The CDC suggests that hospitals treating patients for flu symptoms perform clinical laboratory tests for avian influenza A within 24 hours. This additional testing will pinpoint the specific type of flu infecting an individual patient and help prevent further spread of the bird flu virus.
“It’s the subtyping that takes us from knowing that a virus is in the general bucket of ‘influenza A’ to knowing more specifically whether it’s a garden-variety seasonal version of influenza A or, more rarely, a novel version of influenza A like H5N1,” CDC Principal Deputy Director Nirav Shah, MD, JD, told CNN.
According to the CDC, a panzootic of pathogenic avian H5N1 flu virus is currently affecting wild birds, poultry, dairy cows, and other animals throughout the country. There have been 67 total cases of bird flu identified in humans in the US since 2022, with 66 of those cases occurring in 2024.
The risk of humans contracting bird flu are low but is elevated among those who work closely with wild birds, poultry, and dairy cattle. The incidences of the flu virus in animals continues to increase, so CDC says it is important to identify potential bird flu cases in humans in a timely manner.
This demonstrates recognition by the CDC and the clinical laboratory profession that advances in molecular diagnostics and genetic testing now make it feasible for many hospital labs to perform these tests in-house on relevant patients. Such molecular testing is less expensive and produces a faster answer today, compared to just a few years ago.
This call for more lab tests in hospitals is also recognition of the value near-patient testing has from a public health perspective. Historically, it was regional and local public health labs that were sent specimens for testing from patients identified as having an infection that were a public health concern.
The good news is that this expands the role of hospital laboratories for all the right reasons. The downside is that hospital labs will probably see many test claims for these assays not be paid promptly by payers—or paid after unnecessary delays.
“The system right now tells us what has already happened. What we need is to shift to a system that tells us what’s happening in the moment. That is what we are doing today,” Nirav Shah, MD, JD (above), CDC principal deputy told CNN. Hospital and clinical laboratories will likely see an increase in orders for molecular and genetic testing for influenza A. (Photo copyright: Centers for Disease Control and Prevention.)
CDC Recommendations to Clinical Laboratories
The CDC alert also acknowledges that most individuals infected with avian flu were exposed to the virus via the handling of infected dairy cows or poultry in unprotected workplaces. There are no known cases of human-to-human transmission of the disease.
Most cases of avian flu in humans have been clinically mild and the patients quickly recover. However, on January 6, the CDC announced that an elderly patient with underlying health conditions in Louisiana who was previously hospitalized with severe avian influenza A illness had passed away. This case was the first confirmed death in the US attributed to the illness.
The CDC’s Health Advisory makes the following recommendations to clinical laboratories:
Subtype respiratory specimens that are positive for influenza A, but negative for seasonal influenza A virus subtypes, and forward those specimens to a public health laboratory within 24 hours.
Refrain from batching specimens for consolidated or bulk shipment to public health laboratories if that process could result in shipping delays.
Notify public health officials if a hospital or clinical lab does not have access to influenza A virus subtyping and arrange for a public health or commercial lab with this testing capability to perform the analysis.
Clearly link specimens to clinical information from the patient to ensure the prioritization of severely ill and ICU patients.
Immediately contact local public health authority if a positive result for influenza A (H5) virus is obtained using a laboratory developed test (LDT) or another A (H5) subtyping test to initiate time-critical actions.
The CDC’s Health Advisory also states public health laboratories should complete influenza A subtyping assays within 24 hours of receipt and report those results to the CDC, as required.
“One of the motivators of accelerating testing [is] so that we are, again, able to faster see difference between signal and noise, given that the volume of hospitalizations is going up as expected in a rather routine flu season,” Demetre Daskalakis, MD, MPH, director of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD), told CNN.
Preparing for more Bird Flu in Humans
According to the CDC, approximately 100,000 Americans have been hospitalized with type-A flu this season. The agency expects another 100,000 hospitalizations due to the virus before the end of this year. CDC is tracking flu infections on a weekly basis. Data can be reviewed on its website.
Other government organizations also are developing methods intended to curb the spread of the influenza virus. The federal Department of Agriculture recently launched a national program to test for bird flu in untreated milk. And the US Department of Health and Human Services (HHS) allocated $211 million in new funding to address emerging infectious diseases.
On January 17, the HHS announced it would give $590 million to Moderna to “accelerate the development of mRNA-based pandemic influenza vaccines and enhance mRNA platform capabilities so that the US is better prepared to respond to other emerging infectious diseases.”
“The funding will allow us to bring the benefits of mRNA vaccine technology to bear against a wider array of emerging threats,” said HHS Assistant Secretary for Preparedness and Response Dawn O’Connell, JD, in the announcement. “mRNA technology can be faster to develop and easier to update than other vaccines making it a helpful tool to have against viruses that move fast and mutate quickly.
Hospital laboratories and public health labs should prepare for a spike in test orders for avian influenza A as this year’s flu season progresses. As bird flu increases in animals, it increases the possibility that the disease might infect humans.
“Previously … CDC developed tests for emerging pathogens and then shared those tests with others, and then after that, commercial labs would develop their own tests,” Shah told CNN. “That process took time. Now with these new arrangements, commercial labs will be developing new tests for public health responses alongside CDC, not after CDC.”
In a news release announcing the contract, ARUP Laboratories also characterized the move as a shift for the agency.
“The new contract formalizes ARUP’s relationship with the CDC,” said Benjamin Bradley, MD, PhD, medical director of the ARUP Institute for Research and Innovation in Infectious Disease Genomic Technologies, High Consequence Pathogen Response, Virology, and Molecular Infectious Diseases. “We continue to expand our capabilities to address public health crises and are prepared to scale up testing for H5N1, or develop other tests quickly, should the need arise.”
“To be clear, we have no evidence so far that this [bird flu] virus can easily infect human beings or that it can spread between human beings easily in a sustained fashion,” Jennifer Nuzzo, DrPH (above), Director of the Pandemic Center and Professor of Epidemiology at Brown University School of Public Health, told CNN. “If it did have those abilities, we would be in a pandemic.” Clinical laboratory leaders will recall the challenges at the CDC as it developed its SARS-CoV-2 test early in the COVID-19 pandemic. (Photo copyright: Brown University.)
Missouri Case Raises Concerns
The first human infection of HPAI was reported in late March following a farmer’s “exposure to dairy cows presumably infected with bird flu,” the CDC stated in its June 3, 2024, bird flu Situation Summary. That followed confirmation by the USDA’s Animal and Plant Health Inspection Service (APHIS) of an HPAI outbreak in commercial poultry flocks in February 2022, and the CDC’s confirmation of the first known infections in dairy herds reported on March 25, 2024.
Concerns about the outbreak were heightened in September following news that a person in Missouri had been infected with the virus despite having no known contact with infected animals. CNN reported that it was the 14th human case in the US this year, but all previous cases were in farm workers known to be exposed to infected dairy cattle or poultry.
In a news release, the Missouri Department of Health and Senior Services (DHSS) revealed that the patient, who was not identified, was hospitalized on Aug. 22. This person had “underlying medical conditions,” DHSS reported, and has since recovered and was sent home. Both DHSS and the CDC conducted tests to determine that the virus was the H5 subtype, the news release states.
At present, the CDC states that the public health risk from the virus is low. However, public health experts are concerned that risks could rise as the weather gets cooler, creating opportunities for the virus to mutate “since both cows and other flu viruses will be on the move,” CNN reported.
Concerns over CDC Testing and FDA Oversight
In the months immediately following the first human case of the bird flu virus, Nuzzo was among several public health experts sounding an alarm about the country’s ability to ramp up testing in the face of new pathogens.
“We’re flying blind,” she told KFF Health News in June, due to an inability to track infections in farmworkers. At that time, tests had been distributed to approximately 100 public health labs, but Nuzzo and other experts noted that doctors typically order tests from commercial laboratories and universities.
KFF reported that one diagnostics company, Neelyx Labs, ran into obstacles as it tried to license the CDC’s bird flu test. Founder, CEO, and lead scientist Shyam Saladi, PhD, told KFF that the federal agency had promised to cooperate by facilitating a license and a “right to reference” CDC data when applying for FDA authorization but was slow to come through.
While acknowledging the need for testing accuracy, Greninger contended that the CDC was prioritizing caution over speed, as it did in the early days of the COVID-19 pandemic. “The CDC should be trying to open this up to labs with national reach and a good reputation,” he told KFF.
Another problem, KFF reported, related to the FDA’s new oversight of laboratory developed tests (LDTs), which is causing labs to move cautiously in developing their own tests.
Jennifer Nuzzo, DrPH (above), Director of the Pandemic Center and Professor of Epidemiology at the Brown University School of Public Health co-authored a June 2024 analysis in Health Affairs that called on the CDC to develop “a better testing playbook for biological emergencies.” The authors’ analysis cited earlier problems with the responses to the COVID-19 and mpox (formerly known as monkeypox) outbreaks.
If global surveillance networks have detected a novel pathogen, the authors advise, the US should gather information and “begin examining the existing testing landscape” within the first 48 hours.
Once the pathogen is detected in the US, they continued, FDA-authorized tests should be distributed to public health laboratories and the CDC’s Laboratory Response Network (LRN) laboratories within 48 hours.
Advocates of this approach suggest that within the first week diagnostics manufacturers should begin developing their own tests and the federal government should begin working with commercial labs. Then, within the first month, commercial laboratories should be using FDA-authorized tests to provide “high throughput capacity.”
This may be good advice. Experts in the clinical laboratory and healthcare professions believe there needs to be improvement in how novel tests are developed and made available as novel infectious agents are identified.
Accurate blood-based clinical laboratory testing for cancer promises to encourage more people to undergo early screening for deadly diseases
One holy grail in diagnostics is to develop less-invasive specimen types when screening or testing for different cancers. This is the motivation behind the creation of a new assay for colorectal (colon) cancer that uses a blood sample and that could be offered by clinical laboratories. The data on this assay and its performance was featured in a recent issue of the New England Journal of Medicine(NEJM).
The company developing this new test recognized that more than 50,000 people will die in 2024 from colon cancer, according to the American Cancer Society. That’s primarily because people do not like colonoscopies even though the procedure can detect cancer in its early stages. Similarly, patients tend to find collecting their own fecal samples for colon cancer screening tests to be unpleasant.
But the clinical laboratory blood test for cancer screening developed by Guardant Health may make diagnosing the deadly disease less invasive and save lives. The test “detects 83% of people with colorectal cancer with specificity of 90%,” a company press release noted.
“Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality,” the study authors wrote in the NEJM.
As noted above, this is the latest example of test developers working to develop clinical laboratory tests that are less invasive for patients, while equaling or exceeding the sensitivity and specificity of existing diagnostic assays for certain health conditions.
“I do think having a blood draw versus undergoing an invasive test will reach more people, My hope is that with more tools we can reach more people,” Barbara H. Jung, MD (above), President of the American Gastroenterological Association, told NPR. Clinical laboratory blood tests for cancer may encourage people who do not like colonoscopies to get regular screening. (Photo copyright: American Gastroenterology Association.)
Developing the Shield Blood Test
Colorectal cancer is the “third most common cancer among men and women in the US,” according to the American Gastrological Association (AGA). And yet, millions of people do not get regular screening for the disease.
To prove their Shield blood test, Guardant Health, a precision oncology company based in Redwood City, Calif., enrolled more than 20,000 patients between the ages of 45-84 from across the US in a prospective, multi-site registrational study called ECLIPSE (Evaluation of ctDNA LUNAR Assay In an Average Patient Screening Episode).
“We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions,” the study authors wrote in the NEJM.
In March, Guardant completed clinical trials of its Shield blood test for detecting colorectal cancer (CRC) in men and women. According to the company press release, the test demonstrated:
83% sensitivity in detecting individuals with CRC.
88% sensitivity in detecting pathology-confirmed Stages I-III.
Additionally, the Shield test showed sensitivity by stage of:
65% for pathology-confirmed Stage I,
55% for clinical Stage I,
100% for Stage II, and
100% for Stage III.
“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said molecular biologist and gastroenterologist William M. Grady, MD, Medical Director, Gastrointestinal Cancer Prevention Program at Fred Hutchinson Cancer Center and corresponding author of the ECLIPSE study in the press release. “The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options.”
Are Colonoscopies Still Needed?
“More than three out of four Americans who die from colorectal cancer are not up to date with their recommended screening, highlighting the need for a more convenient and less invasive screening method that can overcome barriers associated with traditional options,” Daniel Chung, MD, gastroenterologist at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, said in the Guardant press release.
Barbara H. Jung, MD, President of the American Gastroenterological Association, says that even if Guardant’s Shield test makes it to the public the “dreaded colonoscopy” will still be needed because the procedure is used to locate and test polyps. “And when you find those you can also remove them, which in turn prevents the cancer from forming,” she told NPR.
There is hope that less invasive clinical laboratory testing will encourage more individuals to get screened for cancer earlier and regularly, and that the shift will result in a reduction in cancer rates.
“Colorectal cancer is highly treatable if caught in the early stages,” said Chris Evans, President of the Colon Cancer Coalition, in the Guardant press release.
Guardant Health’s ECLIPSE study is a prime example of the push clinical laboratory test developers are making to create user-friendly test options that make it easier for patients to follow through with regular screening for early detection of diseases. It echoes a larger effort in the medical community to think outside the box and come up with creative solutions to reach wider audiences in the name of prevention.
Clinical studies show that new ‘cell-free’ test can predict cardiovascular disease risk better than standard HDL cholesterol test
Researchers from the National Institutes of Health (NIH) have developed a diagnostic assay that measures how well high-density lipoprotein (HDL)—the so-called “good” cholesterol—is working in the body. And their findings could lead to new clinical laboratory tests that supplement standard HDL level testing to better determine a person’s risk for heart disease.
Cholesterol tests are among the most commonly performed assays by clinical laboratories. A new test that reveals how well HDL is working in the body would certainly boost a medical laboratory’s test requisition volume.
“Measuring HDL function is limited to research labs and isn’t conducive to large-scale testing by routine clinical laboratories. To try to solve that problem, researchers from NHLBI’s Lipoprotein Metabolism Laboratory created a new diagnostic test,” noted an NHLBI news release.
“This is going to quicken the pace of basic research,” said Edward B. Neufeld, PhD, who along with guest researcher Masaki Sato, PhD, developed the test. “It increases the number of samples that you can study. It increases the number of experiments you can do.”
Such a new cholesterol test would quickly become one of the most commonly performed clinical lab tests because just about every American who has a physical gets cholesterol tests as part of that process.
“Other people may modify this or come up with better versions, which is fine with us,” Edward Neufeld, PhD (above), NHLBI Staff Scientist, said in a news release. “We just really wanted to tackle this problem of evaluating HDL function.” Clinical laboratories may soon have a new cholesterol test to supplement standard HDL level testing. (Photo copyright: ResearchGate.)
Faster Answers Needed about HDL
According to the NIH, the goal should go beyond measuring level of HDL as part of a person’s annual physical. What is also needed is finding out whether HDL cholesterol is effectively doing certain tasks, such as removing extra cholesterol from arteries and transporting it to the liver.
The NHLBI’s new cell-free test may make it possible to step up large-scale clinical testing of HDL function, according to the news release. As it stands now, HDL function study has been limited to research labs where testing involves “harvesting cells in the lab [which] can take days to process,” according to NIH Record.
“Most studies to date that have assessed CAD (coronary artery disease) risk by HDL functionality still use the CEC (cellular cholesterol efflux capacity) in vitro assay and are based on the use of radioisotopes (3H-cholesterol) and cultured cells, which is very labor intensive and impractical to do in a clinical laboratory,” the researchers wrote in The Journal of Clinical Investigation. They also pointed out that CEC batch-to-batch variability does not fit clinical laboratories’ need for standardization.
Advantages of NHLBI’s Test
To overcome these barriers, the NHLBI researchers created an HDL-specific phospholipid efflux (HDL-SPE) assay that has certain advantages over current HDL function assessments done in research labs.
According to the NIH, the HDP-SPE assay:
Is easy to replicate in clinical labs.
Is more suited to automation and large samples.
Offers up results in about an hour.
Is a better predictor of cardiovascular disease risk than HDL cholesterol testing for CAD risk.
“We developed a cell-free, HDL-specific phospholipid efflux assay for the assessment of CAD risk on the basis of HDL functionality in whole plasma or serum. One of the main advantages of the HDL-SPE assay is that it can be readily automated, unlike the various CEC assays currently in use,” the authors noted in their paper.
Here is how the test is performed, according to the NIH:
Plasma with HDL is separated from the patient’s blood.
“Plasma is added to donor particles coated with a lipid mixture resembling plaque and a fluorescent-tagged phospholipid” that only HDL can remove.
The fluorescent signal by HDL is then measured.
A bright signal suggests optimal HDL lipid removal function, while a dim light means reduced function.
The test builds on the scientists’ previous findings and data. In creating the new assay they drew on data from:
A study of 50 severe CAD and 50 non-CAD people.
A Japanese study of 70 CAD and 154 non-CAD participants.
Examined association of HDL-SPE with cardiovascular disease in a study of 340 patients and 340 controls.
“We have established the HDL-SPE assay for assessment of the functional ability of HDL to efflux phospholipids. Our combined data consistently show that our relatively simple HDL-SPE assay captures a pathophysiologically relevant parameter of HDL function that is at least equivalent to the CEC assay in its association with prevalent and incident CAD,” the researchers concluded in The Journal of Clinical Investigation.
Test May Be Subject to New FDA Rule
While HDL cardiovascular-related research is moving forward, studies aimed at the therapeutic side need to pick up, NIH noted.
“Someday we may have a drug that modulates HDL and turns out to be beneficial, but right now we don’t have that,” said Alan Remaley MD, PhD, NHLBI Senior Investigator and Head of the Lipoprotein Metabolism Laboratory, in the news release.
It may be years before the HDL-SPE test is used in medical settings, the researchers acknowledged, adding that more studies are needed with inclusion of different ethnicities.
Additionally, in light of the recently released US Food and Drug Administration (FDA) final rule on regulation of laboratory developed tests (LDT), the company licensed to bring the test to market may need to submit the HDL-SPE assay to the FDA for premarket review and clearance. That could lengthen the time required for the developers to comply with the FDA before the test is used by doctors and clinical laboratories in patient care.
Trifecta of forces at work that will affect the clinical laboratory and pathology industries have been described as a ‘perfect storm’ requiring lab and practice managers to be well informed
Digital pathology, artificial intelligence (AI) in healthcare, and the perfect storm of changing federal regulations, took centerstage at the 29th Executive War College on Diagnostics, Clinical Laboratory, and Pathology Management in New Orleans this week, where more than 1,000 clinical laboratory and pathology leaders convened over three days.
This was the largest number of people ever onsite for what has become the world’s largest event focused exclusively on lab management topics and solutions. Perhaps the highlight of the week was the federal Food and Drug Administration’s (FDA’s) announcement of its final rule on Laboratory Developed Tests (LDTs). Overall, the conference featured more than 120 speakers, many of them national thought leaders on the topic of clinical lab and pathology management. More than 65% of the audience onsite were executive level lab managers.
“The level of interest in the annual Executive War College is testimony to the ongoing need for dynamic, engaging, and highly relevant conference events,” said Robert Michel (above), Editor-in-Chief of Dark Daily and its sister publication The Dark Report, and founder of the Executive War College. “These in-person gatherings present great opportunities for clinical laboratory and pathology managers and leaders to network and speak with people they otherwise might not meet.” (Photo copyright: Dark Intelligence Group.)
Demonstrating Clinical Value
For those who missed the action onsite, the following is a synopsis of the highlights this week.
Lâle White, Executive Chair and CEO of XiFin, spoke about the future of clinical laboratory testing and the factors reshaping the industry. There are multiple dynamics impacting healthcare economics and outcomes—namely rising costs, decreasing reimbursements, and the move to a more consumer-focused healthcare. But it is up to labs, she said, to ensure their services are not simply viewed as a commodity.
“Laboratory diagnostics have the potential to change the economics of healthcare by really gaining efficiencies,” she noted. “And it’s up to labs to demonstrate clinical value by helping physicians manage two key diagnostic decision points—what tests to order, and what to do with the results.”
But even as labs find ways to increase the value offered to clinicians, there are other disruptive factors in play. Consumer-oriented tech companies such as Google, Apple, and Amazon are democratizing access to patient data in unforeseen ways, and Medicare Advantage plans are changing the way claims are processed and paid.
Clinical labs are fundamental components of the public health infrastructure. So, the CDC plans on focusing on delivering high-quality laboratory science, supported by reliable diagnostics and informatics for disease outbreaks and exposures, and engaging with public and private sector partners.
The history of MolDX and Z-Codes were the topics discussed by Gabriel Bien-Willner, MD, PhD, Chief Medical Officer for healthcare claims and transaction processing company Palmetto GBA. Molecular testing is highly complex, and the lack of well-defined billing codes and standardization makes it difficult to know if a given test is reasonable and necessary.
Z-Codes were established to clarify what molecular testing was performed—and why—prompting payers to require both Z-Codes and Current Procedural Terminology (CPT) codes when processing molecular test claims. Medicare’s MolDX program further streamlines the claims process by utilizing expertise in the molecular diagnostics space to help payers develop coverage policies and reimbursement for these tests.
FDA Final Rule on LDT Regulation
Timothy Stenzel, MD, PhD, CEO of Grey Haven Consulting and former director of the FDA’s Office of In Vitro Diagnostics reviewed the latest updates from the FDA’s Final Rule on LDT (laboratory developed test) regulation. Prior to the FDA releasing its final rule, some experts suggested that the new regulations could result in up to 90% of labs discontinuing their LDT programs, impacting innovation, and patient care.
However, the final rule on LDTs is very different from the original proposed rule which created controversy. The final rule actually lowers the regulatory burden to the point that some labs may not have to submit their LDTs at all. The FDA is reviewing dozens of multi-cancer detection assays, some of which have launched clinically as LDTs. The agency is likely to approve those that accurately detect cancers for which there is no formal screening program.
Stenzel explained the FDA’s plan to down-classify most in vitro diagnostic tests, changing them from Class III to Class II, and exempting more than 1,000 assays from FDA review. He also discussed the highlights of the Quality Management System Regulation (QMSR). Launched in January, the QMSR bought FDA requirements in line with ISO 13485, making compliance easier for medical device manufacturers and test developers working internationally.
Looming Perfect Storm of Regulatory Changes
To close out Day 1, Michel took to the stage again with a warning to clinical laboratories about the looming “Perfect Storm” trifecta—the final FDA ruling on LDTs, Z-Code requirements for genetic testing, and updates to CLIA ’92 that could result in patient data being considered a specimen.
Laboratory leaders must think strategically if their labs are to survive the fallout, because the financial stress felt by labs in recent years will only be exacerbated by macroeconomic trends such as:
Staff shortages,
Rising costs,
Decreasing and delayed reimbursements, and
Tightening supply chains.
Lab administrators looking for ways to remain profitable and prosperous should look beyond the transactional Clinical Lab 1.0 fee-for-service model and adopt Clinical Lab 2.0, which embraces HEDIS (Healthcare Effectiveness Data and Information Set) scores and STAR ratings to offer more value to Medicare Advantage and other payers.
Wednesday’s General Session agenda was packed with information about the rise of artificial intelligence, big data, and precision medicine in healthcare. Taking centerstage on the program’s final day was Michael Simpson, President and CEO of Clinisys. Simpson gave a global perspective on healthcare data as the new driver of innovation in diagnostics and patient care.
