laboratories.
“From the time we are born, our immune system is set up so that it can learn as much as it can to distinguish the good from the bad,” Matthew Bettini, PhD, Associate Professor of Pathology said in a University of Utah news release.
Does Gut Bacteria ‘Educate’ the Immune System?
The researchers were attempting to learn how the body develops T cells specific to intestinal microorganisms. T cells, they noted, are “educated” in the thymus, an organ in the upper chest that is key to the adaptive immune system.
“Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection,” they wrote in their study. “Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen, while limiting inflammatory anti-commensal responses.”
Matthew Bettini, PhD (left), Associate Professor of Pathology at the University of Utah, co-authored the study along with Gretchen Diehl, PhD (right), an immunologist at Sloan Kettering Institute. The team also included researchers from the Baylor College of Medicine in Houston and the Washington University School of Medicine in St. Louis. “Our studies make clear that there is a window in which gut microbiota have access to the immune education process. This opens up possibilities for designing therapeutics that can influence the trajectory of the immune system during this early time point,” Bettini said in the University of Utah news release. (Photo copyright: University of Utah/Sloan Kettering Institute.)
Findings Challenge Earlier Assumptions about Microbiota’s Influence on Immunity
The researchers began by seeding the intestines of mice with segmented filamentous bacteria (SFB), which they described as “one of the few commensal microorganisms for which a microorganism-specific T-cell receptor has been identified.” In addition, SFB-specific T cells can be tracked using a magnetic enrichment technique, they wrote in Nature.
They discovered that in young mice, microbial antigens from the intestines migrated to the thymus, resulting in an expansion of T cells specific to SFB. But they did not see an expansion of T cells in adult mice, suggesting that the process of adapting to microbiota happens early.
“Our study challenges previous assumptions that potential pathogens have no influence on immune cells that are developing in the thymus,” Bettini said in the news release. “Instead, we see that there is a window of opportunity for the thymus to learn from these bacteria. Even though these events that shape which T cells are present happen early in life, they can have a greater impact later in life.”
For example, T cells specific to microbiota can also protect against closely related harmful bacteria, the researchers found. “Mice populated with E. coli at a young age were more than six times as likely to survive a lethal dose of Salmonella later in life,” the news release noted. “The results suggest that building immunity to microbiota also builds protection against harmful bacteria the body has yet to encounter.”
According to the researchers, in addition to protecting against pathogens, “microbiota-specific T cells have pathogenic potential.” For example, “defects in these mechanisms could help explain why the immune system sometimes attacks good bacteria in the wrong place, causing the chronic inflammation that’s responsible for inflammatory bowel disease,” they suggested.
Other Clinical Laboratory Research into the Human Microbiome
All of this suggests the potential in the future “for clinical laboratories and microbiologists to do microbiome testing in support of clinical care,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report. Of course, more research is needed in these areas.
“We believe that our findings may be extended to areas of research where certain bacteria have been found to be either protective or pathogenic for other conditions, such as Type 1 and Type 2 diabetes,” Bettini said in the University of Utah news release. “Now we’re wondering, will this window of bacterial exposure and T cell development also be important in initiating these diseases?”
The software applications (apps) and hardware monitoring devices involved in digital therapeutics enable physicians and patients to target and alter specific behaviors that affect certain medical conditions, such as substance abuse or depression. Combined with or without drugs, digital therapeutics are achieving positive results, according to the United Kingdom’s PwC (PricewaterhouseCoopers) Health Research Institute (PwC HRI).
The report goes on to state that digital therapeutics “is
reshaping the landscape for new medicines, product reimbursement and regulatory
oversight … [and that] new data sharing processes and payment models will be
established to integrate these products into the broader treatment arsenal and
regulatory structure for drug and device approvals.
“Connected health services,” the report continues, “enabled by devices that transmit data or connect to the Internet, give additional visibility into care delivery and new ways to improve patient outcomes.”
Digital therapeutics combine apps and monitoring devices for
the management and treatment of medical conditions. While similar to customer
wellness apps, digital therapeutics focus on specific clinical outcomes.
The non-profit Digital Therapeutics Alliance says that, unlike common “wellness” apps, digital therapeutics “possess the unique ability to incorporate additional functionalities into a comprehensive portfolio of synchronous products and services. This includes potential integration with mobile health platforms; the provision of complementary diagnostic or adherence interventions; the ability to pair with devices, sensors, or wearables; the delivery of interventions remotely; and integration into electronic prescribing, dispensing, and medical record platforms.”
“Digital therapeutics are the next frontier,” Sai Jasti, Chief Data and Analytics Officer, GlaxoSmithKline (NYSE:GSK), told PwC HRI. “I think we will see a lot more collaboration between pharmaceutical and technology companies to drive this forward, ultimately to the benefit of patients.”
Digital Therapeutics That Already Have FDA Approval
Digital therapeutics and their connected devices are subject
to the approval process of the federal Food and Drug Administration (FDA), and
some have already received that coveted clearance:
reSET from Pear Therapeutics is a 90-day prescription digital therapeutic (PDT) for substance use disorder (SUD). The Boston-based company also worked with Sandoz Inc., a division of Novartis, to receive FDA approval for reSET-O, a PDT for treating individuals with Opioid Use Disorder (OUD).
“Digital technologies and data science have incredible potential to unlock the next chapter of medical innovation and to help individuals finally take control of their own health in a meaningful way,” said Richard Francis, Division Head and CEO, Sandoz, in a press release. “New digital therapeutics such as reSET-O also have the potential to fundamentally change how patients interact with their therapies and thus improve patient outcomes.”
Both reSET and reSET-O are software mobile apps that use cognitive behavioral therapy (CBT) to help individuals struggling with addictions.
“Nearly 50,000 drug overdose deaths involving opioids, including prescription pain medications and heroin, took place in the U.S. in 2017,” said Corey McCann, MD, PhD, President and CEO of Pear Therapeutics, in the press release following receiving FDA approval. “There is an urgent need for new and innovative therapeutics to address this public health epidemic. This groundbreaking decision by the FDA ushers in a new standard for treating patients with Opioid Use Disorder and it signals a new path for therapeutic software to be used in conjunction with pharmacotherapy to improve efficacy.”
Natural
Cycles is a birth control app created by a Sweden-based company of the same
name. It was approved by the FDA in 2018. This mobile app helps women track
their fertility to prevent unwanted pregnancies via the rhythm method. The app
analyzes data from past menstrual cycles and body temperature readings to
determine when the user is most fertile. On the days the user is most likely to
be ovulating, the app displays “Use Protection” on the mobile device’s screen.
“We know that women are more likely to use contraceptive methods when they have a variety of methods available to them, and the reality is that not every method is going to work for every woman,” Rebecca Simmons, PhD, Research Assistant Professor, Department of Obstetrics and Gynecology, University of Utah, told Health. “This is really exciting, in the sense that the more methods we have, the more likely it is that people can find something that works for them—and then can avoid unwanted pregnancy.”
Apple, headquartered in Cupertino, Calif., received FDA clearance in 2018 for an electrocardiogram (ECG) app for its Apple Watch Series 4 that allows users to take an ECG from their wrist to detect irregular heart rhythms and atrial fibrillation (AFIB).
“The role that technology plays in allowing patients to capture meaningful data about what’s happening with their heart—at the moment when it’s happening, like the functionality of an on-demand ECG—could be significant in new clinical care models and shared decision-making between people and their healthcare providers,” said Nancy Brown, CEO of the American Heart Association, in a press release.
Patients, Providers, and Big Pharma All Like Digital
Therapeutics
There is some evidence that patients and healthcare
providers are intrigued and willing to try digital therapeutics. In a PwC HRI survey,
more than 50% of respondents said they “would be somewhat or very likely to try
an FDA-approved app or online tool for treatment of a medical condition.”
The graphic above is taken from the PwC HRI 2019 annual report on digital therapeutics and connected care. It shows that “a majority of consumers surveyed are interested in FDA approved digital apps or online tools to treat their medical conditions.” (Graphic copyright: PwC HRI.)
Pharmaceutical companies also are interested in digital therapeutics. A 2018 PwC HRI survey found that 80% of pharmaceutical executives had plans to invest in digital therapeutics in the near future.
With precision medicine and pharmacogenetics, clinical laboratories
could play an essential role in supporting digital therapeutics in the future. But
to truly be competitive in this space and take advantage of the opportunity, medical
laboratories will need to increase their information technology and digital
capabilities.
One idea proving attractive to health policymakers is putting a hybrid model into rural towns that includes a freestanding emergency department and primary care
Times are tough for rural hospitals and officials in many states are looking at new models for healthcare delivery in rural areas. Anatomic pathology groups with contracts to serve rural hospitals will be affected by any changes in how rural hospitals are funded and operated.
One suggested approach to replace the existing community hospital model for rural area is called a hybrid model. It is based on freestanding emergency departments (FSED) that have links to primary care providers. Such a care model would challenge clinical laboratories in the region to provide necessary medical laboratory testing to the freestanding EDs in rural communities.
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