DNA analysis of early plague victims pinpoints Black Death’s start on Silk Road trading communities in mountain region of what is now modern-day Kyrgyzstan in Central Asia
Microbiologists and clinical laboratory scientists will likely find it fascinating that an international team of scientists may have solved one of history’s greatest mysteries—the origin of the bubonic plague that ravaged Afro-Eurasia in the mid fourteenth century. Also known as the Black Death, the plague killed 60% of the population of Europe, Asia, and North Africa between 1346-1353 and, until now, the original source of this disease has largely gone unsolved.
In their study published in the journal Nature, titled, “The Source of the Black Death in Fourteenth-Century Central Eurasia,” the authors outlined their investigation of cemeteries in the Chüy Valley of modern-day Kyrgyzstan. The tombstone inscriptions showed a disproportionally high number of burials dating between 1338 and 1339 with inscriptions stating “pestilence” as the cause of death.
Archeological evidence combined with ancient DNA analysis of early plague victims enabled scientists to pinpoint the Black Death’s origins in Kyrgyzstan. “We have basically located the origin in time and space, which is really remarkable,” geneticist Johannes Krause, PhD (above), Professor at the Max Planck Institute for Evolutionary Anthropology, who co-led the study, told The Guardian. “We found not only the ancestor of the Black Death, but the ancestor of the majority of the plague strains that are circulating in the world today.” These new research findings may help microbiologists and clinical pathologists gain new insights into how current strains of Yersinia pestis can be better diagnosed. (Photo copyright: Max Planck Institute.)
Big Bang of Plague
Using 30 skeletons that were excavated from these cemeteries in the late 1880s and moved to St. Petersburg, Russia, the scientists analyzed the DNA of ancient pathogens recovered from the remains of seven people. They discovered Yersinia pestis (Y. pestis) DNA in three burials from Kara-Djigach, which lies in the foothills of the Tian Shan mountains.
According to another article in Nature, the scientists showed that a pair of full Y. pestis genomes from their data were direct ancestors of strains linked to the Black Death, and that the Kara-Djigach strain was an ancestor of the vast majority of Y. pestis lineages circulating today.
“It was like a big bang of plague,” Krause stated at a press briefing, Nature reported.
The research team concluded that the Tian Shan region was the location where Y. pestis first spread from rodents to people, and that the local marmot colonies likely the prevalent rodent carriers of plague.
“We found that modern strains [of the plague] most closely related to the ancient strain are today found in plague reservoirs around the Tian Shan mountains, so very close to where the ancient strain was found. This points to an origin of Black Death’s ancestor in Central Asia,” Krause explained in a Max Planck Institute news release.
He told Nature that fleas likely passed the marmot-based infection on to humans, sparking a local Kyrgyzstan epidemic. The disease then spread along the Silk Road trade routes, eventually reaching Europe, where rats (and the fleas that they carried) spread the disease.
Understanding Context of Plague
Writing in The Conversation, Associate Professor of Medieval and Environmental History Philip Slavin, PhD, University of Stirling, who co-authored the study, explained that Kara-Djigach is unlikely to be “the specific source of the pandemic,” but rather that the “disaster started somewhere in the wider Tian Shan area, perhaps not too far from that site,” where marmot colonies were likely the source of the 1338-1339 outbreak.
Making a modern-day comparison, Krause told Nature, “It is like finding the place where all the strains come together, like with coronavirus where we have Alpha, Delta, Omicron all coming from this strain in Wuhan.”
Slavin maintains that understanding the “big evolutionary picture” is key when studying the phenomenon of emerging epidemic diseases.
“It is important to see how these diseases develop evolutionary and historically, and avoid treating different strains as isolated phenomena,” he wrote in The Conversation. “To understand how the diseases develop and get transmitted, it is also crucial to consider the environmental and socioeconomic contexts.”
Scientists have spent centuries debating the source of the Black Death that devastated the medieval world. The multidisciplinary process used by the Slavin/Krause-led team provides a lesson to clinical laboratory managers and pathologists on the important role they play when collaborating with colleagues from different fields on scientific investigations.
Factors contributing to shortage of med techs and other lab scientists include limited training programs in clinical laboratory science, pay disparity, and staff retention, notes infectious disease specialist Judy Stone, MD
Staff shortages are a growing challenge for medical laboratories, and now the problem has grabbed the attention of a major media outlet.
In a story she penned for Forbes, titled, “We’re Facing a Critical Shortage of Medical Laboratory Professionals,” senior contributor and infectious disease specialist Judy Stone, MD, wrote, “Behind the scenes at every hospital are indispensable medical laboratory professionals. They performed an estimated 13 billion laboratory tests in the United States each year before COVID. Since the pandemic began, they have also conducted almost 997 million diagnostic tests for COVID-19. The accuracy and timeliness of lab tests are critically important, as they shape approximately two-thirds of all medical decisions made by physicians.”
Though Stone states in her Forbes article that clinical laboratories in both the US and Canada are facing staff shortages, she notes that the problem is more acute in the US.
As Dark Daily reported in February, the so-called “Great Resignation” caused by the COVID-19 pandemic has had a severe impact on clinical laboratory staffs, creating shortages of pathologists as well as of medical technologists, medical laboratory technicians, and other lab scientists who are vital to the nation’s network of clinical laboratories.
In her analysis, however, Stone accurately observes that the problem pre-dates the pandemic. For examples she cites two surveys conducted in 2018 by the American Society for Clinical Pathology (ASCP):
Many pathologists and clinical laboratory managers would agree that Stone is right. Dark Daily has repeatedly reported on growing staff shortages at clinical laboratories worldwide.
And in “Lab Staffing Shortages Reaching Dire Levels,” Dark Daily’s sister publication, The Dark Report, noted that CAP Today had characterized the current lab staffing shortage as going “from simmer to rolling boil” and that demand for medical technologists and other certified laboratory scientists far exceeds the supply. Consequently, many labs now use overtime and temp workers to handle daily testing, a strategy that has led to staff burnout and more turnover.
“There is a critical shortage of medical laboratory professionals in the US, and in Canada to a lesser extent,” wrote infectious disease specialist Judy Stone, MD (above), in an article she penned for Forbes. “Here [in the US],” she added, “we are 20-25,000 short on staff, with only 337,800 practicing. That is roughly one medical laboratory scientist per 1,000 people.” Clinical laboratories are well aware of the problem. A solution to solve it and return labs to former staffing levels is proving elusive. (Photo copyright: Forbes.)
Why the Shortfall?
In her Forbes article, Stone notes the following as factors behind the shortages:
Decline in training programs. “There are only [approximately] 240 medical laboratory technician and scientist training programs in the US, a 7% drop from 2000,” Stone wrote, adding that some states have no training programs at all. She notes that lab technicians must have a two-year associate degree while it takes an average of five years of post-secondary education to obtain a lab science degree.
Pay disparities. Citing data from the ASCP, Stone wrote that “medical lab professionals are paid 40%-60% less than nurses, physical therapists, or pharmacists.” Moreover, given the high cost of training, “many don’t feel the salary is worth the high investment,” she added.
Staff retention. In the ASCP’s 2018 job satisfaction survey, 85.3% of respondents reported burnout from their jobs, 36.5% cited problems with inadequate staffing, and nearly that many complained that workloads were too high.
Inconsistent licensing requirements. These requirements “are different from state to state,” Stone wrote. For example, the American Society for Clinical Laboratory Science (ASCLS) notes that 11 states plus Puerto Rico mandate licensure of laboratory personnel whereas others do not. Each of those states has specific licensing requirements, and while most offer reciprocity for other state licenses, “California [for example] does not recognize any certification or any other state license.”
In a 2018 report, “Addressing the Clinical Laboratory Workforce Shortage,” the ASCLS cited other factors contributing to the shortages, including retirement of aging personnel and increased demand for lab services.
Possible Solutions
Stone suggested the following remedies:
Improve working conditions. “We need to reduce the stress and workload of the lab professionals before we reach a greater crisis,” Stone wrote.
Standardize state certification. This will facilitate “mobility of staff and flexibility in responding to needs,” Stone suggested.
Improve education and training opportunities. The ASCLS has called for clinical lab science to be included in the Title VII health professions program, which provides funding for healthcare training. Rodney Rohde, PhD, a clinical laboratory science professor at Texas State University, “also suggests outreach to middle and high school STEM programs, to familiarize students early with career opportunities in the medical laboratory profession,” Stone wrote.
Recruit foreign workers. Stone suggested this as an interim solution, with programs to help them acclimate to practice standards in the US.
It will likely take multiple solutions like these to address the Great Resignation and bring the nation’s clinical laboratory staffing levels back to full. In the meantime, across the nation, a majority of clinical laboratories and anatomic pathology groups operate short-staffed and use overtime and temporary workers as a partial answer to their staffing requirements.
Should the device prove effective, it could replace invasive point-of-care blood draws for clinical laboratory testing during patient drug therapy monitoring
What if it were possible to perform therapeutic drug monitoring (TDM) without invasive blood draws using breath alone? Patients fighting infections in hospitals certainly would benefit. Traditional TDM can be a painful process for patients, one that also brings risk of bloodline infections. Nevertheless, regular blood draws have been the only reliable method for obtaining viable samples for testing.
One area of critical TDM is in antibiotic therapy, also known as personalized antibiotherapy. However, for antibiotic therapy to be successful it typically requires close monitoring using point-of-care clinical laboratory testing.
Now, a team of engineers and biotechnologists from the University of Freiburg in Germany have developed a biosensor that can use breath samples to measure antibiotic concentrations present in blood, according to a University of Freiburg press release.
The team’s non-invasive collection method requires no needle sticks and can allow for frequent specimen collections to closely monitor the levels of an antibiotic prescribed for a patient. The biosensor also provides physicians the ability to tailor antibiotic regimens specific to individual patients, a core element of precision medicine.
“Until now researchers could only detect traces of antibiotics in the breath,” said Can Dincer, PhD (above), Junior Research Group Leader at the University of Freiburg, and one of the authors of the study, in the press release. “With our synthetic proteins on a microfluid chip, we can determine the smallest concentrations in the breath condensate and [how] they correlate with the blood values.” Should the breath biosensor prove effective in clinical settings, painful blood draws for clinical laboratory testing at the point of care could become obsolete. (Photo copyright: Conny Ehm/University of Freiburg.)
Can a Breath Biosensor Be as Accurate as Clinical Laboratory Testing?
The University of Freiburg’s biosensor is a multiplex, microfluid lab-on-a-chip based on synthetic proteins that react to antibiotics. It allows the simultaneous measurement of several breath samples and test substances to determine the levels of therapeutic antibiotics in the blood stream.
To perform their research, the University of Freiburg team tested their biosensor on blood, plasma, urine, saliva, and breath samples of pigs that had been given antibiotics. The results the researchers achieved with their device using breath samples were as accurate as standard clinical laboratory testing, according to the press release.
The microfluidic chip contains synthetic proteins affixed to a polymer film via dry film photoresist (DFR) technology. These proteins are similar to proteins used by drug-resistant bacteria to sense the presence of antibiotics in their environment. Each biosensor contains an immobilization area and an electrochemical cell which are separated by a hydrophobic stopping barrier. The antibiotic in a breath sample binds to the synthetic proteins which generates a change in an electrical current.
“You could say we are beating the bacteria at their own game,” said Wilfried Weber, PhD, Professor of Biology at the University of Freiburg and one of the authors of the research paper, in the press release.
Rapid Monitoring at Point-of-Care Using Breath Alone
The biosensor could prove to be a useful tool in keeping antibiotic levels stable in severely ill patients who are dealing with serious infections and facing the risk of sepsis, organ failure, or even death. Frequent monitoring of therapeutic antibiotics also could prevent bacteria from mutating and causing the body to become resistant to the medications.
“Rapid monitoring of antibiotic levels would be a huge advantage in hospital,” said H. Ceren Ates, PhD, scientific researcher at the University of Freiburg and one of the authors of the study in the press release. “It might be possible to fit the method into a conventional face mask.”
Along those lines, the researchers are also working on a project to create wearable paper sensors for the continuous measurement of biomarkers of diseases from exhaled breath. Although still in the development stages, this lightweight, small, inexpensive paper sensor can fit into conventional respiratory masks, according to a University of Freiburg press release.
Other Breath Analysis Devices Under Development
Devices that sample breath to detect biomarkers are not new. Dark Daily has regularly reported on similar developments worldwide.
Thus, University of Freiburg’s non-invasive lab-on-a-chip biosensor is worth watching. More research is needed to validate the effectiveness of the biosensor before it could be employed in hospital settings, however, monitoring and managing antibiotic levels in the body via breath samples could prove to be an effective, non-invasive method of providing personalized antibiotic therapy to patients.
Clinical trials on human breath samples are being planned by the University of Freiburg team. This type of precision medicine service may give medical professionals the ability to maintain proper medication levels within an optimal therapeutic window.
CDC asks physicians and clinical laboratories to be on the lookout and report symptoms of hepatitis to state health departments
Growing incidences of hepatitis in children are perplexing medical professionals and researchers in several countries around the world. The mysterious outbreak is occurring in otherwise healthy children and, to date, is of unknown origin, though an adenovirus may be involved.
Microbiologists and clinical laboratory scientists who perform virology testing may want to prepare for increased numbers of children presenting with hepatitis symptoms in the US.
On April 21, the Centers for Disease Control and Prevention (CDC) issued a nationwide health alert to notify the public about a cluster of children in Alabama who presented with hepatitis and adenovirus infections. The CDC asked physicians to watch for symptoms in children and to inform local and state health departments of any new suspected cases.
Also in April, the World Health Organization (WHO) issued its own alert to an outbreak of acute hepatitis of unknown etiology among young children in several countries. In addition to the United States, cases were reported in the United Kingdom, Spain, Israel, Denmark, Ireland, the Netherlands, Italy, Norway, France, Romania, and Belgium.
All the cases reported to the WHO involved children between one month and 16 years of age with the majority of cases occurring in children under five.
According to NBC News, as of May 19, the worldwide number of cases “under investigation” had reached 600 in more than 25 countries. In the US, more than 90% of the patients required hospitalization and 14% of those patients needed a liver transplant. The CDC is investigating five pediatric deaths that may be attributed to the mysterious hepatitis outbreak.
“Fifteen days ago, CDC issued a nationwide health alert to notify clinicians and public health authorities about an investigation involving nine children in Alabama identified between October of 2021 and February of 2022 with hepatitis or inflammation of the liver and adenovirus infection,” said pediatrician and epidemiologist Jay Butler, MD (above), Deputy Director for Infectious Diseases at the CDC. “We’re casting a broad net to increase our understanding,” he added. “As we learn more, we’ll share additional information and updates.” Hospital-based clinical laboratories that support emergency departments and urgent care centers with testing for hepatitis will want to monitor for upcoming CDC alerts. (Photo copyright: John Amis/AP/CNN.)
Adenovirus/SARS-CoV-2 May Be Linked to Hepatitis Outbreak
The cause of the hepatitis outbreak is as yet undetermined, but the pre-eminent theory among disease experts points to the presence of an adenovirus, which often causes cold and flu-like symptoms in addition to stomach issues.
NBC News reported that more than half of the US patients, 72% of the UK patients, and 60% of the affected patients across Europe tested positive for human adenovirus type 41. This virus, however, is generally not associated with hepatitis in healthy children, and rarely impacts the liver so severely.
Medical experts are also considering the possibility that COVID-19 infections could somehow be an underlying cause since the hepatitis outbreak occurred during the pandemic. The WHO is investigating whether exposure to the SARS-CoV-2 coronavirus might have prompted the immune systems in the infected children to react abnormally to adenoviruses that are typically non-life threatening.
“The big focus over the next week is really looking at the serological testing for previous exposure and infections with COVID,” Phillipa Easterbrook, MD, a senior scientist at the WHO headquarters in Geneva, told NBC News.
Hepatitis, or inflammation of the liver, is typically caused by heavy alcohol use, exposure to toxins, certain medical conditions and medications, or a virus.
The most recent children diagnosed with hepatitis presented with some or most of these symptoms, particularly stomach issues and fatigue. However, one symptom was present in all the children.
“The big symptom that made all of these kids different was that they all showed signs of jaundice, which is the yellowish coloration of the skin and eyes,” Markus Buchfellner, MD, a pediatric infectious disease fellow at the University of Alabama, told NBC News.
Buchfellner was the first person in the US to notice an unusual pattern of hepatitis among children. He reported his findings to the CDC last fall in 2021.
“We were able to uncover the possible association with the adenovirus 41 strain because it is our standard practice to screen patients diagnosed with hepatitis for adenovirus,” he said. “For us to dig deeper into this medical mystery and see if this strain is the cause of these severe hepatitis cases, we first need more data on how widespread the outbreak is.”
Adenovirus 41 is usually spread through fecal matter, which makes hand washing critical, especially after visits to the bathroom or diaper changes. This type of adenovirus typically presents as diarrhea, vomiting, and fever, and is often accompanied by respiratory issues.
Clinical Labs Performing Gene Sequencing Can Help
Medical scientists around the world are responding to this threat to the youngest and most vulnerable among us. Research is underway into identifying additional cases, determining what is causing the hepatitis globally among children, and establishing preventative measures.
Pathologists and clinical laboratory managers in the US will want to be on the alert for positive hepatitis tests in children whose specimens were tested at their facilities. With advances in gene sequencing that make testing economical and expeditious, more labs have the ability to not only detect hepatitis, but also to identify any genetic variants that may be associated with the increased number of pediatric hepatitis cases appearing around the world.
InspectIR COVID-19 Breathalyzer identifies a chemical signature associated with SARS-CoV-2 in about three minutes with 91.2% sensitivity and 99.3% specificity
One company is hoping that it can make breathalyzers a viable, easier way to screen for SARS-CoV-2. It will soon have the opportunity to learn if consumers will accept this form of screening for COVID-19, as its device recently obtained an Emergency Use Authorization from the FDA.
On April 14, 2022, InspectIR Systems, LLC, of Frisco, Texas, was granted the US Food and Drug Administration’s first-ever emergency use authorization (EUA202006) for a portable breath test device designed to screen for SARS-CoV-2 infection. Clinical laboratories that perform COVID-19 testing will want to compare the high-level sensitivity of this breath test compared to rapid antigen tests currently used for COVID-19 screening.
The device is about the size of a carry-on suitcase. It provides test results in less than three minutes and is currently authorized for use with subjects who are 18 or older.
The FDA’s EUA limits use of the device to “a qualified, trained operator under the supervision of a healthcare provider licensed or authorized by state law to prescribe tests,” the federal agency said. The test “can be performed in environments where the patient specimen is both collected and analyzed, such as doctor’s offices, hospitals, and mobile testing sites.”
The InspectIR COVID-19 Breathalyzer device “is yet another example of the rapid innovation occurring with diagnostic tests for COVID-19,” said Jeffrey Shuren, MD, JD (above), director of the FDA’s Center for Devices and Radiological Health (CDRH), in the news release. A portable device that can identify SARS-CoV-2 infections in a few minutes with 91% specificity may be of great interest to clinical laboratory companies operating COVID-19 popup testing sites around the nation. (Photo copyright: US Food and Drug Administration.)
In granting the authorization, the FDA cited results of a study with 2,409 participants in which the test had sensitivity (correct positive results) of 91.2% and specificity (correct negative results) of 99.3%. “The test performed with similar sensitivity in a follow-up clinical study focused on the Omicron variant,” the agency stated.
“The FDA continues to support the development of novel COVID-19 tests with the goal of advancing technologies that can help address the current pandemic and better position the US for the next public health emergency,” said Jeffrey Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health (CDRH), in the news release.
In its coverage of the EUA, CNET noted that the InspectIR breath test is more sensitive than rapid antigen tests but not as sensitive as PCR tests. The FDA advised that people who receive a positive test result with the InspectIR COVID-19 Breathalyzer should follow up with a PCR molecular test.
How the InspectIR COVID-19 Breathalyzer Works
InspectIR LLC was founded in 2017 by Tim Wing and John Redmond, Forbes reported. Their original goal was to develop a breathalyzer for detection of cannabis or opioid use. However, with the onset of the COVID-19 pandemic, the entrepreneurs decided to adapt the technology into a SARS-CoV-2 diagnostic test.
As described in the FDA’s EUA documents, a subject breathes into the device using a sterilized one-time-use straw. A pre-concentrator collects and concentrates the five targeted VOCs, all from the ketone and aldehyde families of organic compounds. These go to a Residual Gas Analyzer, and an algorithm determines whether the sample contains the chemical signature associated with a SARS-CoV-2 infection.
Redmond told Forbes that the specific mix of VOCs is proprietary. The article notes that Wing, Redmond, and Verbeck have patented the pre-concentrator technology.
The devices are manufactured at a Pfeiffer Vacuum Inc. facility in Indiana. The InspectIR founders told Forbes they expect to produce 100 units per week in a start-up phase with plans to ramp up as sales increase. They also plan to look at applications for other respiratory diseases.
InspectIR has not announced exact pricing, but Time reports that the company will lease the equipment to clients, and that pricing per test will be comparable to rapid antigen tests.
InspectIR’s first breathalyzer device is receiving much positive coverage from the media. Should it prove to effective at spotting COVID-19 at popup testing sites, it may supplant traditional clinical laboratory rapid antigen tests as the screening test of choice.
