Questions remain, however, over how much of the funding will actually reach hospital and health system clinical laboratories
For many cash-strapped clinical laboratories in America, the second round of stimulus funds cannot come soon enough. Thus, lab leaders are encouraged by news that Congress’ $484-billion Paycheck Protection Program and Healthcare Enhancement Act (H.R.266) includes almost $11 billion that will go to states for COVID-19 testing. But how much of that funding will reach the nation’s hospital and health system clinical laboratories?
The Department of Health and Human Services (HHS) announced the new influx of money to the states on May 18. In a news release outlining the initiative, the HHS said the Centers for Disease Control and Prevention (CDC) will deliver $10.25 billion to states, territories, and local jurisdictions to expand testing capacity and testing-related activities.
To qualify for the additional funding, governors or “designee of each State, locality, territory, tribe, or tribal organization receiving funds” must submit to HHS its plan for COVID-19 testing, including goals for the remainder of calendar year 2020, to include:
“Number of tests needed, month-by-month to include diagnostic, serological, and other tests, as appropriate;
“Month-by-month estimates of laboratory and testing capacity, including related to workforce, equipment and supplies, and available tests;
“Description of how the resources will be used for testing, including easing any COVID-19 community mitigation policies.”
“As the nation cautiously begins the phased approach to reopening, this considerable investment in expanding both testing and contact tracing capacity for states, localities, territories, and tribal communities is essential,” said CDC Director Robert R. Redfield, MD, in the HHS statement. “Readily accessible testing is a critical component of a four-pronged public health strategy—including rigorous contact tracing, isolation of confirmed cases, and quarantine.” (Photo copyright: Center for Disease Control and Prevention.)
Funding Should Go Directly to Clinical Laboratories, Says ACLA
The American Clinical Laboratory Association (ACLA), argues the funding needs to go directly to clinical laboratories to help offset the “significant investments” labs have made to ramp up testing capacity during the pandemic.
“Direct federal funding for laboratories performing COVID-19 testing is critical to meet the continued demand for testing,” ACLA President Julie Khani, MPA, said in a statement. “Across the country, laboratories have made significant investments to expand capacity, including purchasing new platforms, retraining staff, and managing the skyrocketing cost of supplies. To continue to make these investments and expand patient access to high-quality testing in every community, laboratories will need designated resources. Without sustainable funding, we cannot achieve sustainable testing.”
Some States Are Increasing Testing, While Others Are Not
Since the first cases of COVID-19 were reported in January, the United States has slowly but significantly ramped up testing capacity. As reported in the Washington Post, states such as Georgia, Oklahoma, and Utah are encouraging residents to get tested even if they are not experiencing coronavirus symptoms. But other states have maintained more restrictive testing policies, even as their testing capacity has increased.
“A lot of states put in very, very restrictive testing policies … because they didn’t have any tests. And they’ve either not relaxed those or the word is not getting out,” Ashish Jha, MD, MPA, Director of the Harvard Global Health Institute, told the Washington Post. “We want to be at a point where everybody who has mild symptoms is tested. That is critical. That is still not happening in a lot of places.”
Meanwhile, Quest Diagnostics and LabCorp continue to expand their diagnostic and antibody testing capabilities.
On May 18, Quest announced it had performed approximately 2.15 million COVID-19 molecular diagnostic tests since March 9 and had a diagnostic capability of 70,000 test each day. The company said it expected to have the capacity to perform 100,000 tests a day in June.
LabCorp’s website lists its molecular test capacity at more than 75,000 tests per day as of May 22, with a capacity for conducting at least 200,000 antibody tests per day. Unlike molecular testing that detects the presence of the SARS-CoV-2 coronavirus, antibody tests detect proteins produced by the body in response to a COVID-19 infection.
As states reopen, and hospitals and healthcare systems resume elective surgeries and routine office visits, clinical laboratories and anatomic pathology groups should begin to see a return to normal specimen flow. Nonetheless, the federal government should continue to compensate laboratories performing COVID-19 testing for the added costs associated with meeting the ongoing and growing demand.
Report’s authors claim the US needs to be testing 20-million people per day in order to achieve ‘full pandemic resilience’ by August
Medical laboratory scientists and clinical laboratory leaders know that the US’ inability to provide widespread diagnostic testing to detect SARS-CoV-2—the novel coronavirus that causes the COVID-19 illness—in the early stages of the outbreak was a major public health failure. Now a Harvard University report argues the US will need to deliver five million tests per day by early June—more than the total number of people tested nationwide to date—to safely begin reopening the economy.
“We need to deliver five million tests per day by early June to deliver a safe social reopening,” the report’s authors state. “This number will need to increase over time (ideally by late July) to 20 million a day to fully remobilize the economy. We acknowledge that even this number may not be high enough to protect public health. In that considerably less likely eventuality, we will need to scale-up testing much further. By the time we know if we need to do that, we should be in a better position to know how to do it. In any situation, achieving these numbers depends on testing innovation.”
The report is the work of a diverse group of experts in economics, public health, technology, and ethics, from major universities and big technology companies (Apple, Microsoft) with support from The Rockefeller Foundation.
“This is the first plan to show operationally how we can scale up COVID-19 testing sufficiently to safely reopen the economy—while safeguarding fundamental American democratic principles of protecting civil rights and liberties,” Danielle Allen, PhD (above), Director of Harvard University’s Edmond J. Safra Center for Ethics, said in a statement that noted it was “in response to the US Department of Health and Human Service’s Report to Congress on its COVID-19 strategic testing plan.” (Photo copyright: Harvard University.)
Under Harvard’s Roadmap plan, massive-scale testing would involve rapid development of:
Streamlined sample collection (for example) involving saliva samples (spit kits) rather than deep nasal swabs that have to be taken by healthcare workers;
Transportation logistics systems able to rapidly collect and distribute samples for testing;
Mega-testing labs, each able to perform in the range of one million tests per day, with automation, streamlined methods, and tightly managed supply chains;
Information systems to rapidly transmit test results; and
Technology necessary to certify testing status.
“The unique value of this approach is that it will prevent cycles of opening up and shutting down,” Anne-Marie Slaughter, CEO of New America, said in the statement. “It allows us to mobilize and re-open progressively the parts of the economy that have been shut down, protect our frontline workers, and contain the virus to levels where it can be effectively managed and treated until we can find a vaccine.”
Is Expanding Clinical Laboratory Testing Even Possible?
But is such a plan realistic? Perhaps not. When questioned by NBC News about the timeline for “broad-based coronavirus testing” that was suggested as part of the Trump Administration’s three-phase plan to reopen the states, former FDA Commissioner Scott Gottlieb, MD, said, “We’re not going to be there. We’re not going to be there in May, we’re not going to be there in June, hopefully, we’ll be there by September.”
In recent weeks, however, US testing capabilities have improved. Quest Diagnostics, which had come under fire for its testing backlog in California, announced it now has the capacity to perform 50,000 diagnostic COVID-19 tests per day or 350,000 tests per week with less than a two-day turnaround for results. “Our test capacity outpaces demand and we have not experienced a test backlog for about a week,” Quest said in a statement.
CDC ‘Modifies’ Its Guidelines for Declaring a Person ‘Recovered’ from COVID-19
Furthermore, the CDC modified its guidance on the medical and testing criteria that must be met for a person to be considered recovered from COVID-19, which initially required two negative test results before a patient could be declared “confirmed recovered” from the virus. The CDC added a non-testing strategy that allowed states to begin counting “discharged” patients who did not have easy access to additional testing as recovered from the virus.
Under the non-test-based strategy, a person may be considered recovered if:
At least three days (72 hours) have passed since recovery, defined as resolution of fever without the use of fever-reducing medications;
Improvement in respiratory symptoms (e.g., cough, shortness of breath); and,
At least seven days have passed since symptoms first appeared.
For now, however, the focus will likely remain on testing for those who are infected, rather than for finding those who have recovered. As of May 30, the COVID Tracking Project reported that only 16,495,443 million tests had been conducted in the US, with 1,759,693 of those test showing positive for COVID-19. That’s closing in on the 10% “test-positivity rate” recommended by the WHO for controlling a pandemic, but it’s not quite there.
As testing for COVID-19 grows exponentially, clinical laboratories should anticipate playing an increasingly important role in the nation’s response to the COVID-19 pandemic.
Medical laboratories are already using gene sequencing as part of a global effort to identify new variants of the coronavirus and their genetic ancestors
Thanks to advances in genetic sequencing technology that enable medical laboratories to sequence organisms faster, more accurately, and at lower cost than ever before, clinical pathology laboratories worldwide are using that capability to analyze the SARS-CoV-2 coronavirus and identify variants as they emerge in different parts of the world.
The US Centers for Disease Control and Prevention (CDC) now plans to harness the power of gene sequencing through a new consortium called SPHERES (SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance) to “coordinate SARS-CoV-2 sequencing across the United States,” states a CDC news release. The consortium is led by the CDC’s Advanced Molecular Detection (AMD) program and “aims to generate information about the virus that will strengthen COVID-19 mitigation strategies.”
The consortium is comprised of 11 federal agencies, 20 academic institutions, state public health laboratories in 21 states, nine non-profit research organizations, and 14 lab and IVD companies, including:
Abbott Diagnostics
bioMérieux
Color Genomics
Ginkgo Bioworks
IDbyDNA
Illumina
In-Q-Tel
LabCorp
One Codex
Oxford Nanopore Technologies
Pacific Biosciences
Qiagen
Quest Diagnostics
Verily Life Sciences
‘Fundamentally Changing How Public Health Responds’
Gene sequencing and related technologies have “fundamentally changed how public health responds in terms of surveillance and outbreak response,” said Duncan MacCannell, PhD, Chief Science Officer for the CDC’s Office of Advanced Molecular Detection (OAMD), in an April 30 New York Times (NYT) article, which stated that the CDC SPHERES program “will help trace patterns of transmission, investigate outbreaks, and map how the virus is evolving, which can affect a cure.”
The CDC says that rapid DNA sequencing of SARS-CoV-2 will help monitor significant changes in the virus, support contact tracing efforts, provide information for developers of diagnostics and therapies, and “advance public health research in the areas of transmission dynamics, host response, and evolution of the virus.”
The sequencing laboratories in the consortium have agreed to “release their information into the public domain quickly and in a standard way,” the NYT reported, adding that the project includes standards for what types of information medical laboratories should submit, including, “where and when a sample was taken,” and other critical details.
Even in its early phase, the CDC’s SPHERES project has “made a tangible impact in the number of sequences we’re able to deposit and make publicly available on a daily basis,” said Pavitra Roychoudhury, PhD (above), Acting Instructor and Senior Fellow at the University of Washington, and Research Associate at Fred Hutchinson Cancer Research Center, in an e-mail to the NYT. “What we’re essentially doing is reading these small fragments of viral material and trying to jigsaw puzzle the genome together,” said Roychoudhury in an April 28 New York Times article which covered in detail how experts are tracking the coronavirus since it arrived in the US. (Photo copyright: LinkedIn.)
Sharing Data Between Sequencing Laboratories and Biotech Companies
The CDC announced the SPHERES initiative on April 30, although it launched in early April, the NYT reported.
According to the CDC, SPHERES’ objectives include:
To bring together a network of sequencing laboratories, bioinformatics capacity and subject matter expertise under the umbrella of a massive and coordinated public health sequencing effort.
To identify and prioritize capabilities and resource needs across the network and to align sources of federal, non-governmental, and private sector funding and support with areas of greatest impact and need.
To improve coordination of genomic sequencing between institutions and jurisdictions and to enable more resilience across the network.
To champion concepts of openness, standards-based analysis, and rapid data sharing throughout the United States and worldwide during the COVID-19 pandemic response.
To provide a common forum for US public, private, and academic institutions to share protocols, methods, bioinformatics tools, standards, and best practices.
To establish consistent data and metadata standards, including streamlined repository submission processes, sample prioritization criteria, and a framework for shared, privacy-compliant unique case identifiers.
To align with other national sequencing and bioinformatics networks, and to support global efforts to advance the use of standards and open data in public health.
Implications for Developing a Vaccine
As the virus continues to mutate and evolve, one question is whether a vaccine developed for one variant will work on others. However, several experts told The Washington Post that the SARS-CoV-2 coronavirus is relatively stable compared to viruses that cause seasonal flu (influenza).
“At this point, the mutation rate of the virus would suggest that the vaccine developed for SARS-CoV-2 would be a single vaccine, rather than a new vaccine every year like the flu vaccine,” Peter Thielen, a molecular biologist at the Johns Hopkins University Applied Physics Laboratory, told the Washington Post.
Nor, he said, is one variant likely to cause worse clinical outcomes than others. “So far, we don’t have any evidence linking a specific virus [strain] to any disease severity score. Right now, disease severity is much more likely to be driven by other factors.”
Fast improvements in gene sequencing technology have made it faster, more accurate, and cheaper to sequence. Thus, as the COVID-19 outbreak happened, there were many clinical laboratories around the world with the equipment, the staff, and the expertise to sequence the novel coronavirus and watch it mutate from generation to generation and from region to region around the globe. This capability has never been available in outbreaks prior to the current SARS-CoV-2 outbreak.
Even more impressive is that the automated testing lab can reportedly process (with results in four hours) up to 3,000 patient samples daily for SARS-CoV-2, the coronavirus that causes the COVID-19 illness.
“All of our laboratories do PCR every day. But for this test we need to go above and beyond to ensure accurate detection,” said Jennifer Doudna, PhD, IGI Executive Director and UC Berkeley Professor of Molecular and Cell Biology, in an IGA news release.
“We put in place a robotic pipeline for doing thousands of tests per day,” she continued, “with a pipeline for managing the data and getting it back to clinicians. Imagine setting that up in a couple of weeks. It’s really extraordinary and something I’ve never seen in my career.”
Robert Sanders, UC Berkeley’s Manager Science Communications, told Dark Daily the COVID-19 lab performs about 180 tests per day and has tested 1,000 people so far—80% of the samples came from the campus community. About 1.5% to 4% of the tests were found to be positive for the SARS-CoV-2 coronavirus among the groups tested.
“We hope other academic institutions will set up testing labs too,” he said.
How Did Berkeley Set Up a COVID-19 Diagnostic Lab So Fast?
To get up and running quickly, university officials drew from the campus and surrounding business community to equip and operate the laboratory, as well as, train researchers to do clinical analysis of patient samples.
Though the methodology to test for the coronavirus—isolating RNA from a biological sample and amplifying it with PCR—is standard fare in most research labs worldwide, including at UC Berkeley, the campus’ research labs were shuttered due to the spread of the coronavirus.
IGI reached out to the idle labs for their high-throughput PCR systems to start-up the lab. Through its partnership with University Health Services and local and national companies, IGI created an automated sample intake and processing workflow.
Additionally, several research scientists who were under government-mandated stay-at-home orders made themselves available. “My own research is shut down—and there’s not very much I can do other than stay in my home … finally I’m useful,” said PhD candidate Holly Gildea in a Berkeleyside article which noted that about 30 people—mostly doctoral students and postdoctoral researchers—are being trained to oversee the process and monitor the automated equipment.
Postdoctoral fellows Jenny Hamilton (left) and Enrique Shao (right) with an automated liquid-handling robot (Hamilton Microlab STAR), which will be used to analyze swabs from patients to diagnose COVID-19. Hamilton and Shao volunteered to train to become CLIA certified so as to process patient samples. When analyzing real samples from patients, they would be wearing full personal protective equipment (PPE), including mask, face shield, gown and gloves. (Photo and caption copyright: Max and Jules Photography/UC Berkeley.)
Federal and State Authorities Remove Hurdles
In her article, “Blueprint for a Pop-up SARS-CoV-2 Testing Lab,” published on the medRxiv servers, Doudna summarized “three regulatory developments [that] allowed the IGI to rapidly transition its research laboratory space into a clinical testing facility.
“The second was California Governor Newsom’s Executive Order N-25-20, which modified the requirements for clinical laboratory personnel running diagnostic tests for SARS-CoV-2 in a certified laboratory.
“The third was increased flexibility and expediency at the state and federal levels for certification and licensure requirements for clinical laboratory facilities under the Clinical Laboratory Improvement Amendments (CLIA) program. Under these emergency conditions, the California Department of Public Health (CDPH) was willing to temporarily extend—once the appropriate regulatory requirements have been fulfilled—an existing CLIA certificate for high-complexity testing to a non-contiguous building on our university campus.”
“These developments,” wrote Doudna, “enabled us to develop and validate a laboratory-developed test (LDT) for SARS-CoV-2, extend the UC Berkeley Student Health Center’s clinical laboratory license to our laboratory space, and begin testing patient samples.”
Lessons Learned Implementing a Pop-Up COVID-19 Testing Laboratory
“Our procedures for implementing the technical, regulatory, and data management workstreams necessary for clinical sample processing provide a roadmap to others in setting up similar testing centers,” she wrote.
Learned strategies Doudna says could aid other academic research labs transform to a “SARS-CoV-2 Diagnostic Testing Laboratory include:
Leveraging licenses from existing CLIA-certified labs;
Following FDA authorized testing procedures;
Using online HIPAA training;
Managing supply chain “bottlenecks” by using donated equipment;
Adopting in-house sample barcoding;
Adapting materials, such as sampling tubes, to work with donated equipment;
Cost of equipment and supplies (not including staff) was $550,000, with a per test cost of $24, Doudna noted.
“As the COVID-19 pandemic continues, our intention is to provide both PCR-based diagnostic testing and to advance research on asymptomatic transmission, analyze virus sequence evolution, and provide benchmarking for new diagnostic technologies,” she added.
Medical laboratory leaders understand that the divide between clinical and research laboratories is not easy to surmount. Nevertheless, UC Berkley’s IGI pulled it off. The lab marshaled resources as it took on the novel coronavirus, quickly developed and validated a test workflow, and assembled and trained staff to analyze tests with fast TAT to providers, students, and area residents. There’s much that can be learned from UC Berkeley IGI’s accomplishments.
Facing a backlog, the state’s public health laboratory turned to the medical laboratory at Dartmouth Hitchcock Medical Center
Much of the attention surrounding the COVID-19
outbreak—the illness caused by the SARS-CoV-2
coronavirus—has focused on large urban areas such as New York City and Los
Angeles. However, the virus is impacting many rural areas as well. This is true
in New Hampshire, where the diagnostic response required close cooperation
between the state’s public health
laboratory and the clinical
laboratory at its lone academic medical center. Their experience offers
lessons for medical
laboratory leaders nationwide.
“When these things happen and you surge beyond what you
could imagine, it’s the relationships with people that matter more than
anything,” said Christine
L. Bean, PhD, Administrator of New
Hampshire Public Health Laboratory Division of Public Health Services , Concord,
N.H., during a recent Dark
Daily webinar, titled, “What Hospital and Health System Labs Need to
Know About Operational Support and Logistics During the COVID-19 Outbreak.”
As Bean explained, during the earliest stages of the
pandemic the “CDC was doing the testing” and the state lab’s role was limited
to submitting samples from patients deemed as “presumptive positives.” Then, on
Feb. 4, the FDA granted an emergency
use authorization (EUA) allowing use of the CDC-developed real-time
reverse transcriptase PCR (RT-PCR) assay by designated labs.
The New Hampshire Public Health Laboratory (NHPHL) received
its first test kit on Feb. 10, Bean said. But the kits were recalled due to
validation problems with one of the reagents. On Feb. 26, the CDC
issued revised test instructions allowing use of the test without the N3
primer and probe set that had caused the early validation issues. The NHPHL
verified the test under the new guidelines and went live on March 2, she said.
However, with a capacity of 150 to 200 tests per day, the
lab wasn’t equipped to handle a large volume. “Much of what we do is really
population-based,” she said. “Most of the time we’re not doing patient
diagnostic testing.”
Christine L. Bean, PhD (left), Administrator of the New Hampshire Public Health Laboratory, and Joel Lefferts, PhD (right), Assistant Professor of Pathology and Laboratory Medicine, and Assistant Director of the Molecular Pathology, at Dartmouth’s Geisel School of Medicine, spoke with Dark Daily’s Editor-in-Chief Robert Michel during a webinar on what hospital and health system labs need to know about operational support and logistics during the COVID-19 outbreak. The webinar can be freely downloaded by clicking here. (Photo copyright: Dark Daily.)
NHPHL Turns to the Medical Laboratory at DHMC-CGHT for
Help
The DHMC-CGHT lab began having its own discussions about
testing in the first week of February, said Joel
A. Lefferts, PhD, HCLD, DABCC, Assistant Professor of Pathology and
Laboratory Medicine and Assistant Director of Molecular Pathology at
Dartmouth’s Geisel School of
Medicine. They were unsure of how much need there would be, but “throughout
the month of February, we started exploring different testing options,” he said
during the Dark Daily webinar.
The Dartmouth-Hitchcock lab team began with the CDC test. However,
Lefferts noted that the initial FDA guidance was “somewhat restrictive” and required
specific RNA extraction
kits and real-time PCR instruments. “If our lab didn’t have the capability to
perform everything exactly as indicated, we would be running it off-label and
would have to possibly submit our own EUA submission to the FDA,” he explained.
Later, though, the FDA and CDC loosened those restrictions and the lab began testing with the CDC assay on March 18, using a Thermo Fisher ABI 7500Dx instrument, Lefferts said. According to Thermo Fisher’s website, the ABI 7500Dx “is a real-time nucleic acid amplification and five-color fluorescence detection system available for in vitro diagnostic use.”
However, Lefferts continued, “we only had one of these
7500Dx instruments, and it was a relatively manual and labor-intensive
process.” It allowed a maximum of 29 samples per run, he said, and took about
five hours to produce results.
Then, the FDA granted an EUA for Abbott’s
m2000 assay, which runs on the company’s m2000rt real-time PCR instrument.
“We were really excited, because we happened to have two of these systems in
our lab,” he said. “We quickly got on the phone and ordered some of these
kits.”
The DHMC-CGHT lab went live with the new system on March 23.
It can handle up to 94 samples per run, said Lefferts, and with two instruments
running from 6 a.m. to 9 p.m., “there’s a potential to do as many as 10 runs
per day.”
This was the system they used to help New Hampshire’s Public
Health Lab with its backlog. “It was unbelievable to see that our backlog could
be really wiped out,” said Bean.
Challenges for Medical Labs
Gearing up for testing in a public health emergency poses
many challenges, Lefferts advised. “You need to look at what instrumentation
you have in your laboratory, what the experience level of your lab team is, how
much space you have, your expected batch size, and your needed turnaround
time.”
The two labs also had to deal with regulatory uncertainty. “This EUA process is something for which we don’t have much experience,” he said. “Trying to juggle CLIA, CAP, the FDA, and possibly state regulations is a bit challenging. You definitely need to do your research and talk to other clinical laboratories that are doing this testing to get advice.”
Lefferts explained that the most significant challenges to
develop and validate a molecular assay for COVID-19 included:
Availability of validation materials.
Obtaining “positive [viral] samples may be a challenge, depending on where you
are and what you have access to,” said Lefferts. However, he credits the FDA
for being “very proactive” in suggesting alternative sources for “viral isolates or genomic RNA that’s been
extracted from some of these viral isolates.”
Availability of collection kits. “We can
do a lot more testing now,” he said, but one bottleneck is the limited
availability of supplies such as nasopharyngeal swabs
and viral transport media. “We’re looking at alternative collection options,”
he said, such as 3D-printed swabs or even Q-tips [household cotton swabs], though
“hopefully it won’t come to that.” The DHMC-CGHT lab also considered producing its
own transport media.
Turnaround times. “Our lab wants to get
those results out as soon as possible,” Lefferts said. “So, we’re looking at
alternative methods to get that testing out sooner.” For example, “do we just
do the SARS-CoV-2 testing on a patient, or do we need to do other influenza and other viral
pathogens,” while also keeping up with other routine testing during the
pandemic?
Staffing issues. “Fatigue is a big issue
with members of our labs who put in lots of extra hours,” he said. The
DHMC-CGHT lab has developed contingency plans in case lab personnel get sick.
This critical information will be highly useful for
Laboratory Directors and Managers, Laboratory Supervisors and Team Leaders,
Integrated Health System Leaders, Hospital Group Leaders, Physicians and
Physician Group Leaders, Phlebotomy Managers, Courier and Logistics Managers,
and Safety and Compliance Managers.
